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Drug overview for CARISOPRODOL-ASPIRIN-CODEINE (carisoprodol/aspirin/codeine phosphate):
Generic name: carisoprodol/aspirin/codeine phosphate (kar-iss-oh-PRO-dole/AS-pir-in/KOE-deen)
Drug class: Central Muscle Relaxants
Therapeutic class: Locomotor System
Aspirin (the prototype of the salicylates) is a nonsteroidal Carisoprodol is a centrally acting skeletal muscle relaxant. anti-inflammatory agent (NSAIA) and also exhibits antithrombotic, analgesic, and antipyretic activity. Codeine is a phenanthrene-derivative opiate agonist.
Aspirin is used extensively in the treatment of mild to moderate pain, fever, and inflammatory diseases. Aspirin is also used in the prevention of arterial and venous thrombosis. Aspirin, however, should be used with extreme caution, if at all, in patients in whom urticaria, angioedema, bronchospasm, severe rhinitis, or shock is precipitated by other salicylates or other NSAIAs.
(See Cautions: Sensitivity Reactions in the Salicylates General Statement 28:08.04.24.)
Generic name: carisoprodol/aspirin/codeine phosphate (kar-iss-oh-PRO-dole/AS-pir-in/KOE-deen)
Drug class: Central Muscle Relaxants
Therapeutic class: Locomotor System
Aspirin (the prototype of the salicylates) is a nonsteroidal Carisoprodol is a centrally acting skeletal muscle relaxant. anti-inflammatory agent (NSAIA) and also exhibits antithrombotic, analgesic, and antipyretic activity. Codeine is a phenanthrene-derivative opiate agonist.
Aspirin is used extensively in the treatment of mild to moderate pain, fever, and inflammatory diseases. Aspirin is also used in the prevention of arterial and venous thrombosis. Aspirin, however, should be used with extreme caution, if at all, in patients in whom urticaria, angioedema, bronchospasm, severe rhinitis, or shock is precipitated by other salicylates or other NSAIAs.
(See Cautions: Sensitivity Reactions in the Salicylates General Statement 28:08.04.24.)
DRUG IMAGES
CARISOPRODOL-ASPIRIN-CODEIN TB
The following indications for CARISOPRODOL-ASPIRIN-CODEINE (carisoprodol/aspirin/codeine phosphate) have been approved by the FDA:
Indications:
Muscle spasm
Professional Synonyms:
Involuntary muscle contraction
Muscle spasticity
Skeletal muscle spasm
Spasticity
Indications:
Muscle spasm
Professional Synonyms:
Involuntary muscle contraction
Muscle spasticity
Skeletal muscle spasm
Spasticity
The following dosing information is available for CARISOPRODOL-ASPIRIN-CODEINE (carisoprodol/aspirin/codeine phosphate):
The recommended dosage of carisoprodol in adults is 250-350 mg 3 times daily and at bedtime. Treatment should be limited to short periods (i.e., up to 2-3 weeks) because adequate evidence of efficacy for more prolonged periods has not been established and because acute, painful musculoskeletal conditions generally are of short duration.
Dosage of codeine sulfate and codeine phosphate is expressed in terms of the salt.
Dosing errors can result in accidental overdose and death. A boxed warning regarding this risk has been included in the prescribing information for oral solutions of codeine. Ensure accuracy when prescribing, dispensing, and administering oral solutions containing codeine.
Instruct patients and caregivers on how to measure and administer the correct dose of oral solutions containing codeine. Instruct patients and caregivers to always use an accurate measuring device when administering the oral solution to ensure that the dose is measured and administered accurately.
Dosage of aspirin must be carefully adjusted according to individual requirements and response, using the lowest possible effective dosage. When used at high (e.g., anti-inflammatory) dosages, the development of tinnitus can be used as a sign of elevated serum salicylate concentrations, except in patients with high-frequency hearing impairment.
When preparations containing aspirin in fixed combination with other drugs are used, the cautions, precautions, and contraindications applicable to each ingredient must be considered.
Following oral administration of single doses of rapidly absorbed aspirin dosage forms, salicylate is detected in serum within 5-30 minutes, and peak serum salicylate concentrations are attained within 0.25-2 hours, depending on dosage form and specific formulation. Clinically important differences in the onset or intensity of analgesia produced by rapidly absorbed dosage forms or specific preparations have not been established.
Following oral administration of a single 650-mg dose of aspirin as an effervescent or noneffervescent aqueous solution in healthy adults, average peak plasma aspirin concentrations of about 13 mcg/mL are attained within 15-40 minutes and average peak plasma salicylate concentrations of about 40-55 mcg/mL are attained within 30-60 minutes. After a single 650-mg oral dose of aspirin (as two 325-mg uncoated plain tablets) in fasting healthy adults, average peak plasma aspirin concentrations of about 7-9 mcg/mL occur within 25-40 minutes and average peak plasma salicylate concentrations of about 35-50 mcg/mL occur within 1.5-2 hours.
Following oral administration of a single 650-mg dose of buffered aspirin (as 2 tablets, each containing 325 mg of aspirin), average peak plasma salicylate concentrations of about 40-60 mcg/mL are attained within 45-60 minutes.
In one study in healthy fasting adults given a single 975-mg oral dose of aspirin (as three 325-mg uncoated plain tablets), peak serum salicylate concentrations averaged 60-75 mcg/mL and occurred within 2 hours. In another study in fasting rheumatoid arthritis patients given a single 1.95-g oral dose of aspirin (as six325-mg uncoated plain tablets), peak plasma aspirin concentrations of about 12-16 mcg/mL occurred within 1 hour and peak plasma salicylate concentrations of about 110-160 mcg/mL occurred within 4 hours. When these patients were given the same dose of buffered aspirin (as 6 tablets, each containing 325 mg of aspirin), peak plasma aspirin concentrations of about 14-18 mcg/mL occurred within 1-2 hours and peak plasma salicylate concentrations of about 140-160 mcg/mL occurred within 1-2 hours.
Dosage of codeine sulfate and codeine phosphate is expressed in terms of the salt.
Dosing errors can result in accidental overdose and death. A boxed warning regarding this risk has been included in the prescribing information for oral solutions of codeine. Ensure accuracy when prescribing, dispensing, and administering oral solutions containing codeine.
Instruct patients and caregivers on how to measure and administer the correct dose of oral solutions containing codeine. Instruct patients and caregivers to always use an accurate measuring device when administering the oral solution to ensure that the dose is measured and administered accurately.
Dosage of aspirin must be carefully adjusted according to individual requirements and response, using the lowest possible effective dosage. When used at high (e.g., anti-inflammatory) dosages, the development of tinnitus can be used as a sign of elevated serum salicylate concentrations, except in patients with high-frequency hearing impairment.
When preparations containing aspirin in fixed combination with other drugs are used, the cautions, precautions, and contraindications applicable to each ingredient must be considered.
Following oral administration of single doses of rapidly absorbed aspirin dosage forms, salicylate is detected in serum within 5-30 minutes, and peak serum salicylate concentrations are attained within 0.25-2 hours, depending on dosage form and specific formulation. Clinically important differences in the onset or intensity of analgesia produced by rapidly absorbed dosage forms or specific preparations have not been established.
Following oral administration of a single 650-mg dose of aspirin as an effervescent or noneffervescent aqueous solution in healthy adults, average peak plasma aspirin concentrations of about 13 mcg/mL are attained within 15-40 minutes and average peak plasma salicylate concentrations of about 40-55 mcg/mL are attained within 30-60 minutes. After a single 650-mg oral dose of aspirin (as two 325-mg uncoated plain tablets) in fasting healthy adults, average peak plasma aspirin concentrations of about 7-9 mcg/mL occur within 25-40 minutes and average peak plasma salicylate concentrations of about 35-50 mcg/mL occur within 1.5-2 hours.
Following oral administration of a single 650-mg dose of buffered aspirin (as 2 tablets, each containing 325 mg of aspirin), average peak plasma salicylate concentrations of about 40-60 mcg/mL are attained within 45-60 minutes.
In one study in healthy fasting adults given a single 975-mg oral dose of aspirin (as three 325-mg uncoated plain tablets), peak serum salicylate concentrations averaged 60-75 mcg/mL and occurred within 2 hours. In another study in fasting rheumatoid arthritis patients given a single 1.95-g oral dose of aspirin (as six325-mg uncoated plain tablets), peak plasma aspirin concentrations of about 12-16 mcg/mL occurred within 1 hour and peak plasma salicylate concentrations of about 110-160 mcg/mL occurred within 4 hours. When these patients were given the same dose of buffered aspirin (as 6 tablets, each containing 325 mg of aspirin), peak plasma aspirin concentrations of about 14-18 mcg/mL occurred within 1-2 hours and peak plasma salicylate concentrations of about 140-160 mcg/mL occurred within 1-2 hours.
Carisoprodol is administered orally with or without food. Codeine-containing preparations are administered orally. Codeine sulfate is commercially available as a single-entity tablet preparation.
Codeine phosphate is commercially available in the following fixed-combination preparations for oral use: codeine/acetaminophen, promethazine/codeine, promethazine/phenylephrine/codeine, butalbital/acetaminophen/caffeine/codeine, and butalbital/aspirin/caffeine/codeine. See the full prescribing information for additional information on these combination preparations. Codeine also may be commercially available in over-the-counter (OTC) preparations in combination with antihistamines, expectorants, or decongestants.
See the FDA Orange Book and the manufacturer's Drug Facts for additional information. Codeine sulfate tablets should be stored at 20-25degreesC (excursions permitted between 15-30degreesC) in a secure location; protect from moisture. Aspirin is usually administered orally, preferably with food or a large quantity (240 mL) of water (unless the patient is fluid restricted) or milk to minimize gastric irritation.
In patients unable to take or retain oral medication, aspirin suppositories may be administered rectally; however, rectal absorption may be slow and incomplete. (See Pharmacokinetics: Absorption.) Aspirin tablets should not be administered rectally, since they are likely to cause irritation and erosion of the rectal mucosa. Aspirin preparations should not be used if a strong vinegar-like odor is present.
(See Chemistry and Stability: Stability.) If an unpleasant taste or aftertaste, burning in the throat, or difficulty in swallowing occurs with uncoated aspirin-containing tablets, these effects may be reduced with film-coated tablets. Although specific data are not available, these effects are also likely to be reduced with enteric-coated tablets. If gastric irritation and/or symptomatic GI disturbances occur with uncoated aspirin-containing tablets, these effects may be reduced with enteric-coated tablets or extended-release tablets.
If a liquid dosage form of aspirin is desired for short-term treatment of pain, an oral solution may be prepared from commercially available effervescent tablets (e.g., Alka-Seltzer(R)) by dissolving tablets in 120 mL of water; ingest the entire solution to ensure adequate dosing. In addition to potentially reducing adverse GI effects, some clinicians suggest that enteric-coated tablets may be swallowed more easily by children receiving chronic therapy with the drug and may therefore result in increased compliance. Aspirin or buffered aspirin preparations should not be chewed before swallowing for at least 7 days following tonsillectomy or oral surgery because of possible injury to oral tissues from prolonged contact with aspirin particles.
In addition, aspirin or buffered aspirin tablets should not be placed directly on a tooth or gum surface because of possible injury to tissues. Capsules containing the fixed combination of aspirin and extended-release dipyridamole should be swallowed whole and should not be chewed. Chewable aspirin tablets may be chewed, crushed, and/or dissolved in a liquid, or swallowed whole, followed by approximately 120 mL of water, milk, or fruit juice immediately after administration of the drug.
For information on the concomitant administration of aspirin with nonsteroidal anti-inflammatory agents (NSAIAs), see Drug Interactions: Nonsteroidal Anti-inflammatory Agents, in the Salicylates General Statement 28:08.04.24.
Codeine phosphate is commercially available in the following fixed-combination preparations for oral use: codeine/acetaminophen, promethazine/codeine, promethazine/phenylephrine/codeine, butalbital/acetaminophen/caffeine/codeine, and butalbital/aspirin/caffeine/codeine. See the full prescribing information for additional information on these combination preparations. Codeine also may be commercially available in over-the-counter (OTC) preparations in combination with antihistamines, expectorants, or decongestants.
See the FDA Orange Book and the manufacturer's Drug Facts for additional information. Codeine sulfate tablets should be stored at 20-25degreesC (excursions permitted between 15-30degreesC) in a secure location; protect from moisture. Aspirin is usually administered orally, preferably with food or a large quantity (240 mL) of water (unless the patient is fluid restricted) or milk to minimize gastric irritation.
In patients unable to take or retain oral medication, aspirin suppositories may be administered rectally; however, rectal absorption may be slow and incomplete. (See Pharmacokinetics: Absorption.) Aspirin tablets should not be administered rectally, since they are likely to cause irritation and erosion of the rectal mucosa. Aspirin preparations should not be used if a strong vinegar-like odor is present.
(See Chemistry and Stability: Stability.) If an unpleasant taste or aftertaste, burning in the throat, or difficulty in swallowing occurs with uncoated aspirin-containing tablets, these effects may be reduced with film-coated tablets. Although specific data are not available, these effects are also likely to be reduced with enteric-coated tablets. If gastric irritation and/or symptomatic GI disturbances occur with uncoated aspirin-containing tablets, these effects may be reduced with enteric-coated tablets or extended-release tablets.
If a liquid dosage form of aspirin is desired for short-term treatment of pain, an oral solution may be prepared from commercially available effervescent tablets (e.g., Alka-Seltzer(R)) by dissolving tablets in 120 mL of water; ingest the entire solution to ensure adequate dosing. In addition to potentially reducing adverse GI effects, some clinicians suggest that enteric-coated tablets may be swallowed more easily by children receiving chronic therapy with the drug and may therefore result in increased compliance. Aspirin or buffered aspirin preparations should not be chewed before swallowing for at least 7 days following tonsillectomy or oral surgery because of possible injury to oral tissues from prolonged contact with aspirin particles.
In addition, aspirin or buffered aspirin tablets should not be placed directly on a tooth or gum surface because of possible injury to tissues. Capsules containing the fixed combination of aspirin and extended-release dipyridamole should be swallowed whole and should not be chewed. Chewable aspirin tablets may be chewed, crushed, and/or dissolved in a liquid, or swallowed whole, followed by approximately 120 mL of water, milk, or fruit juice immediately after administration of the drug.
For information on the concomitant administration of aspirin with nonsteroidal anti-inflammatory agents (NSAIAs), see Drug Interactions: Nonsteroidal Anti-inflammatory Agents, in the Salicylates General Statement 28:08.04.24.
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| CARISOPRODOL-ASPIRIN-CODEIN TB | Maintenance | Adults take 1 tablet by oral route 4 times per day as needed |
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| CARISOPRODOL-ASPIRIN-CODEIN TB | Maintenance | Adults take 1 tablet by oral route 4 times per day as needed |
The following drug interaction information is available for CARISOPRODOL-ASPIRIN-CODEINE (carisoprodol/aspirin/codeine phosphate):
There are 4 contraindications.
These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.
| Drug Interaction | Drug Names |
|---|---|
| Opioid Antagonists/Opioid Analgesics SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Naltrexone, nalmefene, and samidorphan are opioid antagonists and thus inhibit the effects of opioid analgesics.(1-3) CLINICAL EFFECTS: Concurrent administration or the administration of naltrexone within 7-10 days of opioids may induce acute abstinence syndrome or exacerbate a pre-existing subclinical abstinence syndrome.(1,4) Patients taking naltrexone may not experience beneficial effects of opioid-containing medications.(4) Samidorphan can precipitate opioid withdrawal in patients who are dependent on opioids. In patients who use opioids, delay initiation of samidorphan for a minimum of 7 days after last use of short-acting opioids and 14 days after last use of long-acting opioids.(3) Concurrent use of nalmefene tablets with opioid agonists may prevent the beneficial effects of the opioid.(2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of naltrexone states that the administration of naltrexone concurrently with opioids or to patients dependent on opioids is contraindicated.(1,4) Patients previously dependent on short-acting opioids should be opioid-free for a minimum of seven to ten days before beginning naltrexone therapy. Patients previously on buprenorphine or methadone may be vulnerable to withdrawal symptoms for as long as 2 weeks.(1,4) The manufacturer of naltrexone states that the naloxone challenge test, described in the naltrexone prescribing information, can be administered to determine if patients are opioid free.(1) The manufacturer of samidorphan states the concurrent use of samidorphan in patients using opioids or undergoing acute opioid withdrawal is contraindicated. Prior to initiating samidorphan, there should be at least a 7-day opioid free interval from the last use of short-acting opioids, and at least a 14-day opioid free interval from the last use of long-acting opioids.(3) The UK manufacturer of nalmefene tablets (for reduction of alcohol consumption) states the concurrent use of opioid analgesics is contraindicated.(2) Suspend the use of nalmefene tablets for 7 days prior to the anticipated use of opioids (e.g., elective surgery).(2) DISCUSSION: A double-blind, randomized, placebo-control study evaluated pain relief and side effects of 35 opioid-naive patients undergoing cesarean section. All patients received spinal anesthesia (bupivacaine and morphine) and were randomized to also receive placebo, naltrexone 3 mg, or naltrexone 6 mg. Patients treated with naltrexone experienced shorter duration of pain relief (not statistically significant), however incidence of opioid-induced side effects was reduced. Patients in the naltrexone 6 mg group had lower rates of pruritus, vomiting, and somnolence (all statistically significant) compared to the placebo group.(5) In a double-blind, randomized, placebo-control trial ten recreational opioid users were studied to determine the effects of hydromorphone (4 mg and 16 mg), tramadol (87.5 mg, 175 mg, and 350 mg), and placebo after pretreatment with naltrexone (50 mg) or placebo. Results show that lower doses of hydromorphone and tramadol acted similar to placebo. Hydromorphone 16 mg alone caused euphoria and miosis which were blocked by naltrexone. Tramadol 350 mg produced a lower magnitude of euphoria and miosis compared to hydromorphone. Naltrexone partially diminished the euphoria caused by tramadol, while it enhanced some of the unpleasant monoaminergic effects (flushing, malaise, vomiting).(6) A case report describes a 28 year-old ex-heroin addict who was stable on methadone 100 mg daily and simultaneously stopped using heroin and began drinking alcohol. He was admitted to the hospital for alcohol detoxification and, by mistake, was given naltrexone 100 mg instead of methadone 100 mg. The patient experienced withdrawal symptoms including chills, agitation, muscle and abdominal pain, generalized piloerection, and dilated pupils. Treatment of withdrawal was titrated to treat symptoms and required administration 78 mg of parenteral hydromorphone, after which the patient experienced relief for the following six hours.(8) Intentional administration of an opioid antagonist, naloxone, with opioid analgesics has been performed with close monitoring to lower required opioid dose by inducing withdrawal. Three case reports describe patients who had improved pain relief on significantly reduced doses of opioid analgesics.(8) In a double-blind controlled trial, 267 trauma patients were randomized to receive 0.05 mg/kg intravenous morphine either alone or in combination with 5 mg naltrexone oral suspension. Evaluated endpoints include reduction of pain and incidence of side effects. Results indicate that ultra-low dose naltrexone does not alter opioid requirements for pain control, but does lower incidence of nausea [2 (1.16%) vs 16 (11.6%), p<0.001].(9) |
CONTRAVE, LOTREXONE, LYBALVI, NALTREX, NALTREXONE BASE MONOHYDRATE, NALTREXONE HCL, NALTREXONE HCL DIHYDRATE, NALTREXONE HCL MICRONIZED, OPVEE, VIVITROL |
| Ketorolac (Non-Injection)/NSAID; Aspirin (Greater Than 300 mg); Salicylates SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Possible additive or synergistic side effects.(1,2) CLINICAL EFFECTS: Concurrent use of multiple doses of ketorolac with other non-steroidal anti-inflammatory agents (NSAIDs), salicylates or aspirin may result in an increase in NSAID-related side effects such as bleeding or renal impairment.(1-3) PREDISPOSING FACTORS: Patients with pre-existing renal impairment may be at an increased risk of adverse effects from this interaction. The risk for bleeding episodes may be greater in patients with multiple disease-associated factors (e.g. thrombocytopenia, advanced liver disease). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g., anticoagulants, antiplatelets, corticosteroids, selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). Risk of GI bleed may be increased in patients who are of older age, in poor health status, or who use alcohol or smoke. Risk may also be increased with longer duration of NSAID use and prior history of peptic ulcer disease and/or GI bleeding. PATIENT MANAGEMENT: Manufacturers of ketorolac state that concurrent use of ketorolac with either other NSAIDs or aspirin is contraindicated.(1,2) If concurrent therapy is deemed medically necessary, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Conduct periodic monitoring of renal function, especially in patients with renal impairment. Instruct patients to report any signs and symptoms of bleeding, such as unusual bruising; red or black, tarry stools; acute abdominal or joint pain and/or swelling. DISCUSSION: Based upon similar pharmacodynamic effects and potentially cumulative risks of serious NSAID-related adverse events, manufacturers of ketorolac state the concurrent administration of ketorolac with other NSAIDs or aspirin is contraindicated.(1,2) |
KETOROLAC TROMETHAMINE, SPRIX |
| Mifepristone/Anticoagulants; Antiplatelets SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Anticoagulants may result in excessive bleeding following the abortion. CLINICAL EFFECTS: The concurrent use of mifepristone with anticoagulants may result in excessive bleeding following the abortion. PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: The manufacturer of mifepristone states that mifepristone is contraindicated in patients receiving concurrent anticoagulant therapy.(1) If concurrent therapy is deemed medically necessary, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug. DISCUSSION: The manufacturer of mifepristone states that mifepristone is contraindicated in patients receiving concurrent anticoagulant therapy.(1) |
MIFEPREX, MIFEPRISTONE |
| Ketorolac (Injectable)/NSAIDs; Aspirin (Greater Than 300 mg); Salicylates SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Possible additive or synergistic side effects.(1) CLINICAL EFFECTS: Concurrent use of multiple doses of ketorolac with other non-steroidal anti-inflammatory agents (NSAIDs), salicylates or aspirin may result in an increase in NSAID-related side effects such as bleeding or renal impairment.(1-3) PREDISPOSING FACTORS: Patients with pre-existing renal impairment may be at an increased risk of adverse effects from this interaction. The risk for bleeding episodes may be greater in patients with multiple disease-associated factors (e.g. thrombocytopenia, advanced liver disease). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g., anticoagulants, antiplatelets, corticosteroids, selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). Risk of GI bleed may be increased in patients who are of older age, in poor health status, or who use alcohol or smoke. Risk may also be increased with longer duration of NSAID use and prior history of peptic ulcer disease and/or GI bleeding. PATIENT MANAGEMENT: The manufacturer of ketorolac states that concurrent use of ketorolac with either other NSAIDs, salicylates or aspirin is contraindicated.(1) If concurrent therapy is deemed medically necessary, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. DISCUSSION: Manufacturers of ketorolac state that concurrent use of ketorolac with either other NSAIDs, salicylates or aspirin is contraindicated.(1,2) If concurrent therapy is deemed medically necessary, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Conduct periodic monitoring of renal function, especially in patients with renal impairment. |
BUPIVACAINE-KETOROLAC-KETAMINE, KETOROLAC TROMETHAMINE, R.E.C.K.(ROPIV-EPI-CLON-KETOR), ROPIVACAINE-CLONIDINE-KETOROLC, ROPIVACAINE-KETOROLAC-KETAMINE, TORONOVA II SUIK, TORONOVA SUIK |
There are 20 severe interactions.
These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.
| Drug Interaction | Drug Names |
|---|---|
| Selected Anticoagulants (Vitamin K antagonists)/Aspirin (Greater Than 100 mg); Salicylates SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Multiple processes are involved: 1) Salicylate doses greater than 3 gm daily decrease plasma prothrombin levels. 2) Salicylates may also displace anticoagulants from plasma protein binding sites. 3) Aspirin is an irreversible platelet inhibitor. Salicylates impair platelet function, resulting in prolonged bleeding time. 4) Salicylates may cause gastrointestinal(GI) bleeding due to irritation. CLINICAL EFFECTS: The concurrent use of anticoagulants and salicylates leads to blockade of two distinct coagulation pathways and may increase the risk for bleeding. PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: Avoid concomitant administration of these drugs. When aspirin is required for cardioprotection, a low dose (less than 100 mg daily) is recommended to decrease the risk for aspirin-induced GI bleeding. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. DISCUSSION: This interaction has been reported between aspirin and warfarin and between aspirin and dicumarol. Diflunisal, sodium salicylate, and topical methyl salicylate have been shown to interact with anticoagulants as well. Based on the proposed mechanisms, other salicylates would be expected to interact with anticoagulants as well. A self-controlled case study of 1,622 oral anticoagulant-precipitant drug pairs were reviewed and found 14% of drug pairs were associated with a statistically significant elevated risk of thromboembolism. Concurrent use of warfarin and diflunisal resulted in a ratio of rate ratios (RR) (95% CI) of 3.85 (1.34-11.03); warfarin and aspirin ratio of RR 2.13 (1.72-2.64); warfarin and dipyridamole ratio of RR 2.07 (1.65-2.6); and warfarin and clopidogrel ratio of RR 1.69 (1.56-1.84). A large systematic review was performed on 72 warfarin drug-drug interactions studies that reported on bleeding, thromboembolic events, or death. Most studies were retrospective cohorts. A meta-analysis of 38 of those studies found a higher rate of clinically significant bleeding in patients on warfarin and antiplatelets (OR=1.74; 95% CI 1.56-1.94). Increased bleeding risk was also seen in subgroup analyses with aspirin (OR=1.50; 95% CI 1.29-1.74), clopidogrel (OR=3.55; 95% CI 2.78-4.54), and aspirin plus clopidogrel or ticlopidine (OR=2.07, 95% CI 1.33-3.21).(17) |
ANISINDIONE, DICUMAROL, JANTOVEN, PHENINDIONE, WARFARIN SODIUM |
| Methotrexate (low strength injection, oral)/Select Salicylates SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Salicylates may inhibit the renal tubular excretion of methotrexate. CLINICAL EFFECTS: The concurrent use of methotrexate and salicylates may result in an increase in the therapeutic and toxic effects of methotrexate, leading to increased risk of severe neurotoxicity, stomatitis, and myelosuppression, including neutropenia. PREDISPOSING FACTORS: Risk factors for methotrexate toxicity include: - High-dose oncology regimens - Anti-inflammatory doses of aspirin/salicylates - impaired renal function, ascites, or pleural effusions PATIENT MANAGEMENT: US manufacturer prescribing information for methotrexate states nonsteroidal anti-inflammatory drugs, including salicylates should not be administered prior to or concomitantly with high doses of methotrexate. If concurrent therapy is warranted, methotrexate plasma levels should be monitored and patients should be observed for methotrexate toxicity. The dosage of methotrexate may need to be adjusted. Use caution when administering salicylates and low dose methotrexate. Salicylate doses > or = 2 grams per day have been associated with hepatic impairment or impaired renal elimination of methotrexate. It would be prudent to avoid high-dose aspirin, especially in patients with renal impairment or near the time of methotrexate dosage (in patients receiving weekly therapy). The Australian prescribing information for aspirin DL-lysine states coadministration with methotrexate at doses of 15 mg/week or greater is contraindicated. DISCUSSION: Several studies and case reports have reported increased and prolonged methotrexate levels in patients receiving concurrent aspirin. One study noted an effect with average weekly doses of methotrexate of 16.6 mg, but not weekly doses of 7.5 mg. Decreased renal function has also been reported with the combination. Single ingredient aspirin or buffered aspirin products with strengths < or = to 325 mg or formulations which are associated with once daily use for cardiovascular protection are not linked to this interaction. Other lower-strength aspirin formulations (e.g. headache, cough & cold, opioid combinations) which could be consumed multiple times a day remain linked to this interaction. |
JYLAMVO, METHOTREXATE, RASUVO, TREXALL, XATMEP |
| Selected Immunosuppressants/NSAIDs; Salicylates SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Cyclosporine increases the production of prostaglandin E2 and I2. Prostaglandin E2 has been shown to prevent cyclosporine -induced renal toxicity in animals. NSAIDS and salicylates may increase cyclosporine-induced renal toxicity by blocking the formation of prostaglandins. Concurrent use of everolimus, sirolimus or tacrolimus with NSAIDs or salicylates may result in additive nephrotoxicity. CLINICAL EFFECTS: Concurrent administration of cyclosporine, everolimus, sirolimus, or tacrolimus and a NSAID or salicylate may result in a decrease in renal function, with or without an alteration in immunosuppressant levels. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: If possible, avoid the concurrent use of NSAIDs or salicylates in patients maintained on cyclosporine, everolimus, sirolimus, or tacrolimus. If concurrent therapy is warranted, patients should be monitored for a decrease in renal function. The NSAID or salicylate may need to be discontinued. DISCUSSION: A decrease in renal function has been reported with concurrent cyclosporine and diclofenac, sulindac, mefenamic acid, ketoprofen, piroxicam, and naproxen. Decreasing the cyclosporine dose without discontinuing the NSAID does not appear to improve renal function. The use of agents which decrease renal function concurrently with everolimus, sirolimus or tacrolimus should be approached with caution. An observational study of 63 inpatient encounters for 57 transplant patients evaluated concurrent use between calcineurin inhibitor (CNI) therapy and NSAID use. Patients were matched to 126 transplant patients on CNI therapy without NSAID use. Patients who received at least one dose of NSAID had a 12.2% rate of treatment emergent acute kidney injury (AKI). The relative risk ratio for AKI in patient exposed to NSAID therapy was 2.20 (95% CI 0.74-6.54). An increase in 48 hour post NSAID exposure serum creatinine above baseline was documented in 65.9% of patients compared to 46% in the non NSAID group (p=0.016). Multivariate analysis revealed changes in serum creatinine at 48 hours after admission were independently associated with age (p=0.008) and NSAID use (p=0.026).(12) |
AFINITOR, AFINITOR DISPERZ, ASTAGRAF XL, CYCLOSPORINE, CYCLOSPORINE MODIFIED, ENVARSUS XR, EVEROLIMUS, FYARRO, GENGRAF, NEORAL, PROGRAF, SANDIMMUNE, SIROLIMUS, TACROLIMUS, TACROLIMUS XL, TORPENZ, ZORTRESS |
| Influenza Virus Vaccine Live/Salicylates SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Use of salicylates during influenza infection has been associated with Reye's Syndrome.(1,2) CLINICAL EFFECTS: Use of the live influenza virus vaccine in children and adolescents (patients age 2-17 years) receiving salicylate therapy may increase the risk of Reye's Syndrome.(1,2) Symptoms of Reye's syndrome include drowsiness, confusion, seizures, coma. In severe cases, Reye's syndrome can result in death. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The use of live influenza virus vaccine in children and adolescents (patients age 2-17 years) receiving salicylate therapy is contraindicated.(1,2) Use of salicylates should be avoided for 4 weeks after administration of live influenza vaccine.(1) DISCUSSION: Because the use of salicylates during influenza infection has been associated with Reye's Syndrome, the use of live influenza virus vaccine in children and adolescents (patients age 2-17 years) receiving salicylate therapy is contraindicated.(1,2) |
FLUMIST 2025-2026, FLUMIST HOME 2025-2026 |
| Pemetrexed/Selected NSAIDs; Aspirin (Greater Than 325 mg) SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: NSAIDs may decrease the clearance of pemetrexed.(1) This decreased clearance may be the result of chronic renal toxicity from NSAIDs or NSAIDs may compete with pemetrexed for tubular secretion.(2) CLINICAL EFFECTS: Concurrent use of pemetrexed and NSAIDs may result in elevated levels of and toxicity from pemetrexed, including myelosuppression, neutropenia, renal toxicity, and gastrointestinal toxicity.(1) PREDISPOSING FACTORS: This interaction is expected to be more severe in patients with mild to moderate renal insufficiency (creatinine clearance (CrCl) of 45 ml/min to 79 ml/min) and/or patients taking long acting NSAIDs. (1) PATIENT MANAGEMENT: In patients with normal renal function (CrCl equal to or greater than 80 ml/min), ibuprofen (400 mg 4 times daily) can be administered with pemetrexed. Aspirin in low to moderate doses (325 mg every 6 hours) does not affect the pharmacokinetics of pemetrexed.(1) In patients with mild to moderate renal insufficiency (CrCl from 45 ml/min to 79 ml/min), NSAIDs with short half-lives should be avoided for 2 days before, the day of, and 2 days after pemetrexed administration. Ibuprofen should be administered with caution in these patients.(1) NSAIDs and salicylates with long half-lives should be avoided for at least 5 days before, the day of, and 2 days following pemetrexed administration in all patients.(1,2) If NSAIDs are required, patients should be monitored for pemetrexed toxicity, especially myelosuppression, renal toxicity, and gastrointestinal toxicity.(1) DISCUSSION: In patients with normal renal function, ibuprofen (400 mg 4 times daily) decreased the clearance of pemetrexed by 20% and increased its area-under-curve (AUC) by 20%.(1) In a Phase I clinical trial, two patients receiving high dose pemetrexed therapy experienced severe toxicity, both were receiving a NSAID. Following these reports, all patients were required to stop aspirin or other NSAIDs 2 days before and not resume these agents until 2 days after pemetrexed.(2) In two randomized, controlled cross-over trials, 27 cancer patients with a creatinine clearance (CrCl) less than or equal to 60 ml/min received pemetrexed (500 mg/m2) infusion on Day 1 of a 21-day cycle and either aspirin 325 mg or ibuprofen 400 mg orally every 6 hours starting 2 days before pemetrexed administration. Coadministration of aspirin did not affect pemetrexed pharmacokinetics. Ibuprofen decreased the clearance of pemetrexed by 16%, increased its maximum concentration (Cmax) by 15%, and increased the AUC by 20%.(3) Aspirin products linked to this monograph are single ingredient aspirin products with greater than 325 mg strength, and aspirin combination products (e.g. opioid-aspirin or cough/cold/allergy products) with a reasonable likelihood of a total daily aspirin dose > or = 1,300 mg per day. |
AXTLE, PEMETREXED, PEMETREXED DISODIUM, PEMFEXY, PEMRYDI RTU |
| Dabigatran/Antiplatelets; Aspirin (Greater Than 100 mg) SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Dabigatran is a direct thrombin inhibitor and when taken with agents that effect platelet aggregation increased bleeding episodes can occur.(1,2) CLINICAL EFFECTS: Concurrent use of dabigatran with antiplatelet agents may result in additive or synergistic effects resulting in unwanted bleeding episodes.(1,2) PREDISPOSING FACTORS: Factors associated with an increase risk for bleeding include renal impairment, concomitant use of P-glycoprotein inhibitors, patient age >74 years, coexisting conditions (e.g. recent trauma) or use of drugs (e.g. NSAIDs) associated with bleeding risk, and patient weight <50 kg.(1-3) The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: Patients requiring concurrent therapy with dabigatran and an antiplatelet agent should be closely monitored for signs of bleeding. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug. Discontinue dabigatran in patients with active bleeding. DISCUSSION: Dabigatran is a direct thrombin inhibitor and when taken with agents that effect platelet aggregation and/or other clotting factors increased bleeding episodes can occur.(1,2) In the RE-LY trial, 40% of patients were on aspirin at baseline.(1) In the RE-MEDY trial, 7.7% of patients were on aspirin at baseline.(1) In the RE-DUAL PCI trial, patients were randomly assigned to one of three treatments: (A) dual therapy with dabigatran 110 mg twice daily plus either clopidogrel or ticagrelor, (B) dual therapy with dabigatran 150 mg twice daily plus either clopidogrel or ticagrelor, or (C) triple therapy with warfarin (goal INR 2-3) plus aspirin (< or = 100 mg daily) plus either clopidogrel or ticagrelor. The incidence of the first major or clinically relevant non-major (CRNM) bleeding event was 15.4% in group A compared with 26.9% in group C (hazard ratio, 0.52; 95% CI 0.42 to 0.63; p<0.001 for noninferiority; p<0.001 for superiority) and 20.2% in group B compared to 25.7% in corresponding group C (hazard ratio, 0.72; 95% CI 0.58 to 0.88; p<0.001 for noninferiority). For major bleeding as defined by Thrombolysis in Myocardial Infarction (TIMI) criteria, the rate was lower in both dual-therapy groups than in the triple-therapy group: 1.4% in group A compared to 3.8% in group C (hazard ratio, 0.37; 95% CI 0.2 to 0.68; p=0.002) and 2.1% in group B compared to 3.9% in corresponding group C (hazard ratio, 0.51; 95% CI 0.28 to 0.93; p=0.03). Incidence of composite efficacy end point of thromboembolic events (myocardial infarction, stroke, or systemic embolism), death, or unplanned revascularization was 13.7% in groups A and B compared to 13.4% in group C (hazard ratio, 1.04; 95% CI 0.84 to 1.29; p=0.005 for noninferiority).(4) A meta-analysis of 9 studies identified 13,459 patients taking direct oral anticoagulants (DOACs), 1,692 of whom also took an antiplatelet agent. Of the patients on antiplatelet agents, 1,254 took aspirin while the rest was unspecified. Most of the trials restricted patients to use of low-dose aspirin, with the highest allowable dose being 165 mg/day. Compared with DOACs alone, the use of DOACs with antiplatelet agents was associated with an increased risk of major bleeding (OR 1.89; 95% CI, 1.04-3.44) and CRNM bleeding (OR 1.82; 95% CI, 1.50-2.22). There was no difference between groups in the efficacy outcome of symptomatic recurrent venous thromboembolism (VTE) or VTE-related death.(5) |
DABIGATRAN ETEXILATE, PRADAXA |
| Varicella Virus Vaccine Live/Salicylates SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Use of salicylates during natural varicella infection has been associated with Reye's Syndrome.(1-4) CLINICAL EFFECTS: Use of the live varicella virus vaccine in patients receiving salicylate therapy or use of salicylates within 6 weeks after vaccination with the live varicella virus vaccine may increase the risk of Reye's Syndrome.(1-4) Symptoms of Reye's syndrome include drowsiness, confusion, seizures, coma. In severe cases, Reye's syndrome can result in death. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The Canadian, UK, and US manufacturers of live varicella virus vaccine indicated for the prevention of chicken pox state that vaccine recipients should avoid the use of salicylates for 6 weeks after vaccination.(1-4) There is no such restriction in the labeling for live varicella virus vaccine indicated for the prevention of shingles, which is only indicated for patients age 60 and older.(5) DISCUSSION: Because the use of salicylates during natural varicella infection has been associated with Reye's Syndrome, the use of salicylates for 6 weeks following vaccination with live varicella virus vaccine should be avoided.(1-4) |
PROQUAD, VARIVAX VACCINE |
| Sodium Phosphate Bowel Cleanser/NSAIDs; Salicylates SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Bowel cleansing with sodium phosphate causes dehydration, decreased intravascular volume and hyperphosphatemia, which increases phosphate levels in the renal tubules. Abnormally high levels of calcium and phosphate in the renal tubules may precipitate out, resulting in renal injury.(1) CLINICAL EFFECTS: Use of sodium phosphate for bowel cleansing in patients maintained on nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of acute phosphate nephropathy, which is an acute kidney injury associated with deposits of calcium phosphate crystal in the renal tubules that may result in permanent renal function impairment. Acute phosphate nephropathy presents as acute kidney injury with minimal proteinuria and a bland urine sediment.(2) Use of oral sodium phosphate products at laxative doses has not been associated with acute kidney injury.(3) PREDISPOSING FACTORS: Patients who may be at an increased risk of acute phosphate nephropathy include those who are over age 55; are hypovolemic or have decreased intravascular volume; have baseline kidney disease, bowel obstruction, or active colitis; and who are using medications that affect renal perfusion or function (such as diuretics, ACE inhibitors, angiotension receptor blockers [ARBs]), and NSAIDs.(2) PATIENT MANAGEMENT: If possible, use an alternative agent for bowel cleansing.(1) Use sodium phosphate products with caution in patients taking medications that affect kidney function or perfusion, such as ACE inhibitors or ARBs. Obtain baseline and post-procedure labs (electrolytes, calcium, phosphate, BUN, creatinine, and [in smaller, frail individuals] glomerular filtration rate). Instruct patients to drink sufficient quantities of clear fluids before, during, and after bowel cleansing and to avoid other laxatives that contain sodium phosphate. Consider hospitalization and intravenous hydration during bowel cleansing to support frail patients who may be unable to drink an appropriate volume of fluid or who may be without assistance at home.(2) Use of an electrolyte solution for rehydration may decrease the risk of acute phosphate nephropathy.(4,5) DISCUSSION: Since May 2006, the FDA has received 20 reports of acute phosphate nephropathy associated with the use of Osmo Prep. Concomitant medications included ACE inhibitors or ARBs (11), diuretics (6), and NSAIDs (4).(2) In a retrospective review of colonoscopy patients, simultaneous use of ACE inhibitors or ARBs significantly increased the risk of acute kidney injury from oral sodium phosphate. Diuretic use was also a risk factor.(6) In a case series study of 21 cases of acute phosphate nephropathy in patients who had used oral sodium phosphate, 14 patients received an ACE inhibitor or ARB, 4 used a diuretic, and 3 used an NSAID.(7) Cases have also been reported with rectal products.(8) |
MB CAPS, SODIUM PHOSPHATE DIBASIC, URIMAR-T, URNEVA |
| Ticagrelor/High-Dose Aspirin SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: The exact mechanism is unknown. CLINICAL EFFECTS: Chronic use of high-dose aspirin may decrease the efficacy of ticagrelor.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: After an initial loading dose, low dose aspirin is indicated with concurrent ticagrelor for the prevention of thrombotic events. Specific dosage recommendations vary between countries, however all agree that the maintenance aspirin dose should be < or = 150 mg per day. US prescribing information recommends the following based on indication: -For Acute Coronary Syndrome or Myocardial Infarction - Initiate ticagrelor with a maintenance dose of aspirin 75 mg to 100 mg. -For Coronary Artery Disease but No Prior Stroke or Myocardial Infarction - Use ticagrelor with a daily maintenance dose of aspirin of 75 mg to 100 mg. -For Acute Ischemic Stroke or Transient Ischemic Attack - Use ticagrelor with a loading dose of aspirin (300 mg to 325 mg) and a daily maintenance dose of 75 mg to 100 mg.(1) Canada and UK prescribing information recommends a maintenance aspirin dose of 75 mg to 150 mg daily.(2,3) For use other than platelet aggregation, it would be prudent to recommend an alternative product that does not contain aspirin for patients maintained on ticagrelor. DISCUSSION: Ticagrelor is indicated with concurrent aspirin for the prevention of thrombotic events. In the PLATO trial, there was a relationship between the maintenance dose of aspirin and efficacy of ticagrelor. At increased aspirin dosages, ticagrelor was less effective.(1-3) |
BRILINTA, TICAGRELOR |
| Rivaroxaban/Selected Antiplatelets; Aspirin (Greater Than 100 mg) SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Additive effects on hemostasis.(1) CLINICAL EFFECTS: Concurrent use of rivaroxaban with anticoagulants, antiplatelets, or thrombolytics may increase the risk of bleeding.(1) PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: Avoid concurrent use of rivaroxaban and higher doses of aspirin unless the benefit is expected to outweigh the increased risk of bleeding. In the ROCKET AF trial, concomitant use of low dose aspirin (almost exclusively at less than or equal to 100 mg daily) was identified as an independent risk factor for bleeding.(1) If the benefit of concurrent use of rivaroxaban with other antiplatelets is expected to outweigh the increased risk of bleeding, closely monitor patients for signs or symptoms of bleeding.(1) The UK manufacturer of rivaroxaban states that rivaroxaban 2.5 mg twice daily is indicated with aspirin 75 - 100 mg with or without clopidogrel 75 mg or standard dose ticlopidine for post-acute coronary syndrome and in patients with CAD and PAD, weighing the risk for ischemic events against the bleeding risks. Long-term dual antiplatelet therapy should be avoided. Clinical monitoring is recommended throughout treatment.(2) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug. DISCUSSION: In two clinical trials in healthy subjects, concurrent clopidogrel (300 mg loading dose, then 75 mg daily) and rivaroxaban (15 mg single dose) increased bleeding time to 45 minutes in 45% and 30% of subjects. This was twice the maximum increase in bleeding time seen with either agent alone.(1) In the ROCKET AF trial, concomitant aspirin use (almost exclusively at < or = to 100 mg daily) was identified as an independent risk factor for bleeding.(1) In a study, concurrent enoxaparin (40 mg) and rivaroxaban (10 mg) resulted in additive effects on anti-factor Xa activity with no effects on the pharmacokinetics of rivaroxaban.(1) In a study, concurrent warfarin (15 mg) and rivaroxaban (5 mg) resulted in additive effects on factor Xa inhibition and PT with no effects on the pharmacokinetics of rivaroxaban.(1) In a single dose study, there were no pharmacokinetic or pharmacodynamic interactions between rivaroxaban and aspirin.(1) A self-controlled case study of 1,622 oral anticoagulant-precipitant drug pairs were reviewed and found 14% of drug pairs were associated with a statistically significant elevated risk of thromboembolism. Concurrent use of rivaroxaban and dipyridamole resulted in a ratio of rate ratios (95% CI) of 3.49 (1.08-6.64); and rivaroxaban and aspirin ratio of rate ratios 2.19 (1.21-2.95).(3) A meta-analysis of 9 studies identified 13,459 patients taking direct oral anticoagulants (DOACs), 1,692 of whom also took an antiplatelet agent. Of the patients on antiplatelet agents, 1,254 took aspirin while the rest was unspecified. Most of the trials restricted patients to use of low-dose aspirin, with the highest allowable dose being 165 mg/day. The use of DOACs with antiplatelet agents was associated with an increased risk of major bleeding (OR 1.89; 95% CI, 1.04-3.44) and clinically relevant non-major bleeding (OR 1.82; 95% CI, 1.50-2.22). There was no difference between groups in the efficacy outcome of symptomatic recurrent venous thromboembolism (VTE) or VTE-related death.(4) |
RIVAROXABAN, XARELTO |
| Apixaban/Antiplatelets; Aspirin (Greater Than 100 mg) SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Additive effects on hemostasis.(1-4) CLINICAL EFFECTS: Concurrent use of apixaban with antiplatelets may increase the risk of bleeding.(1-4) PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: Patients requiring concurrent therapy with apixaban and an antiplatelet agent should be closely monitored for signs of bleeding. Monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. Discontinue apixaban in patients with active bleeding. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug. DISCUSSION: Concurrent administration of enoxaparin (40 mg single dose) and apixaban (5 mg single dose) resulted in additive effects on anti-Factor Xa activity.(1) Concurrent apixaban and aspirin (325 mg daily) resulted in no pharmacokinetic or pharmacodynamic interactions.(1) Concurrent apixaban with clopidogrel (75 mg daily) or with combination clopidogrel (75 mg daily) and aspirin (162 mg daily) produced no relevant increases in bleeding time, platelet aggregation, or clotting tests (PI, INR, and aPTT) compared either clopidogrel alone or clopidogrel with aspirin without apixaban.(1) Significant bleeding risk was reported with the combination of apixaban, aspirin, and clopidogrel in patients with acute coronary syndrome.(1) A self-controlled case study of 1,622 oral anticoagulant-precipitant drug pairs were reviewed and found 14% of drug pairs were associated with a statistically significant elevated risk of thromboembolism. Concurrent use of apixaban and clopidogrel resulted in a ratio of rate ratios (95% CI) of 1.96 (1.53-2.51).(5) A meta-analysis of 9 studies identified 13,459 patients taking direct oral anticoagulants (DOACs), 1,692 of whom also took an antiplatelet agent. Of the patients on antiplatelet agents, 1,254 took aspirin while the rest was unspecified. Most of the trials restricted patients to use of low-dose aspirin, with the highest allowable dose being 165 mg/day. The use of DOACs with antiplatelet agents was associated with an increased risk of major bleeding (OR 1.89; 95% CI, 1.04-3.44) and clinically relevant non-major bleeding (OR 1.82; 95% CI, 1.50-2.22). There was no difference between groups in the efficacy outcome of symptomatic recurrent venous thromboembolism (VTE) or VTE-related death.(3) |
ELIQUIS, ELIQUIS SPRINKLE |
| Anagrelide/Aspirin SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Anagrelide may affect platelet function in a way that synergizes with low-dose aspirin.(1) CLINICAL EFFECTS: Concurrent use of anagrelide and aspirin may increase the risk of hemorrhage.(1,2) PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: The concurrent use of anagrelide and aspirin should be approached with caution, especially in patients with a high risk profile for hemorrhage.(2) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. DISCUSSION: In healthy subjects, the administration of of single dose anagrelide (1 mg) and aspirin (900 mg) or multiple dose anagrelide (1 mg daily) and aspirin (75 mg daily) resulted in greater anti-platelet aggregation effects than aspirin alone. Concurrent single doses of both anagrelide and aspirin had no effects on bleeding time, prothrombin time, or activated partial thromboplastin time.(2) A study in 809 patients with essential thrombocythemia compared the combination of low-dose aspirin with hydroxyurea to the combination of low-dose aspirin with anagrelide. While patients receiving low-dose aspirin with anagrelide had lower rates of venous thromboembolism, the combination was associated with increased rates of arterial myelofibrosis, serious hemorrhage, and transformation to myelofibrosis.(1) |
AGRYLIN, ANAGRELIDE HCL |
| Edoxaban/Antiplatelets; Aspirin (Greater Than 100 mg) SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Anticoagulants and antiplatelet agents have additive effects on hemostasis.(1) In addition, aspirin doses greater than or equal to 325 mg daily increase edoxaban exposure.(1) CLINICAL EFFECTS: Concurrent use of edoxaban with antiplatelets may increase the risk of bleeding.(1) PREDISPOSING FACTORS: Bleeding risk may be increased in patients with renal impairment and in patients > 75 years of age.(1) Use of multiple agents which affect hemostasis increases the risk for bleeding. The risk for bleeding episodes may be greater in patient with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: Patients requiring concurrent therapy with edoxaban and an antiplatelet agent should be closely monitored for signs of bleeding. Edoxaban and aspirin at dosages of 100 mg or less may be coadministered.(2,3) Monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. Discontinue edoxaban in patients with active bleeding. DISCUSSION: Concomitant use of edoxaban and antiplatelet agents may increase the risk of bleeding. In edoxaban clinical trials concomitant use of low dose aspirin (< or = 100 mg daily), thienopyridines, and NSAIDs was permitted and resulted in increased rates of clinically relevant bleeding. The rates of major bleeding on edoxaban and warfarin were generally consistent among subgroups. Bleeding rates appeared higher in both treatment arms (edoxaban and warfarin) in patients taking aspirin. Co-administration of aspirin (100 mg or 325 mg) and edoxaban increased bleeding time relative to that seen with either drug alone.(1) About 30% of the population in ENGAGE-AF received concomitant therapy with aspirin because of co-morbid conditions. While aspirin is known to increase risk for bleeds and the annualized event rate for major bleeds was higher than that in patients not receiving aspirin (3.87% vs. 2.13%), the risk for bleeds in patients receiving edoxaban 60 mg on a background of aspirin was lower than that for warfarin on a background of aspirin (HR 0.78 (95%CI 0.65,0.94). Based on these data no dose adjustments/contraindications are required.(4) Edoxaban and aspirin at dosages of 100 mg or less may be coadministered.(2,3) A meta-analysis of 9 studies identified 13,459 patients taking direct oral anticoagulants (DOACs), 1,692 of whom also took an antiplatelet agent. Of the patients on antiplatelet agents, 1,254 took aspirin while the rest was unspecified. Most of the trials restricted patients to use of low-dose aspirin, with the highest allowable dose being 165 mg/day. The use of DOACs with antiplatelet agents was associated with an increased risk of major bleeding (OR 1.89; 95% CI, 1.04-3.44) and clinically relevant non-major bleeding (OR 1.82; 95% CI, 1.50-2.22). There was no difference between groups in the efficacy outcome of symptomatic recurrent venous thromboembolism (VTE) or VTE-related death.(5) |
SAVAYSA |
| Methotrexate (Oncology-Injection)/Selected Salicylates SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Salicylates may inhibit the renal tubular excretion of methotrexate. CLINICAL EFFECTS: The concurrent use of methotrexate and salicylates may result in an increase in the therapeutic and toxic effects of methotrexate, leading to increased risk of severe neurotoxicity, stomatitis, and myelosuppression, including neutropenia. PREDISPOSING FACTORS: Risk factors for methotrexate toxicity include: - High-dose oncology regimens - Anti-inflammatory doses of aspirin/salicylates - Impaired renal function, ascites, or pleural effusions PATIENT MANAGEMENT: US manufacturer prescribing information for methotrexate states nonsteroidal anti-inflammatory drugs should not be administered prior to or concomitantly with high doses of methotrexate. If concurrent therapy is warranted, methotrexate plasma levels should be monitored and patients should be observed for methotrexate toxicity. The dosage of methotrexate may need to be adjusted. Use caution when administering higher doses of salicylates with lower doses of methotrexate. Salicylate doses > or = 2 grams per day have been associated with hepatic impairment or impaired renal elimination of methotrexate. It would be prudent to avoid high-dose aspirin, especially in patients with renal impairment or near the time of methotrexate dosage (in patients receiving weekly therapy). The Australian prescribing information for aspirin DL-lysine states coadministration with methotrexate at doses of 15 mg/week or greater is contraindicated. DISCUSSION: Several studies and case reports have reported increased and prolonged methotrexate levels in patients receiving concurrent aspirin. One study noted an effect with average weekly doses of methotrexate of 16.6 mg, but not weekly doses of 7.5 mg. Decreased renal function has also been reported with the combination. Single ingredient aspirin or buffered aspirin products with strengths < or = to 325 mg or formulations which are associated with once daily use for cardiovascular protection are not linked to this interaction. Other lower-strength aspirin formulations (e.g. headache, cough & cold, opioid combinations) which could be consumed multiple times a day remain linked to this interaction. |
METHOTREXATE, METHOTREXATE SODIUM, METHOTREXATE-NACL |
| Sodium Oxybate/Codeine; Tramadol SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Oxybate by itself may be associated with severe somnolence or respiratory depression. Concurrent use with other CNS depressants may further increase the risk for respiratory depression or loss of consciousness.(1-3) Codeine and tramadol are converted to their more active opioid metabolites (morphine and O-desmethyltramadol respectively) by CYP2D6. CLINICAL EFFECTS: Concurrent use of sodium oxybate and opioids such as tramadol, or alcohol may further increase the risk for respiratory depression and profound sedation, syncope or coma.(1,2) Fatalities have been reported.(3) PREDISPOSING FACTORS: Based upon FDA evaluation of deaths in patients taking sodium oxybate, risk factors may include: use of multiple drugs which depress the CNS, more rapid than recommended oxybate dose titration, exceeding the maximum recommended oxybate dose, and prescribing for unapproved uses such as fibromyalgia, insomnia or migraine. Note that in oxybate clinical trials for narcolepsy 78% - 85% of patients were also receiving concomitant CNS stimulants.(1-3) In patients receiving codeine or tramadol, ultrarapid metabolizers of CYP2D6 are more likely to have higher than normal systemic concentrations of the active opioid.(4) Other patients at high risk from this interaction include: adolescents between 12 and 18 years who are obese or have conditions such as obstructive sleep apnea or severe lung disease, which may increase the risk of respiratory depression; and breastfeeding women (due to the risk of serious adverse reactions in breastfed infants).(5) PATIENT MANAGEMENT: Avoid use of oxybate when concomitant opioids, benzodiazepines, sedating antidepressants, sedating antipsychotics, general anesthetics, or muscle relaxants, particularly when predisposing risk factors are present. If combination use is required, dose reduction or discontinuation of one or more CNS depressants should be considered. If short term use of an opioid or general anesthetic is required, consider interruption of sodium oxybate treatment.(1,2) Codeine and tramadol are converted to their active opioid metabolites by CYP2D6. Ultrarapid metabolizers of CYP2D6 more rapidly convert codeine or tramadol to their active metabolites (morphine and o-desmethyltramadol respectively) and so are more likely to have higher than normal systemic concentrations of the active opioid. Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(6) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(7) DISCUSSION: The FDA evaluated sodium oxybate postmarket fatal adverse event reports from the FDA Adverse Event Reporting System(AERS) and from the manufacturer. Although report documentation was not always optimal or complete, useful information was obtained. Factors which may have contributed to fatal outcome: concomitant use of one or more drugs which depress the CNS, more rapid than recommended oxybate dose titration, exceeding the maximum recommended oxybate dose, and prescribing for unapproved uses such as fibromyalgia, insomnia or migraine. FDA reported the case of a 5-year-old patient who received one dose of tramadol following a tonsillectomy and experienced slow, difficult breathing requiring emergency intervention and hospitalization. The child was subsequently found to be an ultrarapid metabolizer of CYP2D6.(4) Many deaths occurred in patients with serious psychiatric disorders such as depression and substance abuse. Other concomitant diseases may have also contributed to respiratory and CNS depressant effects of oxybate.(3) |
LUMRYZ, LUMRYZ STARTER PACK, SODIUM OXYBATE, XYREM, XYWAV |
| Opioids (Cough and Cold)/Muscle Relaxants SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Concurrent use of opioids and muscle relaxants may result in additive CNS depression.(1) CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as muscle relaxants, may result in profound sedation, respiratory depression, coma, and/or death.(1) PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. PATIENT MANAGEMENT: Avoid prescribing opioid-including cough medications for patients taking CNS depressants such as muscle relaxants.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3) DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(4) A retrospective cohort study compared the risk of opioid overdose associated with concomitant use of opioids and skeletal muscle relaxants versus opioid use alone. The study examined two types of opioid users (naive opioid use and prevalent opioid use) with and without exposure to skeletal muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the naive and prevalent opioid user cohorts, respectively, generating a combined estimate of 1.21. The risk increased with treatment duration (less than or equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80) and for the use of baclofen and carisoprodol (HR 1.83 and 1.84, respectively). Elevated risk was associated with concomitant users with daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and 1.39, respectively).(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10) |
HYCODAN, HYDROCODONE-CHLORPHENIRAMNE ER, HYDROCODONE-HOMATROPINE MBR, HYDROMET, PROMETHAZINE-CODEINE, TUXARIN ER |
| Eluxadoline/Anticholinergics; Opioids SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Eluxadoline is a mixed mu-opioid and kappa-opioid agonist and delta-opioid antagonist and may alter or slow down gastrointestinal transit.(1) CLINICAL EFFECTS: Constipation related adverse events that sometimes required hospitalization have been reported, including the development of intestinal obstruction, intestinal perforation, and fecal impaction.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Avoid use with other drugs that may cause constipation. If concurrent use is necessary, evaluate the patient's bowel function regularly. Monitor for symptoms of constipation and GI hypomotility, including having bowel movements less than three times weekly or less than usual, difficulty having a bowel movement or passing gas, nausea, vomiting, and abdominal pain or distention.(1) Instruct patients to stop eluxadoline and immediately contact their healthcare provider if they experience severe constipation. Loperamide may be used occasionally for acute management of severe diarrhea, but must be discontinued if constipation develops.(1) DISCUSSION: In phase 3 clinical trials, constipation was the most commonly reported adverse reaction (8%). Approximately 50% of constipation events occurred within the first 2 weeks of treatment while the majority occurred within the first 3 months of therapy. Rates of severe constipation were less than 1% in patients receiving eluxadoline doses of 75 mg and 100 mg.(1) |
VIBERZI |
| Vorapaxar/Aspirin (> 100 mg) SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Additive effects on hemostasis.(1-3) CLINICAL EFFECTS: Concurrent use of vorapaxar with high-dose aspirin may increase the risk of bleeding while decreasing the efficacy of vorapaxar.(1-3) PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: Vorapaxar is indicated for concurrent use with antiplatelet dosages of aspirin. Use of high-dose aspirin should be avoided with vorapaxar. Patients requiring concurrent therapy with vorapaxar and high-dose aspirin should be closely monitored for signs of bleeding.(1-3) Monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. Discontinue vorapaxar in patients with active bleeding. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug. DISCUSSION: In the TRA2P and TRACER clinical trials, GUSTO moderate/severe bleeding was increased with higher dosages of aspirin (>= 300 mg), while efficacy of vorapaxar was decreased.(2,3) |
ZONTIVITY |
| Abrocitinib/Antiplatelets; Aspirin (Greater Than 100 mg) SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Abrocitinib has been associated with transient, dose-dependent thrombocytopenia. The nadir platelet count occurs at a median of 24 days after receiving abrocitinib 200 mg once daily and a 40% recovery occurs by 12 weeks. Concurrent use with agents that affect platelet aggregation may result in an additive risk of bleeding.(1) CLINICAL EFFECTS: Concurrent use of abrocitinib with antiplatelet agents may increase the risk of bleeding.(1) PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. pre-existing thrombocytopenia). Abrocitinib is not recommended for patients with a platelet count less than 150,000/mm3.(1) Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding. PATIENT MANAGEMENT: The concurrent use of abrocitinib with antiplatelet agents (except aspirin < or = 81 mg daily) is contraindicated during the first 3 months of abrocitinib therapy. Prior to starting abrocitinib therapy, obtain a complete blood count and recheck at 4 weeks after initiation and 4 weeks after a dose increase. Discontinuation of abrocitinib is required if platelets drop below 50,000/mm3.(1) If concurrent therapy is warranted after the first 3 months of abrocitinib therapy, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. DISCUSSION: Abrocitinib has been associated with transient, dose-dependent thrombocytopenia and is more severe with lower baseline platelet counts. At baseline platelet counts of 170,000/mm3, 220,000/m3 and 270,000/mm3, the nadirs were -41.2%, -33.4%, and -26.5%, respectively. Recovery of platelet count (about 40% recovery by 12 weeks) occurred without discontinuation of the treatment.(1) |
CIBINQO |
| Caplacizumab/Anticoagulants; Antiplatelets; Thrombolytics SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Bleeding has been reported with the use of caplacizumab.(1) CLINICAL EFFECTS: Concurrent use of caplacizumab with anticoagulants, antiplatelets, or thrombolytics may increase the risk of hemorrhage.(1) PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. hemophilia, coagulation factor deficiencies). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: Avoid the use of caplacizumab with anticoagulants, antiplatelets, and thrombolytics. Interrupt caplacizumab therapy if clinically significant bleeding occurs. Patients may require von Willebrand factor concentrate to rapidly correct hemostasis. If caplacizumab is restarted, closely monitor for signs of bleeding.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug. DISCUSSION: Bleeding has been reported with caplacizumab. In clinical studies, severe bleeding adverse reactions of epistaxis, gingival bleeding, upper gastrointestinal hemorrhage, and metrorrhagia were each reported in 1% of patients. Overall, bleeding events occurred in approximately 58% of patients on caplacizumab versus 43% of patients on placebo.(1) In post-marketing reports, cases of life-threatening and fatal bleeding were reported with caplacizumab.(1) |
CABLIVI |
There are 48 moderate interactions.
The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.
| Drug Interaction | Drug Names |
|---|---|
| Heparin/Selected Salicylates SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Additive prolongation of bleeding time. CLINICAL EFFECTS: Increased risk of bleeding which may extend for several days beyond discontinuation of salicylates. PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: Avoid concomitant administration of these drugs. If this combination is used, monitor patients for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. A non-acetylated salicylate may be used to avoid antiplatelet activity. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. Single ingredient aspirin or buffered aspirin products with strengths < or = 325 mg and combination aspirin products which are used to treat cardiovascular disease (e.g. aspirin+statins, aspirin+dipyridamole) are not included in this interaction. DISCUSSION: This interaction is likely to occur. |
ARIXTRA, ELMIRON, ENOXAPARIN SODIUM, ENOXILUV, FONDAPARINUX SODIUM, FRAGMIN, HEPARIN SODIUM, HEPARIN SODIUM IN 0.45% NACL, HEPARIN SODIUM-0.45% NACL, HEPARIN SODIUM-0.9% NACL, HEPARIN SODIUM-D5W, LOVENOX, PENTOSAN POLYSULFATE SODIUM |
| Uricosurics/Aspirin (Greater Than 100 mg); Salicylates SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Not clearly established. Protein binding displacement is a possibility. CLINICAL EFFECTS: May observe hyperuricemia and gout resulting from reduced uricosuric response. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Avoid chronic, moderate to high doses of salicylates. DISCUSSION: This interaction is well documented. Occasional small doses of salicylates do not appear to inhibit the action of uricosurics. |
ORLYNVAH, PROBENECID, PROBENECID-COLCHICINE |
| NSAIDs; Salicylates/Loop Diuretics SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: During concurrent administration of a loop diuretic and a nonsteroidal anti-inflammatory drug (NSAID), patients may retain sodium as a result of NSAID-induced prostaglandin inhibition. CLINICAL EFFECTS: The pharmacological effects of loop diuretics may be decreased due to reduced antihypertensive and diuretic actions. Concurrent use of NSAIDs with loop diuretics and renin-angiotensin system (RAS) inhibitors may result in increased risk of acute kidney injury (AKI). PREDISPOSING FACTORS: Low water intake/dehydration, drug sensitivity, greater than 75 years of age, and renal impairment may increase an individuals susceptibility to AKI. PATIENT MANAGEMENT: Monitor patients for a decrease in the effects of the loop diuretic. It may be necessary to administer a higher dose of the diuretic or an alternative anti-inflammatory agent. Concurrent use of NSAIDs with loop diuretics and RAS inhibitors should be used with caution and monitored closely for signs of AKI. DISCUSSION: In a computational study, the risk of AKI using triple therapy with a diuretic, RAS inhibitor, and NSAID was assessed. The study found the following factors may increase an individual's susceptibility to AKI: low water intake, drug sensitivity, greater than 75 years of age, and renal impairment.(19,20) In an observational study, current use of a triple therapy with a diuretic, RAS inhibitor, and NSAID, was associated with an increased rate of acute kidney injury (rate ratio (RR) 1.31, 95% confidence interval (CI) 1.12-1.53). The highest risk of AKI associated with triple therapy were observed in the first 30 days of use (RR 1.82, CI 1.35-2.46). (21) Administration of indomethacin alone has been reported to decrease sodium excretion and increase blood pressure. In patients receiving a loop diuretic (e.g., bumetanide, furosemide), these effects interfere with clinical management. Several NSAIDs have been shown to interact with loop diuretics interfering with the pharmacological effects of the diuretic. In volunteers on sodium restricted diets, ibuprofen and indomethacin inhibited furosemide diuresis. |
BUMETANIDE, EDECRIN, ENBUMYST, ETHACRYNATE SODIUM, ETHACRYNIC ACID, FUROSCIX, FUROSEMIDE, FUROSEMIDE-0.9% NACL, LASIX, LASIX ONYU, SOAANZ, TORSEMIDE |
| Antidiabetics, Oral/Aspirin (Greater Than 100 mg); Salicylates SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Complex. Salicylates appear to have intrinsic glucose lowering properties via several proposed mechanisms. Also, salicylates may cause protein binding displacement of antidiabetics. Decreased renal clearance may also occur. CLINICAL EFFECTS: Potentiation of hypoglycemic effects may be observed. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Hypoglycemic signs and blood glucose levels should be monitored. Adjust the antidiabetic dose as needed. Particular caution should be taken when salicylates are started or stopped in patients previously stabilized on antidiabetics. DISCUSSION: Additional documentation is necessary to confirm this potential interaction. |
DUETACT, GLIMEPIRIDE, GLIPIZIDE, GLIPIZIDE ER, GLIPIZIDE XL, GLIPIZIDE-METFORMIN, GLYBURIDE, GLYBURIDE-METFORMIN HCL, NATEGLINIDE, PIOGLITAZONE-GLIMEPIRIDE |
| NSAIDs; Salicylates/Lithium SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Decreased renal excretion of lithium, possibly resulting from NSAID-induced prostaglandin inhibition. CLINICAL EFFECTS: May observe increased lithium toxicity. PREDISPOSING FACTORS: Risk factors for lithium toxicity include: renal impairment or worsening of existing renal disease, dehydration, low sodium diet, and concomitant use of multiple medications which may impair renal elimination of lithium (e.g. ARBs, ACE Inhibitors, NSAIDs, diuretics). Patients who require higher therapeutic lithium levels to maintain symptom control are particularly susceptible to these factors. PATIENT MANAGEMENT: The magnitude of this interaction is highly variable. Patients with predisposing factors, e.g. dehydration, renal impairment, or concurrent use of other agents which may impair lithium elimination, are expected to have a higher risk for lithium toxicity. If both drugs are administered, monitor plasma lithium levels and observe the patient for signs and symptoms of lithium toxicity or changes in renal function. Full effects of the addition or an increase in NSAID dose may not be seen for one to two weeks. Adjust the dose of lithium accordingly. If lithium is to be started in a patient stabilized on chronic NSAID therapy, consider starting with a lower lithium dose and titrate slowly as half-life may be prolonged. Monitor lithium concentrations until stabilized on the combination. Counsel the patient to contact their prescriber before starting an OTC NSAID. Assure that patients are familiar with signs and symptoms of lithium toxicity (e.g. new or worsening tremor, nausea/vomiting, diarrhea, ataxia, or altered mental status) and to report signs and symptoms of toxicity. DISCUSSION: Numerous studies and case reports have been documented that administration of a NSAID to a patient stabilized on lithium therapy may result in increased serum lithium levels and possible toxicity. Full effects may take 1 to 2 weeks to develop and may persist for a week after the NSAID is discontinued. |
LITHIUM CARBONATE, LITHIUM CARBONATE ER, LITHIUM CITRATE, LITHIUM CITRATE TETRAHYDRATE, LITHOBID |
| NSAIDs; Aspirin (Non-Cardioprotective)/Beta-Blockers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Unknown; however, possibly related to inhibition of prostaglandin by NSAIDs. CLINICAL EFFECTS: The antihypertensive action of beta-blockers may be decreased. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Monitor patient's blood pressure and adjust the dose of the beta-blocker as needed. DISCUSSION: Concurrent administration of beta-blockers and NSAIDs has been associated with a clinically significant loss in antihypertensive response. The magnitude of the effect of NSAIDs on control of blood pressure by beta-blockers needs to be determined for each anti-inflammatory agent. One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology. |
ACEBUTOLOL HCL, ATENOLOL, ATENOLOL-CHLORTHALIDONE, BETAPACE, BETAPACE AF, BETAXOLOL HCL, BISOPROLOL FUMARATE, BISOPROLOL-HYDROCHLOROTHIAZIDE, BREVIBLOC, BYSTOLIC, CARVEDILOL, CARVEDILOL ER, COREG, COREG CR, ESMOLOL HCL, ESMOLOL HCL-SODIUM CHLORIDE, ESMOLOL HCL-WATER, HEMANGEOL, INDERAL LA, INDERAL XL, INNOPRAN XL, LABETALOL HCL, LABETALOL HCL-WATER, NADOLOL, NEBIVOLOL HCL, PINDOLOL, PROPRANOLOL HCL, PROPRANOLOL HCL ER, PROPRANOLOL-HYDROCHLOROTHIAZID, RAPIBLYK, SOTALOL, SOTALOL AF, SOTALOL HCL, SOTYLIZE, TENORETIC 100, TENORETIC 50, TENORMIN, TIMOLOL MALEATE |
| Acetazolamide; Methazolamide/Aspirin (Greater Than 100 mg); Salicylates SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Acetazolamide and methazolamide may reduce blood pH, causing a shift of salicylates from plasma into tissues (eg, central nervous system). Alternatively, toxicity may be due to salicylate-induced displacement of the carbonic anhydrase inhibitor from its protein binding sites and inhibition of renal tubular secretion. CLINICAL EFFECTS: An increase in the pharmacologic effects of salicylates with possible toxicity may occur. PREDISPOSING FACTORS: High doses of salicylates, low body weight. PATIENT MANAGEMENT: Avoid the combination if possible. If it is necessary to administer these drugs concurrently, monitor salicylate levels and monitor the patient for symptoms of toxicity. Adjust the dose as needed. DISCUSSION: Two young patients with unimpaired renal and hepatic function were found to have developed metabolic acidosis after treatment for glaucoma and joint pain with a combination of salicylates and carbonic anhydrase inhibitors in normal doses.(1) A 67-year old woman and a 75-year old woman taking carbonic anhydrase inhibitors for therapy of glaucoma and high doses of aspirin for arthritis developed severe acid-base imbalance and salicylate intoxication.(2) Neither patient exhibited ill effects when taking high aspirin doses without a carbonic anhydrase inhibitor. Carbonic anhydrase inhibitor-induced acidemia increases the risk of developing salicylate intoxication in patients receiving high aspirin doses. Two elderly patients, who were chronically receiving aspirin developed lethargy, incontinence, and confusion after dosing with acetazolamide.(3) These effects could have been due to either drug (see mechanism). |
ACETAZOLAMIDE, ACETAZOLAMIDE ER, ACETAZOLAMIDE SODIUM, METHAZOLAMIDE |
| Triamterene; Amiloride/Selected NSAIDs; Salicylates SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The exact mechanism is unknown; however, nonsteroidal anti-inflammatory (NSAID) inhibition of prostaglandins may allow triamterene or amiloride- induced nephrotoxicity or hyperkalemia to occur in some patients. CLINICAL EFFECTS: Possible renal failure or hyperkalemia. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: When possible, avoid concurrent therapy with triamterene or amiloride with NSAIDs. If these agents are used concurrently, monitor renal function and serum electrolytes. If decreased renal function or hyperkalemia develops, discontinue both agents. DISCUSSION: Although acute renal failure and hyperkalemia have only been reported in studies and case reports involving indomethacin, diclofenac, flurbiprofen, and ibuprofen with either triamterene or amiloride, the proposed mechanism suggests that all nonsteroidal anti-inflammatory agents may be capable of this interaction. Patients receiving diuretics are at an increased risk of NSAID-induced renal failure. |
AMILORIDE HCL, AMILORIDE-HYDROCHLOROTHIAZIDE, DYRENIUM, TRIAMTERENE, TRIAMTERENE-HYDROCHLOROTHIAZID |
| Valproic Acid/Salicylates SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Multiple mechanisms appear to be involved. Salicylates may displace valproic acid from plasma protein binding sites. Salicylates may also affect the metabolism of valproate by increasing conjugation and decreasing oxidation of valproic acid. CLINICAL EFFECTS: Concurrent use of salicylates may increase the unbound fraction of serum valproic acid concentration, resulting in toxicity. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Patients receiving concurrent salicylate therapy should be observed for signs of valproic acid toxicity (e.g., ataxia, drowsiness, nystagmus, tremor). The dosage of valproic acid may need to be adjusted. DISCUSSION: In two studies involving 6 epileptic children taking valproic acid, concurrent aspirin led to an increase in serum valproic acid free fraction and an increased half-life. Renal clearance of free valproic acid was found to decrease.(1,2) In another study involving 5 children, concurrent valproic acid and aspirin resulted in a decrease in free valproic acid clearance although total valproic acid levels did not change significantly.(3) However, one study reported that the concurrent use of valproic acid and aspirin leads to an increased excretion of valproic acid and a decreased total salicylate excretion.(4) In 3 case reports, aspirin given to children taking valproic acid resulted in valproic acid toxicity (tremor, nystagmus, truncal ataxia). There was an increase in free valproic acid levels in two cases, however, a reduction in the free fraction and the total valproic acid levels occurred in the third patient.(5) In another case report, a patient was maintained on divalproex sodium (2500 mg/day) and aspirin (325 mg/day) with a trough valproate level of 24.7 ng/ml and a total valproate level of 64.0 ng/ml. Five days after aspirin was discontinued for a procedure, trough valproate levels fell to 3.9 ng/ml and a total valproate level fell to 36.0 ng/ml with no change in divalproex dosing.(6) In a study in 7 healthy males, concurrent diflunisal (250 mg twice daily) increased the unbound fraction of valproic acid (200 mg twice daily) by 20%. The area-under-curve (AUC) of 3-oxo-valproic acid increased by 35%. There were no effects on diflunisal levels.(7) |
DEPAKOTE, DEPAKOTE ER, DEPAKOTE SPRINKLE, DIVALPROEX SODIUM, DIVALPROEX SODIUM ER, SODIUM VALPROATE, VALPROATE SODIUM, VALPROIC ACID |
| Codeine/Strong CYP2D6 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Strong inhibitors of CYP2D6 may inhibit the metabolism of codeine to its active form, morphine. CLINICAL EFFECTS: The concurrent administration of codeine and a strong inhibitor of CYP2D6 may result in decreased efficacy of codeine. If a strong CYP2D6 inhibitor is discontinued, the effects of codeine may be increased, including respiratory depression. PREDISPOSING FACTORS: Patients with CYP2D6 ultrarapid, normal, and intermediate metabolizer phenotypes may be affected to a greater extent by CYP2D6 inhibitors. For patients on strong CYP2D6 inhibitors, the predicted phenotype is a CYP2D6 poor metabolizer. Patients who are CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by CYP2D6 inhibition. PATIENT MANAGEMENT: Patients receiving concurrent therapy with codeine and a strong CYP2D6 inhibitor should be observed for decreased effectiveness of codeine. Dose increase of codeine may be required, or an alternative analgesic, such as morphine, may need to be considered. After discontinuation of a CYP2D6 inhibitor, consider reducing the dosage of codeine and monitor the patient for signs and symptoms of respiratory depression or sedation. DISCUSSION: Strong inhibitors of CYP2D6 have been shown to decrease the metabolism of codeine to morphine at CYP2D6. Quinidine has also been shown to decrease cerebrospinal fluid levels of morphine after codeine administration. Concurrent administration resulted in decreased effects of codeine. Strong CYP2D6 inhibitors linked to this monograph are: bupropion, dacomitinib, fluoxetine, hydroquinidine, paroxetine, quinidine and terbinafine. |
APLENZIN, AUVELITY, BUPROPION HCL, BUPROPION HCL SR, BUPROPION XL, CONTRAVE, FLUOXETINE DR, FLUOXETINE HCL, NUEDEXTA, OLANZAPINE-FLUOXETINE HCL, PAROXETINE CR, PAROXETINE ER, PAROXETINE HCL, PAROXETINE MESYLATE, PAXIL, PAXIL CR, PROZAC, QUINIDINE GLUCONATE, QUINIDINE SULFATE, TERBINAFINE HCL, VIZIMPRO, WELLBUTRIN SR, WELLBUTRIN XL |
| SSRIs; SNRIs/Selected NSAIDs; Aspirin SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Serotonin release by platelets plays a role in hemostasis.(1,2) The increased risk of bleeding may be a result of a decrease in serotonin reuptake by platelets. CLINICAL EFFECTS: Concurrent use of a selective serotonin reuptake inhibitor(1-7,13) or a serotonin-norepinephrine reuptake inhibitor(8-10) and a NSAID may result in bleeding. PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with multiple disease-associated factors (e.g. thrombocytopenia, advanced liver disease). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g., anticoagulants, antiplatelets, or corticosteroids. Risk of GI bleed may be increased in patients who are of older age, in poor health status, or who use alcohol or smoke. Risk may also be increased with longer duration of NSAID use and prior history of peptic ulcer disease and/or GI bleeding. Renal impairment has been associated with an elevated risk of GI bleed in patients on SSRIs.(15) PATIENT MANAGEMENT: Selective serotonin reuptake inhibitors(1-7,13) or serotonin-norepinephrine reuptake inhibitors(8-10) and NSAIDs should be used concurrently with caution. Patients should be warned about the increased risk of bleeding and be educated about signs and symptoms of bleeding.(1-11,13) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Discontinue anti-platelet agents in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. DISCUSSION: In a retrospective review of 5 years of data from the Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper gastro-intestinal bleeding in antidepressant users were compared to those in non-antidepressant users. The risk of a bleed in a patient using an NSAID only based on an observed-expected ratio was 4.5 and in a patient using low-dose aspirin only was 2.5. Concurrent use of a selective serotonin reuptake inhibitor with NSAIDs or low-dose aspirin increased the risk of bleeding to 12.2 and 5.2, respectively.(11) In another study, there were 16 cases of upper gastrointestinal bleeding in patients receiving concurrent therapy with selective serotonin reuptake inhibitors and NSAIDs. Adjusted relative risk of bleeding with NSAIDs, selective serotonin reuptake inhibitors, or both were 3.7, 2.6, or 15.6, respectively.(12) |
CELEXA, CITALOPRAM HBR, DESVENLAFAXINE ER, DESVENLAFAXINE SUCCINATE ER, DRIZALMA SPRINKLE, DULOXETINE HCL, DULOXICAINE, EFFEXOR XR, ESCITALOPRAM OXALATE, FETZIMA, FLUOXETINE DR, FLUOXETINE HCL, FLUVOXAMINE MALEATE, FLUVOXAMINE MALEATE ER, LEXAPRO, MILNACIPRAN HCL, OLANZAPINE-FLUOXETINE HCL, PAROXETINE CR, PAROXETINE ER, PAROXETINE HCL, PAROXETINE MESYLATE, PAXIL, PAXIL CR, PRISTIQ, PROZAC, SAVELLA, SERTRALINE HCL, TRINTELLIX, VENLAFAXINE BESYLATE ER, VENLAFAXINE HCL, VENLAFAXINE HCL ER, VIIBRYD, VILAZODONE HCL, ZOLOFT |
| ACE Inhibitors/High-Dose Aspirin SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: NSAIDs inhibit prostaglandin synthesis which can lead to afferent arteriolar vasoconstriction and decreased renal blood flow. ACE inhibitors can cause vasodilation of the efferent renal arteriole which may result in decreased glomerular filtration rate. CLINICAL EFFECTS: Concurrent use of aspirin may result in decreased antihypertensive effects of the ACE inhibitor. Concurrent use of ACE inhibitors with aspirin and diuretics may result in increased risk of acute kidney injury (AKI). PREDISPOSING FACTORS: Low water intake/dehydration, drug sensitivity, greater than 75 years of age, and use of diuretics can lead to hypovolemia and increased risk of AKI. PATIENT MANAGEMENT: Monitor patients receiving doses of aspirin higher than 150 mg daily for decreased antihypertensive effects of their ACE inhibitor. The use of alternative agents may need to be considered. Concurrent use of ACE inhibitors with aspirin and diuretics should be used with caution and monitored for signs of AKI. DISCUSSION: Several studies have documented decreased effectiveness of various ACE inhibitors, including captopril, enalapril, and lisinopril following the addition of aspirin therapy. Conflicting evidence exists on the use of small (less than 150 mg) daily doses of aspirin with ACE inhibitors, although some guidelines still suggest they may be beneficial. In a population based cohort study, the concurrent use of NSAIDs with renin-angiotensin system (RAS) inhibitors in 5,710 hypertensive patients stabilized on antihypertensive therapy required hypertension treatment intensification. Adjusted hazard ratios (HR) for hypertension treatment intensification were 1.34 [95% CI 1.05-1.71] for NSAIDs in general, 1.79 (95% CI 1.15-2.78) for diclofenac and 2.02 (95% CI 1.09-3.77) for piroxicam. There were significant interactions between NSAIDs and angiotensin converting enzyme inhibitors (ACE inhibitors; HR 4.09, 95% CI 2.02-8.27) or angiotensin receptor blockers (ARBs; HR 3.62, 95% CI 1.80-7.31), but not with other antihypertensive drugs. In a computational study, the risk of AKI using triple therapy (combination of a diuretic, renin-angiotensin system (RAS) inhibitor, and NSAID) was assessed. The study found the following factors may increase an individual's susceptibility to AKI: low water intake, drug sensitivity, greater than 75 years of age, and renal impairment.(20,21) In an observational study, current use of a triple therapy combination was associated with an increased rate of acute kidney injury (rate ratio (RR) 1.31, 95% confidence interval (CI) 1.12-1.53). The highest risk of AKI associated with triple therapy were observed in the first 30 days of use (RR 1.82, CI 1.35-2.46).(22) One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology. |
ALTACE, AMLODIPINE BESYLATE-BENAZEPRIL, BENAZEPRIL HCL, BENAZEPRIL-HYDROCHLOROTHIAZIDE, CAPTOPRIL, CAPTOPRIL-HYDROCHLOROTHIAZIDE, ENALAPRIL MALEATE, ENALAPRIL-HYDROCHLOROTHIAZIDE, ENALAPRILAT, EPANED, FOSINOPRIL SODIUM, FOSINOPRIL-HYDROCHLOROTHIAZIDE, LISINOPRIL, LISINOPRIL-HYDROCHLOROTHIAZIDE, LOTENSIN, LOTENSIN HCT, LOTREL, MOEXIPRIL HCL, PERINDOPRIL ERBUMINE, PRESTALIA, QBRELIS, QUINAPRIL HCL, QUINAPRIL-HYDROCHLOROTHIAZIDE, RAMIPRIL, TRANDOLAPRIL, TRANDOLAPRIL-VERAPAMIL ER, VASERETIC, VASOTEC, ZESTORETIC, ZESTRIL |
| Drospirenone/NSAIDs; Salicylates SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Drospirenone has antimineralocorticoid activity and may cause hyperkalemia. NSAIDs may also increase potassium levels.(1) CLINICAL EFFECTS: Concurrent use of drospirenone and NSAIDs may result in hyperkalemia.(1) PREDISPOSING FACTORS: Renal insufficiency, hepatic dysfunction, adrenal insufficiency, and use of potassium supplements, ACE inhibitors, angiotensin II receptor antagonists, heparin, and potassium-sparing diuretics may increase potassium levels.(1) PATIENT MANAGEMENT: Patients receiving drospirenone with a NSAID should have their serum potassium level checked during the first treatment cycle.(1) DISCUSSION: Drospirenone has antimineralocorticoid activity comparable to 25 mg of spironolactone and may result in hyperkalemia. Concurrent use of NSAIDs may also increase potassium levels.(1) Occasional or chronic use of NSAIDs was not restricted in clinical trials of drospirenone.(1) |
ANGELIQ, BEYAZ, DROSPIRENONE-ETH ESTRA-LEVOMEF, DROSPIRENONE-ETHINYL ESTRADIOL, JASMIEL, LO-ZUMANDIMINE, LORYNA, NEXTSTELLIS, NIKKI, OCELLA, SAFYRAL, SLYND, SYEDA, TYDEMY, VESTURA, YASMIN 28, YAZ, ZARAH, ZUMANDIMINE |
| Opioids/Buprenorphine; Pentazocine SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Buprenorphine is a partial agonist at mu-opiate receptors, exhibiting a ceiling effect at which higher doses produce no further effect. Pentazocine is a mixed agonist-antagonist at opiate receptors.(1) Full mu-opioid agonists (e.g., morphine, methadone) continue to have increased effects at higher doses without ceiling effects.(2) CLINICAL EFFECTS: Concurrent use of buprenorphine or pentazocine with other opioids in opioid dependent patients may result in withdrawal symptoms. Concurrent use in other patients may result in additive or decreased analgesia and decreased opioid side effects. PREDISPOSING FACTORS: Patients dependent on opioids or who take higher dosages of opioids may be more likely to experience withdrawal symptoms with concurrent use. PATIENT MANAGEMENT: Use buprenorphine and pentazocine with caution in patients maintained or dependent on other opioids and monitor for signs of withdrawal. In other patients, also monitor for changes in analgesic effects. The manufacturer of Sublocade states buprenorphine may precipitate opioid withdrawal in patients who are currently physically dependent on full opioid agonists. The risk of withdrawal may be increased if buprenorphine is given less than 6 hours after short-acting opioids (such as heroin, morphine) and less than 24 hours after long-acting opioids (such as methadone).(3) DISCUSSION: Concurrent use of buprenorphine with other opioids in opioid dependent patients could result in withdrawal symptoms. Concurrent use in other patients may result in additive or decreased analgesia, decreased opioid side effects, and/or renarcotization.(2) In clinical trials, administration of buprenorphine injection produced withdrawal symptoms in patients maintained on methadone (30 mg daily) when administered 2 hours post-methadone,(4) but not when administered 20 hours post-methadone.(5) In another study, sublingual buprenorphine produced withdrawal symptoms in patients maintained on methadone. Symptoms were more pronounced in patients maintained on 60 mg daily doses than in patients maintained on 30 mg daily doses.(6) In a study of 10 patients maintained on methadone (100 mg daily), only three were able to tolerate escalating sublingual doses of buprenorphine/naloxone up to 32/8 mg. Split doses produced less withdrawal symptoms than full doses.(7) In a case report, a heroin-user maintained in a buprenorphine-maintenance program began stockpiling his buprenorphine instead of ingesting it and began using heroin. He then decided to re-initiate treatment on his own and ingested between 80 and 88 mg of buprenorphine over a two day period and experienced extreme withdrawal symptoms, despite restarting heroin during these symptoms. Methadone relieved his withdrawal symptoms.(8) |
BELBUCA, BRIXADI, BUPRENORPHINE, BUPRENORPHINE HCL, BUPRENORPHINE-NALOXONE, BUTRANS, PENTAZOCINE-NALOXONE HCL, SUBLOCADE, SUBOXONE, ZUBSOLV |
| Gabapentinoids/Opioids (IR & ER) SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Opioid-induced reduction in GI motility may increase the absorption of gabapentin and pregabalin.(1) Gabapentin and pregabalin may reverse opioid-induced tolerance of respiratory depression.(2) Concurrent use may result in profound sedation, respiratory depression, coma, and/or death.(3) CLINICAL EFFECTS: Concurrent use of opioids may result in elevated levels of and toxicity from gabapentin and pregabalin, including profound sedation, respiratory depression, coma, and/or death.(1-7) PREDISPOSING FACTORS: Patients who are elderly, are taking other CNS depressants, have decreased renal function, and/or have conditions that reduce lung function (e.g. Chronic Obstructive Pulmonary Disease [COPD]) may be at a higher risk of this interaction. PATIENT MANAGEMENT: Limit prescribing opioid analgesics and gabapentinoids to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a gabapentinoid with an opioid analgesic, prescribe a lower initial dose of the gabapentinoid than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a gabapentinoid, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(8) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(9) DISCUSSION: In a study in 12 healthy males, administration of a single dose of morphine (60 mg sustained release) increased the area-under-curve (AUC) of a single dose of gabapentin (600 mg) by 44%.(1,3,4) There were no affects on the pharmacokinetics of morphine.(1,3,4) The combination of gabapentin plus morphine increased pain tolerance over the combination of morphine plus placebo. Side effects were not significantly different between morphine plus placebo and morphine plus gabapentin.(1) A retrospective, case-control study of opioid users in Ontario, Canada between August 1, 1997 and December 31, 2013 who died of an opioid-related cause matched cases to up to 4 controls who also used opioids. Use of gabapentin in the 120 days prior to death resulted in a significant increase in odds of opioid-related death (OR 1.99, CI=1.61-2.47, p<0.001), compared to opioid use alone. Use of moderate dose (900 mg to 1,799 mg daily) or high dose (>= 1,800 mg daily) gabapentin increased the odds of opioid-related death 60% compared to opioid use without gabapentin. Review of gabapentin prescriptions from calendar year 2013 found that 46% of gabapentin users received at least 1 opioid prescription.(3) Among 49 case reports submitted to FDA over a 5 year period (2012-2017), 12 people died from respiratory depression with gabapentinoids. Two randomized, double-blind, placebo-controlled clinical trials in healthy people, three observational studies, and several studies in animals were reviewed. A trial showed that using pregabalin alone and using it with an opioid pain reliever can depress breathing function. Three observational studies showed a relationship between gabapentinoids given before surgery and respiratory depression occurring after surgery. Several animal studies also showed that pregabalin plus opioids can depress respiratory function.(7) A retrospective cohort study evaluated the risk of mortality among Medicare beneficiaries aged 65 and older who were taking gabapentin with or without concurrent use of opioids. All-cause mortality in gabapentin users compared to duloxetine users was 12.16 per 1,000 person years vs. 9.94 per 1,000 person years, respectively. Adjusted for covariates, the risk of all-cause mortality among gabapentin users on high-dose opioids was more than double the control group (hazard ratio (HR) 2.03, CI=1.19-3.46).(10) |
GABAPENTIN, GABAPENTIN ER, GABARONE, GRALISE, HORIZANT, LYRICA, LYRICA CR, NEURONTIN, PREGABALIN, PREGABALIN ER, RELGAABI |
| Opioids/Butorphanol SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Butorphanol antagonize mu-opiate receptors. Other opioids agonize mu-opiate receptors.(1) CLINICAL EFFECTS: Concurrent use of butorphanol with other opioids in opioid dependent patients may result in withdrawal symptoms. Concurrent use in other patients may result in additive or decreased analgesia and decreased opioid side effects. PREDISPOSING FACTORS: Patients dependent on opioids may be more likely to experience withdrawal symptoms with concurrent use. Patients using higher doses of opioids may also be at a higher risk. PATIENT MANAGEMENT: Use butorphanol with caution in patients maintained or dependent on other opioids and monitor for signs of withdrawal. In other patients, also monitor for changes in analgesic effects. DISCUSSION: Because butorphanol antagonizes mu-opiate receptors and other opioids agonize mu-opiate receptors, concurrent use of buprenorphine with other opioids in opioid dependent patients may result in withdrawal symptoms. Concurrent use in other patients may result in additive or decreased analgesia and decreased opioid side effects.(1) In a study in patients maintained on methadone, butorphanol produced withdrawal symptoms comparable to naloxone.(2) In a case report, the use of remifentanil for conscious sedation in a patient maintained on butorphanol produced severe withdrawal symptoms.(3) |
BUTORPHANOL TARTRATE |
| Opioids/Nalbuphine SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Nalbuphine(1) antagonizes mu-opiate receptors. Other opioids agonize mu-opiate receptors. CLINICAL EFFECTS: Concurrent use of nalbuphine with other opioids in opioid dependent patients may result in withdrawal symptoms. Concurrent use in other patients may result in additive or decreased analgesia, decreased opioid side effects, and/or renarcotization. PREDISPOSING FACTORS: Patients dependent on opioids may be more likely to experience withdrawal symptoms with concurrent use. In opioid naive patients, higher doses of nalbuphine may result in decreased analgesic effects. PATIENT MANAGEMENT: Use nalbuphine with caution in patients maintained or dependent on other opioids and monitor for signs of withdrawal. In other patients, also monitor for changes in analgesic effects. If nalbuphine is used to reverse opioid anesthesia, monitor patients for renarcotization. DISCUSSION: Nalbuphine has been successfully used as an adjunct to morphine without decreasing analgesic effects.(2,3) However, other studies reported increased morphine requirements in patients who had initially received nalbuphine.(4,5) Nalbuphine has been used to reverse fentanyl anesthesia;(8-13) however, patients often required additional pain medication(5-7) and some studies reported renarcotization after the effects of nalbuphine wore off.(9,10) Nalbuphine has also been used to prevent epidural fentanyl,(13) morphine(14-16), and hydromorphone induced pruritus;(17-18) however, one study reported shortening of the duration of analgesia(16) and another reported increased PCA demands.(17) In methadone-dependent subjects, administration of nalbuphine produced withdrawal symptoms similar to naloxone.(19,20) Administration of nalbuphine to patients maintained on controlled-release morphine resulted in withdrawal symptoms.(20,21) |
NALBUPHINE HCL |
| Ibrutinib/Selected Anticoagulants; Antiplatelets SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Ibrutinib administration lowers platelet count in the majority of patients.(1,2) In addition, ibrutinib has been shown to inhibit collagen-mediated platelet aggregation.(3-4) Bleeding has been reported with the use of ibrutinib,(1-4) anticoagulants, or antiplatelets alone. CLINICAL EFFECTS: Concurrent use of ibrutinib with either anticoagulants or antiplatelets may increase the risk of hemorrhage. PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: The Canadian product monograph for ibrutinib recommends concurrent use with anticoagulants or antiplatelets should be approached with caution. If therapeutic anticoagulation is required, consider temporarily withholding ibrutinib therapy until stable anticoagulation in achieved.(2) The US prescribing information for ibrutinib states patients receiving concurrent therapy with ibrutinib and anticoagulants and/or antiplatelets should be closely monitored for changes in platelet count or in International Normalized Ratio (INR). Carefully weigh the risks vs. benefits of concurrent therapy in patients with significant thrombocytopenia. If a bleeding event occurs, follow manufacturer instructions for ibrutinib dose adjustment.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug. DISCUSSION: Bleeding has been reported with ibrutinib alone.(1-3) Across 27 clinical trials, grade 3 or higher bleeding events, e.g. subdural hematoma, gastrointestinal bleeding or hematuria, have occurred in up to 4% of patients, with 0.4% fatality. Grade 3 or 4 thrombocytopenia occurred in 5-19% of patients. Bleeding events of any grade occurred in 39% of patients treated with ibrutinib.(1) Concurrent use of anticoagulants or antiplatelets has been reported to increase the risk for major bleeding. In clinical trials, major bleeding occurred in 3.1% of patients taking ibrutinib without concurrent anticoagulants or antiplatelets, 4.4% of patients on concurrent antiplatelets with or without anticoagulants, and 6.1% of patients on concurrent anticoagulants with or without antiplatelets.(1) In an open-label, phase 2 trial of patients with relapsed/refractory mantle cell lymphoma on ibrutinib, 61 patients (55%) on concurrent anticoagulants or antiplatelets had a higher rate of bleeding (69% any grade, 8% grade 3-4) than patients not on anticoagulants or antiplatelets (28% any grade, 4% grade 3-4).(5) A retrospective trial found a hazard ratio of 20 (95% CI, 2.1-200) for patients on ibrutinib with concurrent anticoagulants and antiplatelets. There was a trend towards an increased bleeding risk in patients on either anticoagulants or antiplatelets, but this was not statistically significant on multivariate analysis.(6) A case report of 2 patients with chronic lymphocytic leukemia (CLL) on ibrutinib and dabigatran demonstrated no stroke nor bleeding events during the mean 11.5 month follow-up.(7) A case report of 4 patients with lymphoproliferative disease on concurrent dabigatran and ibrutinib demonstrated no stroke nor major bleeding events. 1 patient experienced grade 2 conjunctival hemorrhage whilst on both ibrutinib and dabigatran. The anticoagulant was withheld and successfully re-initiated at a lower dose with no further bleeding events.(8) |
IMBRUVICA |
| Opioids (Immediate Release)/Benzodiazepines SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Concurrent use of opioids and benzodiazepines may result in additive CNS depression.(1) CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as benzodiazepines, may result in profound sedation, respiratory depression, coma, and/or death.(1) PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as benzodiazepines to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3) DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(4) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(5) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(6) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(7) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(8) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(9) A study of 315,428 privately insured patients who filled at least one prescription for an opioid from 2001 to 2013 were enrolled in a retrospective study. Concurrent use of a benzodiazepine was recorded as having at least one day of overlap in a given calendar year. Baseline characteristics among opioid users with concurrent use of a benzodiazepine were older (44.5 v. 42.4, p<0.001), less likely to be men (35% v. 43%, p<0.001), and had a higher prevalence rate of every comorbidity examined (p<0.001). The proportion of opioid users with concurrent benzodiazepine use nearly doubled from 9% in 2001 to 17% in 2013. The primary outcome was an emergency room visit or inpatient admission for opioid overdose within a calendar year. Among all opioid users, the annual adjusted incidence for the primary outcome was 1.16% without concurrent benzodiazepine use compared to 2.42% with concurrent benzodiazepine use (OR 2.14; 95% CI 2.05-2.24; p<0.001). Intermittent opioid users (1.45% v. 1.02%; OR 1.42; 95% CI 1.33-1.51; p<0.001) and chronic opioid users (5.36% v. 3.13%; OR 1.81; 95% CI 1.67-1.96; p<0.001) also experienced a higher adjusted incidence of the primary outcome with concurrent benzodiazepine use compared to without concurrent benzodiazepine use, respectively.(10) In a nested case-control study of adults with a new opioid dispensing between 2010-2018, patients with concurrent use of an opioid with a benzodiazepine were significantly more likely to have opioid-related overdose compared to patients receiving opioids, benzodiazepines, or neither (OR 9.28; 95% CI 7.87, 10.93). Longer concurrent use of 1-7, 8-30, and 31-90 days was associated with 4.6, 12.1, and 26.7-fold higher likelihood of opioid-related overdose (p<0.01). Patients with overlapping prescriptions during previous 0-30, 31-60, and 61-90 days were 13.2, 6.0, and 3.2-times more likely to experience an overdose (p<0.01).(11) |
ALPRAZOLAM, ALPRAZOLAM ER, ALPRAZOLAM INTENSOL, ALPRAZOLAM ODT, ALPRAZOLAM XR, ATIVAN, BYFAVO, CHLORDIAZEPOXIDE HCL, CHLORDIAZEPOXIDE-AMITRIPTYLINE, CHLORDIAZEPOXIDE-CLIDINIUM, CLOBAZAM, CLONAZEPAM, CLORAZEPATE DIPOTASSIUM, DIAZEPAM, DORAL, ESTAZOLAM, FLURAZEPAM HCL, HALCION, KLONOPIN, LIBRAX, LORAZEPAM, LORAZEPAM INTENSOL, LOREEV XR, MIDAZOLAM, MIDAZOLAM HCL, MIDAZOLAM HCL-0.8% NACL, MIDAZOLAM HCL-0.9% NACL, MIDAZOLAM HCL-D5W, MIDAZOLAM HCL-NACL, MIDAZOLAM-0.9% NACL, MIDAZOLAM-NACL, MKO (MIDAZOLAM-KETAMINE-ONDAN), NAYZILAM, ONFI, OXAZEPAM, QUAZEPAM, RESTORIL, SYMPAZAN, TEMAZEPAM, TRIAZOLAM, VALIUM, VALTOCO, XANAX, XANAX XR |
| Opioids (Immediate Release)/Sleep Drugs SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Concurrent use of opioids and sleep drugs may result in additive CNS depression and sleep-related disorders.(1) CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as sleep drugs, may result in profound sedation, respiratory depression, coma, and/or death.(1) Concurrent use of opioids with eszopiclone, zaleplon, or zolpidem may increase the risk of sleep-related disorders including central sleep apnea and sleep-related hypoxemia and complex sleep behaviors like sleepwalking, sleep driving, and other activities while not fully awake. Rarely, serious injuries or death have resulted from complex sleep behaviors.(2) PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as sleep drugs to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(3) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Eszopiclone, zaleplon, and zolpidem are contraindicated in patients who have had a previous episode of complex sleep behavior.(2) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(4) DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10) As of April 2019, the FDA had identified 66 cases of complex sleep behaviors with eszopiclone, zaleplon, or zolpidem, of which 20 cases resulted in death and the remainder resulted in serious injuries. It was not reported how many of the cases involved concomitant use of other CNS depressants.(2) |
AMBIEN, AMBIEN CR, BELSOMRA, DAYVIGO, EDLUAR, ESZOPICLONE, LUNESTA, QUVIVIQ, RAMELTEON, ROZEREM, ZALEPLON, ZOLPIDEM TARTRATE, ZOLPIDEM TARTRATE ER |
| Opioids (Extended Release)/Muscle Relaxants SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Concurrent use of opioids and muscle relaxants may result in additive CNS depression.(1) CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as muscle relaxants, may result in profound sedation, respiratory depression, coma, and/or death.(1) PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as muscle relaxants to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3) DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(4) A retrospective cohort study compared the risk of opioid overdose associated with concomitant use of opioids and skeletal muscle relaxants versus opioid use alone. The study examined two types of opioid users (naive opioid use and prevalent opioid use) with and without exposure to skeletal muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the naive and prevalent opioid user cohorts, respectively, generating a combined estimate of 1.21. The risk increased with treatment duration (less than or equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80) and for the use of baclofen and carisoprodol (HR 1.83 and 1.84, respectively). Elevated risk was associated with concomitant users with daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and 1.39, respectively).(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10) |
BUPRENORPHINE, BUTRANS, CONZIP, FENTANYL, HYDROCODONE BITARTRATE ER, HYDROMORPHONE ER, HYSINGLA ER, MORPHINE SULFATE ER, MS CONTIN, NUCYNTA ER, OXYCODONE HCL ER, OXYCONTIN, OXYMORPHONE HCL ER, TAPENTADOL ER, TRAMADOL HCL ER, XTAMPZA ER |
| Aldosterone Receptor Antagonists/NSAIDs; Salicylates SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The exact mechanism is unknown; however, nonsteroidal anti-inflammatory (NSAID) inhibition of prostaglandins may allow eplerenone, finerenone, or spironolactone-induced nephrotoxicity or hyperkalemia to occur in some patients.(1-3) In some patients, NSAIDs may reduce the diuretic, natriuretic and antihypertensive effects of eplerenone, finerenone, or spironolactone.(1-3) CLINICAL EFFECTS: Concurrent use of eplerenone, finerenone, or spironolactone with NSAIDs may result in renal failure or hyperkalemia. The effects of the diuretic, natriuretic, or antihypertensive effects of eplerenone, finerenone, or spironolactone may be decreased.(1-3) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: When possible, avoid concurrent therapy with eplerenone, finerenone, or spironolactone with NSAIDs. If these agents are used concurrently, monitor renal function and serum electrolytes. If decreased renal function or hyperkalemia develops, discontinue both agents. The manufacturer of eplerenone recommends checking serum potassium and serum creatinine within 3-7 days of concurrent therapy with NSAIDs.(1) The manufacturer of spironolactone states concurrent use with NSAIDs may lead to severe hyperkalemia and extreme caution should be used during concurrent therapy.(2) DISCUSSION: Although acute renal failure and hyperkalemia have only been reported in studies and case reports involving indomethacin, diclofenac, flurbiprofen, and ibuprofen with either triamterene or amiloride, the proposed mechanism suggests that all nonsteroidal anti-inflammatory agents may be capable of this interaction with all potassium-sparing diuretics. Patients receiving diuretics are at an increased risk of NSAID-induced renal failure. |
ALDACTONE, CAROSPIR, EPLERENONE, INSPRA, KERENDIA, SPIRONOLACTONE, SPIRONOLACTONE-HCTZ |
| Mifepristone (Cushing)/Anticoagulants; Antiplatelets SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Mifepristone is an antagonist at the progesterone receptor which can result in endometrium thickening, cystic dilatation of endometrial glands, or excessive vaginal bleeding. Concurrent use with anticoagulants or antiplatelets may further increase risk. CLINICAL EFFECTS: The concurrent use of mifepristone with anticoagulants or antiplatelets may result in endometrium thickening, cystic dilatation of endometrial glands, or excessive vaginal bleeding. PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: The manufacturer of mifepristone states that mifepristone should be used with caution in patients receiving concurrent anticoagulant or antiplatelet therapy.(1) If concurrent therapy is deemed medically necessary, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. Women experiencing vaginal bleeding during concurrent use should be referred to a gynecologist for further evaluation. DISCUSSION: The manufacturer of mifepristone states that mifepristone should be used with caution in patients receiving concurrent anticoagulant or antiplatelet therapy.(1) |
KORLYM, MIFEPRISTONE |
| Desmopressin/Agents with Hyponatremia Risk SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Carbamazepine, chlorpromazine, lamotrigine, NSAIDs, opioids, SSRIs, thiazide diuretics, and/or tricyclic antidepressants increase the risk of hyponatremia.(1-3) CLINICAL EFFECTS: Concurrent use may increase the risk of hyponatremia with desmopressin.(1-3) PREDISPOSING FACTORS: Predisposing factors for hyponatremia include: polydipsia, renal impairment (eGFR < 50 ml/min/1.73m2), illnesses that can cause fluid/electrolyte imbalances, age >=65, medications that cause water retention and/or increase the risk of hyponatremia (glucocorticoids, loop diuretics). PATIENT MANAGEMENT: The concurrent use of agents with a risk of hyponatremia with desmopressin may increase the risk of hyponatremia. If concurrent use is deemed medically necessary, make sure serum sodium levels are normal before beginning therapy and consider using the desmopressin nasal 0.83 mcg dose. Consider measuring serum sodium levels more frequently than the recommended intervals of: within 7 days of concurrent therapy initiation, one month after concurrent therapy initiation and periodically during treatment. Counsel patients to report symptoms of hyponatremia, which may include: headache, nausea/vomiting, feeling restless, fatigue, drowsiness, dizziness, muscle cramps, changes in mental state (confusion, decreased awareness/alertness), seizures, coma, and trouble breathing. Counsel patients to limit the amount of fluids they drink in the evening and night-time and to stop taking desmopressin if they develop a stomach/intestinal virus with nausea/vomiting or any nose problems (blockage, stuffy/runny nose, drainage).(1) DISCUSSION: In clinical trials of desmopressin for the treatment of nocturia, 4 of 5 patients who developed severe hyponatremia (serum sodium <= 125 mmol/L) were taking systemic or inhaled glucocorticoids. Three of these patients were also taking NSAIDs and one was receiving a thiazide diuretic.(2) Drugs associated with hyponatremia may increase the risk, including loop diuretics, carbamazepine, chlorpromazine, glucocorticoids, lamotrigine, NSAIDs, opioids, SSRIs, thiazide diuretics, and/or tricyclic antidepressants.(1,3-4) |
DDAVP, DESMODA, DESMOPRESSIN ACETATE, NOCDURNA |
| Buprenorphine for MAT/Muscle Relaxants SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Concurrent use of buprenorphine and muscle relaxants may result in additive CNS depression.(1,2) CLINICAL EFFECTS: Concurrent use of buprenorphine and other CNS depressants, such as muscle relaxants, may result in profound sedation, respiratory depression, coma, and/or death.(1,2) PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. PATIENT MANAGEMENT: Medication assisted treatment (MAT) with buprenorphine is not contraindicated in patients taking CNS depressants; however, discontinuation of CNS depressants is preferred in most cases. In some cases, monitoring at a higher level of care for tapering may be appropriate. In others, gradual tapering or decreasing to the lowest effective dose of the CNS depressant is appropriate. Ensure that other health care providers prescribing other CNS depressants are aware of the patient's buprenorphine treatment.(2) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(3) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing opioid reversal agents (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(4) DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) A retrospective cohort study compared the risk of opioid overdose associated with concomitant use of opioids and skeletal muscle relaxants versus opioid use alone. The study examined two types of opioid users (naive opioid use and prevalent opioid use) with and without exposure to skeletal muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the naive and prevalent opioid user cohorts, respectively, generating a combined estimate of 1.21. The risk increased with treatment duration (less than or equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80) and for the use of baclofen and carisoprodol (HR 1.83 and 1.84, respectively). Elevated risk was associated with concomitant users with daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and 1.39, respectively).(6) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(7) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(8) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(9) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(10) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(11) While concomitant use of MAT with CNS depressants increases the risk of adverse reactions, barriers to MAT can pose a greater risk of morbidity and mortality due to opioid use disorder.(2) |
BRIXADI, BUPRENORPHINE HCL, BUPRENORPHINE-NALOXONE, SUBLOCADE, SUBOXONE, ZUBSOLV |
| Aliskiren/NSAIDs; Salicylates SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The exact mechanism is unknown. It is believed to be related to inhibition of prostaglandin synthesis by the NSAIDs. Use of an NSAID in combination with aliskiren, whose hypotensive effects may be related to the increase in hypotensive prostaglandins, may negate any decrease in blood pressure. CLINICAL EFFECTS: Concurrent use of aliskiren with NSAIDs may result in decreased antihypertensive effects. In patients with existing renal impairment, the use of these agents together may also result in further deterioration of renal clearance caused by renal hypoperfusion. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Patients maintained on aliskiren should be monitored for a loss of blood pressure control and a change in renal function if an NSAID is added to their regimen. Patients receiving concurrent therapy may require higher doses of aliskiren. If blood pressure control cannot be achieved or if the patient's renal function deteriorates, the NSAID may need to be discontinued. Patients should be monitored for hypotension if NSAIDs are withdrawn from concurrent aliskiren therapy. DISCUSSION: Indomethacin has been shown to inhibit the antihypertensive effect of captopril, cilazapril, enalapril, losartan, perindopril, and valsartan. Ibuprofen has been shown to decrease the antihypertensive effects of captopril. Two separate case reports describe individuals suspected of ACEI-associated angioedema precipitated by NSAIDs. Both cases reported symptom resolution after cessation of the NSAID. Studies have shown that sulindac does not affect the antihypertensive effects of captopril and enalapril. |
ALISKIREN, TEKTURNA |
| Codeine; Levorphanol (IR)/Slt Antipsychotics; Phenothiazines SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Concurrent use of opioids such as codeine and levorphanol and antipsychotics, including phenothiazine derivatives, may result in additive CNS depression.(1) CLINICAL EFFECTS: Concurrent use of opioids such as codeine and levorphanol and other CNS depressants, such as antipsychotics, including phenothiazine derivatives, may result in profound sedation, respiratory depression, coma, and/or death.(1) PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. PATIENT MANAGEMENT: Limit prescribing opioid analgesics such as codeine and levorphanol with CNS depressants such as antipsychotics, including phenothiazine derivatives, to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3) DISCUSSION: A nested case-control study looked at the relationship between antipsychotic use and risk of acute respiratory failure. Current use of antipsychotics was associated with a 2.33-fold increase in risk of respiratory failure compared to no use of antipsychotics. The risk was also significantly increased in patients with recent use of antipsychotics (within the past 15-30 days, OR = 1.79) and recent past use (within 31-90 days OR = 1.41). The risk increased with higher doses and longer duration of use.(4) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10) |
ABILIFY, ABILIFY ASIMTUFII, ABILIFY MAINTENA, ADASUVE, ARIPIPRAZOLE, ARIPIPRAZOLE ODT, ARISTADA, ARISTADA INITIO, ASENAPINE MALEATE, BARHEMSYS, CAPLYTA, CHLORPROMAZINE HCL, CLOZAPINE, CLOZAPINE ODT, CLOZARIL, COMPAZINE, COMPRO, DROPERIDOL, ERZOFRI, FANAPT, FLUPHENAZINE DECANOATE, FLUPHENAZINE HCL, GEODON, HALOPERIDOL, HALOPERIDOL DECANOATE, HALOPERIDOL LACTATE, INVEGA, INVEGA HAFYERA, INVEGA SUSTENNA, INVEGA TRINZA, LATUDA, LOXAPINE, LURASIDONE HCL, MOLINDONE HCL, NUPLAZID, OLANZAPINE, OLANZAPINE ODT, OLANZAPINE-FLUOXETINE HCL, OPIPZA, PALIPERIDONE ER, PERPHENAZINE, PERPHENAZINE-AMITRIPTYLINE, PHENERGAN, PIMOZIDE, PROCHLORPERAZINE, PROCHLORPERAZINE EDISYLATE, PROCHLORPERAZINE MALEATE, PROMETHAZINE HCL, PROMETHAZINE HCL-0.9% NACL, PROMETHAZINE VC, PROMETHAZINE-CODEINE, PROMETHAZINE-DM, PROMETHAZINE-PHENYLEPHRINE HCL, PROMETHEGAN, QUETIAPINE FUMARATE, QUETIAPINE FUMARATE ER, REXULTI, SAPHRIS, SECUADO, SEROQUEL, SEROQUEL XR, THIORIDAZINE HCL, THIORIDAZINE HYDROCHLORIDE, THIOTHIXENE, TRIFLUOPERAZINE HCL, VERSACLOZ, VRAYLAR, ZIPRASIDONE HCL, ZIPRASIDONE MESYLATE, ZYPREXA, ZYPREXA RELPREVV, ZYPREXA ZYDIS |
| Codeine; Dihydrocodeine; Levorphanol (IR)/Risperidone SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Concurrent use of opioids such as codeine or levorphanol and antipsychotics such as risperidone may result in additive CNS depression.(1) CLINICAL EFFECTS: Concurrent use of opioids such as codeine or levorphanol and other CNS depressants, such as risperidone, may result in profound sedation, respiratory depression, coma, and/or death.(1) PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. PATIENT MANAGEMENT: Limit prescribing opioid analgesics such as codeine or levorphanol with CNS depressants such as risperidone to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing opioid reversal agents (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3) DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(4) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(5) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(6) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(7) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(8) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(9) |
PERSERIS, RISPERDAL, RISPERDAL CONSTA, RISPERIDONE, RISPERIDONE ER, RISPERIDONE ODT, RYKINDO, UZEDY |
| Opioids (Immediate Release)/Selected Stimulants SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Opioids and stimulants exhibit opposing effects on the CNS. CLINICAL EFFECTS: Concurrent use of opioids and stimulants may have unpredictable effects and may mask overdose symptoms of the opioid, such as drowsiness and inability to focus. PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS stimulants such as amphetamines to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(1) Monitor patients receiving concurrent therapy for signs of substance abuse. Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness. Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program). DISCUSSION: A total of 70,237 persons died from drug overdoses in the United States in 2017; approximately two thirds of these deaths involved an opioid.(2). The CDC analyzed 2016-2017 changes in age-adjusted death rates involving cocaine and psychostimulants by demographic characteristics, urbanization levels, U.S. Census region, 34 states, and the District of Columbia (DC). The CDC also examined trends in age-adjusted cocaine-involved and psychostimulant-involved death rates from 2003 to 2017 overall, as well as with and without co-involvement of opioids. Among all 2017 drug overdose deaths, 13,942 (19.8%) involved cocaine, and 10,333 (14.7%) involved psychostimulants. Death rates increased from 2016 to 2017 for both drug categories across demographic characteristics, urbanization levels, Census regions, and states. In 2017, opioids were involved in 72.7% and 50.4% of cocaine-involved and psychostimulant-involved overdoses, respectively, and the data suggest that increases in cocaine-involved overdose deaths from 2012 to 2017 were driven primarily by synthetic opioids.(3) There was opioid co-involvement in 72.7 percent of cocaine and 50.4 percent of stimulant-involved overdose deaths. This was largely driven by synthetic opioids such as fentanyl. However, stimulant-involved overdose without opioid co-involvement is also increasing.(2) |
ADDERALL, ADDERALL XR, ADZENYS XR-ODT, AMPHETAMINE ER ODT, AMPHETAMINE SULFATE, APTENSIO XR, ARYNTA, AZSTARYS, CONCERTA, COTEMPLA XR-ODT, DAYTRANA, DESOXYN, DEXEDRINE, DEXMETHYLPHENIDATE HCL, DEXMETHYLPHENIDATE HCL ER, DEXTROAMPHETAMINE SULFATE, DEXTROAMPHETAMINE SULFATE ER, DEXTROAMPHETAMINE-AMPHET ER, DEXTROAMPHETAMINE-AMPHETAMINE, DYANAVEL XR, EVEKEO, FOCALIN, FOCALIN XR, JORNAY PM, LISDEXAMFETAMINE DIMESYLATE, METADATE CD, METHAMPHETAMINE HCL, METHYLIN, METHYLPHENIDATE, METHYLPHENIDATE ER, METHYLPHENIDATE ER (LA), METHYLPHENIDATE HCL, METHYLPHENIDATE HCL CD, METHYLPHENIDATE HCL ER (CD), MYDAYIS, PROCENTRA, QUILLICHEW ER, QUILLIVANT XR, RELEXXII, RITALIN, VYVANSE, XELSTRYM, ZENZEDI |
| Dichlorphenamide/Aspirin (Less Than or Equal To 325 mg) SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Carbonic anhydrase inhibitors (eg, acetazolamide) may reduce blood pH, causing a shift of salicylates from plasma into tissues (eg, central nervous system).(1) Alternatively, toxicity may be due to salicylate-induced displacement of the carbonic anhydrase inhibitor from its protein binding sites and inhibition of renal tubular secretion. CLINICAL EFFECTS: An increase in the pharmacologic effects of salicylates with possible toxicity may occur. Anorexia, tachypnea, lethargy, and coma have been reported.(1) PREDISPOSING FACTORS: High doses of salicylates, low body weight. PATIENT MANAGEMENT: The concurrent use of high-dose aspirin or other salicylates with dichlorphenamide is contraindicated. If it is necessary to administer a low-dose salicylate concurrently, use the lowest dose possible or replace it with a non-salicylate anti-inflammatory agent. Monitor salicylate levels and serum bicarbonate concentrations, and monitor the patient for symptoms of toxicity. Adjust the dose as needed.(1) DISCUSSION: An 8-year-old boy with unimpaired renal and hepatic function was found to have developed metabolic acidosis after treatment for glaucoma and joint pain with a combination of aloxiprin 3.6 gram daily and dichlorphenamide 25 mg three times daily. His symptoms resolved after discontinuation of both aloxiprin and dichlorphenamide and did not recur on subsequent therapy with naproxen and dichlorphenamide.(2) A 75-year old woman taking dichlorphenamide 100 mg to 150 mg daily for therapy of glaucoma and high doses of aspirin (975 mg 4 to 5 times daily) for arthritis developed severe acid-base imbalance and salicylate intoxication. The patient did not exhibit ill effects when taking high aspirin doses without dichlorphenamide.(3) |
DICHLORPHENAMIDE, KEVEYIS, ORMALVI |
| Methadone (Immediate Release)/Selected Muscle Relaxants SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Concurrent use of methadone and muscle relaxants may result in additive CNS depression.(1) CLINICAL EFFECTS: Concurrent use of methadone and other CNS depressants, such as muscle relaxants, may result in profound sedation, respiratory depression, coma, and/or death.(1) PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. PATIENT MANAGEMENT: Limit prescribing methadone with CNS depressants such as muscle relaxants to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3) DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(4) A retrospective cohort study compared the risk of opioid overdose associated with concomitant use of opioids and skeletal muscle relaxants versus opioid use alone. The study examined two types of opioid users (naive opioid use and prevalent opioid use) with and without exposure to skeletal muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the naive and prevalent opioid user cohorts, respectively, generating a combined estimate of 1.21. The risk increased with treatment duration (less than or equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80) and for the use of baclofen and carisoprodol (HR 1.83 and 1.84, respectively). Elevated risk was associated with concomitant users with daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and 1.39, respectively).(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10) |
METHADONE HCL, METHADONE HCL-0.9% NACL, METHADONE HCL-NACL |
| Selected Opioids for MAT/Selected Muscle Relaxants SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Concurrent use of diacetylmorphine or methadone and muscle relaxants may result in additive CNS depression.(1-3) Levomethadone is an enantiomer of methadone.(4) CLINICAL EFFECTS: Concurrent use of diacetylmorphine or methadone and other CNS depressants, such as muscle relaxants, may result in profound sedation, respiratory depression, coma, and/or death.(1-3) PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. PATIENT MANAGEMENT: Medication assisted treatment (MAT) with diacetylmorphine or methadone is not contraindicated in patients taking CNS depressants; however, discontinuation of CNS depressants is preferred in most cases. In some cases, monitoring at a higher level of care for tapering may be appropriate. In others, gradual tapering or decreasing to the lowest effective dose of the CNS depressant is appropriate. Ensure that other health care providers prescribing other CNS depressants are aware of the patient's diacetylmorphine or methadone treatment.(2) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(5) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(6) DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(7) A retrospective cohort study compared the risk of opioid overdose associated with concomitant use of opioids and skeletal muscle relaxants versus opioid use alone. The study examined two types of opioid users (naive opioid use and prevalent opioid use) with and without exposure to skeletal muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the naive and prevalent opioid user cohorts, respectively, generating a combined estimate of 1.21. The risk increased with treatment duration (less than or equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80) and for the use of baclofen and carisoprodol (HR 1.83 and 1.84, respectively). Elevated risk was associated with concomitant users with daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and 1.39, respectively).(8) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(9) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(10) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(11) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(12) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(13) While concomitant use of MAT with CNS depressants increases the risk of adverse reactions, barriers to MAT can pose a greater risk of morbidity and mortality due to opioid use disorder.(2) |
DISKETS, METHADONE HCL, METHADONE INTENSOL, METHADOSE |
| Icosapent Ethyl/Anticoagulant;Antiplatelet;Thrombolytic SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: In vitro data suggests that fish oils can competitively inhibit cyclooxygenase which decreases synthesis of thromboxane A1 leading to a decrease in platelet aggregation.(1) CLINICAL EFFECTS: Concurrent use of anticoagulant, antiplatelet, or thrombolytic agents increase bleeding risks. PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: If concurrent therapy is deemed medically necessary, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug. DISCUSSION: Specific studies with icosapent ethyl and affects on bleeding risk have not been conducted. Concurrent use of anticoagulant, antiplatelet, or thrombolytic agents may increase bleeding risks by impairing platelet function and prolonging bleeding time.(1) Several case reports have shown increased bleeding time and an increased risk of adverse effects from concurrent therapy.(2,3,4) A randomized placebo controlled study of 40 people taking omega-3 fatty acids and oral anticoagulants showed a significant prolongation in bleeding time.(5) |
ICOSAPENT ETHYL, VASCEPA |
| Fruquintinib; Surufatinib/Anticoagulants; Antiplatelets SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Bleeding has been reported with the use of fruquintinib and surufatinib.(1,2) CLINICAL EFFECTS: Concurrent use of fruquintinib or surufatinib with either anticoagulants or antiplatelets may increase the risk of hemorrhage.(1,2) PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: Patients receiving concurrent therapy with fruquintinib and anticoagulants and/or antiplatelets should be closely monitored for changes in platelet count or in International Normalized Ratio (INR). If a serious bleeding event occurs, the manufacturer recommends permanent discontinuation of fruquintinib.(1) Patients receiving concurrent therapy with surufatinib and anticoagulants and/or antiplatelets should be closely monitored for changes in platelet count or in INR.If a serious bleeding event occurs, the manufacturer recommends permanent discontinuation of surufatinib.(2) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug. DISCUSSION: Bleeding has been reported with fruquintinib in three randomized, double-blinded, placebo-controlled clinical trials. The incidence of grade 1 and grade 2 bleeding events was 28.2%, including gastrointestinal bleeding (10.9%), hematuria (10.6%), and epistaxis (7.5%). The incidence of grade 3 or higher bleeding events was 2.1% and included gastrointestinal bleeding (1.6%) and hemoptysis (0.5%).(1) Bleeding has been reported with surufatinib in clinical trials. Grade 1 and 2 bleeding events included gastrointestinal bleeding, blood in the urine, and gum bleeding. The incidence of grade 3 or greater bleeding events was 4.5%, including gastrointestinal hemorrhage (1.9%), and cerebral hemorrhage (1.1%). Fatalities due to bleeding were reported in 0.3% of patients. The incidence of permanent discontinuation due to bleeding was 2.6% and the incidence of suspension of surufatinib due to bleeding was 3.8%.(2) |
FRUZAQLA |
| Plasminogen/Anticoagulants; Antiplatelets SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Bleeding has been reported with the use of plasminogen.(1) CLINICAL EFFECTS: Concurrent use of plasminogen with either anticoagulants or antiplatelets may increase the risk of active bleeding during plasminogen therapy, including bleeding from mucosal disease-related lesions that may manifest as gastrointestinal (GI) bleeding, hemoptysis, epistaxis, vaginal bleeding, or hematuria.(1) PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: Patients receiving concurrent therapy with plasminogen and anticoagulants and/or antiplatelets should be closely monitored during plasminogen therapy for active bleeding from mucosal disease-related lesions, including GI bleeding, hemoptysis, epistaxis, vaginal bleeding, or hematuria.(1) Prior to initiation of treatment with plasminogen, confirm healing of lesions or wounds suspected as a source of a recent bleeding event. Monitor patients during and for 4 hours after infusion when administering plasminogen with concurrent anticoagulants, antiplatelet drugs, or other agents which may interfere with normal coagulation.(1) If patient experiences uncontrolled bleeding (defined as any gastrointestinal bleeding or bleeding from any other site that persists longer than 30 minutes), seek emergency care and discontinue plasminogen immediately.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug. DISCUSSION: Plasminogen has not been studied in patients at an increased risk of bleeding. Bleeding has been reported with plasminogen in a two single-arm, open-label clinical trials as well as in compassionate use programs. The incidence of hemorrhage in patients with Plasminogen Deficiency Type 1 was 16% (3/19 patients).(1) One of the bleeding events occurred two days after receiving the second dose of plasminogen in a patient with a recent history of GI bleeding due to gastric ulcers. The patient received plasminogen through a compassionate use program and the dose was 6.6 mg/kg body weight every 2 days. Endoscopy showed multiple ulcers with one actively bleeding ulcer near the pylorus.(1) |
RYPLAZIM |
| Tisotumab/Anticoagulants; Antiplatelets SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Bleeding, including hemorrhage, has been reported with the use of tisotumab.(1) CLINICAL EFFECTS: Concurrent use of tisotumab with either anticoagulants, antiplatelets, or NSAIDs may increase the risk of hemorrhage.(1) PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: Patients receiving concurrent therapy with tisotumab and anticoagulants, antiplatelets, and/or NSAIDs should be closely monitored for signs and symptoms of bleeding and changes in platelet count or International Normalized Ratio (INR). For patients experiencing pulmonary or central nervous system (CNS) hemorrhage, permanently discontinue tisotumab. For grade 2 or greater hemorrhage in any other location, withhold until bleeding has resolved, blood hemoglobin is stable, there is no bleeding diathesis that could increase the risk of continuing therapy, and there is no anatomical or pathologic condition that can increase the risk of hemorrhage. After resolution, either resume treatment or permanently discontinue tisotumab.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug. DISCUSSION: Hemorrhage occurred in 62% of patients with cervical cancer treated with tisotumab across clinical trials. The most common all grade hemorrhage adverse reactions were epistaxis (44%), hematuria (10%), and vaginal hemorrhage (10%). Grade 3 hemorrhage occurred in 5% of patients.(1) |
TIVDAK |
| Selected Opioids (Immediate Release)/Metaxalone SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Concurrent use of opioids and metaxalone may result in additive CNS depression.(1) CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as the muscle relaxant metaxalone, may result in profound sedation, respiratory depression, coma, and/or death.(1) PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as the muscle relaxant metaxalone to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3) DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(4) A retrospective cohort study compared the risk of opioid overdose associated with concomitant use of opioids and skeletal muscle relaxants versus opioid use alone. The study examined two types of opioid users (naive opioid use and prevalent opioid use) with and without exposure to skeletal muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the naive and prevalent opioid user cohorts, respectively, generating a combined estimate of 1.21. The risk increased with treatment duration (less than or equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80) and for the use of baclofen and carisoprodol (HR 1.83 and 1.84, respectively). Elevated risk was associated with concomitant users with daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and 1.39, respectively).(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10) |
METAXALONE |
| Opioids (Immediate Release)/Cyclobenzaprine SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Concurrent use of opioids and cyclobenzaprine may result in additive CNS depression.(1) CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as cyclobenzaprine, may result in profound sedation, respiratory depression, coma, and/or death.(1) PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as muscle relaxants to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3) DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(4) A retrospective cohort study compared the risk of opioid overdose associated with concomitant use of opioids and skeletal muscle relaxants versus opioid use alone. The study examined two types of opioid users (naive opioid use and prevalent opioid use) with and without exposure to skeletal muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the naive and prevalent opioid user cohorts, respectively, generating a combined estimate of 1.21. The risk increased with treatment duration (less than or equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80) and for the use of baclofen and carisoprodol (HR 1.83 and 1.84, respectively). Elevated risk was associated with concomitant users with daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and 1.39, respectively).(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10) |
AMRIX, CYCLOBENZAPRINE HCL, CYCLOBENZAPRINE HCL ER, CYCLOPAK, CYCLOTENS, FEXMID, TONMYA |
| Select Opioids (Immediate Release)/Select Tranquilizers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Concurrent use of opioids and tranquilizers may result in additive CNS depression.(1) CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants such as tranquilizers may result in profound sedation, respiratory depression, coma, and/or death.(1) PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as tranquilizers to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3) DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(4) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(5) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(6) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(7) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(8) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(9) |
PENTOBARBITAL SODIUM |
| Sparsentan/NSAIDs; Salicylates SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Sparsentan is an endothelin and angiotensin II receptor antagonist.(1) Angiotensin II receptor blockers can cause vasodilation of the efferent renal arteriole which may result in decreased glomerular filtration rate. NSAIDs inhibit prostaglandin synthesis which can lead to afferent arteriolar vasoconstriction. CLINICAL EFFECTS: Concurrent use of sparsentan with NSAIDs (including selective COX-2 inhibitors) may result in renal hypoperfusion and deterioration of renal clearance, including possible acute kidney injury (AKI). These effects are usually reversible.(1) PREDISPOSING FACTORS: Patients older than 75 years old, with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion (including from diuretic use and dehydration) may be at greater risk for AKI.(1-3) PATIENT MANAGEMENT: Monitor for signs of worsening renal function if an NSAID (including selective COX-2 inhibitors) is used concurrently with sparsentan. If renal function deteriorates, the NSAID may need to be discontinued.(1) DISCUSSION: In a computational study, the risk of AKI using triple therapy with a diuretic, renin-angiotensin system (RAS) inhibitor, and NSAID was assessed. The study found the following factors may increase an individual's susceptibility to AKI: low water intake, drug sensitivity, greater than 75 years of age, and renal impairment.(2,3) In an observational study, current use of a triple therapy combination was associated with an increased rate of acute kidney injury (rate ratio (RR) 1.31, 95% confidence interval (CI) 1.12-1.53). The highest risk of AKI associated with triple therapy were observed in the first 30 days of use (RR 1.82, CI 1.35-2.46).(4) |
FILSPARI |
| Lecanemab/Antiplatelets SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Microhemorrhage has been reported with the use of lecanemab. Radiographic changes on brain MRI have been noted as amyloid related imaging abnormalities-hemosiderin deposition (ARIA-H) which included microhemorrhage. In addition, intracerebral hemorrhages (ICH) greater than 1 cm in diameter have occurred in patients treated with lecanemab.(1) CLINICAL EFFECTS: Concurrent use of lecanemab with antiplatelets may increase the risk of hemorrhage.(1) PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: Lecanemab should be used with extreme caution in patients treated with antiplatelets. Evaluate the risks and benefits of concurrent use of lecanemab with antiplatelets.(1) Appropriate use recommendations for lecanemab state antiplatelets may be used at standard doses if patients meet other criteria for lecanemab therapy. Use of antiplatelet agents in patients who are homozygous for the APOE4 gene may have an increased risk of ARIA with lecanemab therapy.(2) Patients receiving concurrent therapy with lecanemab and antiplatelets should be closely monitored for signs and symptoms of bleeding and changes in platelet count or International Normalized Ratio (INR).(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of microhemorrhage, including headache, nausea/vomiting, confusion, dizziness, visual disturbance, gait difficulties, and loss of coordination. General signs of blood loss include decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Instruct patients to report any signs and symptoms of bleeding, such as confusion, headache, dizziness, nausea, visual changes, unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. DISCUSSION: In clinical studies, lecanemab was observed to increase ARIA-H, including microhemorrhage and intracerebral hemorrhage. Radiographic changes were classified as mild (<=4 new incidences), moderate (5 to 9 new incidences), or severe (10 or more new incidences. Patients were excluded from clinical trials if taking concurrent anticoagulants or anti-platelets.(1) In Studies 1 and 2, the maximum severity of ARIA-H microhemorrhage was mild in 9% (79/898), moderate in 2% (19/898), and severe in 3% (28/898) of patients. Intracerebral hemorrhage greater than 1 cm in diameter was reported in 0.7% (6/898) of patients in Study 2 after treatment with lecanemab compared to 0.1% (1/897) on placebo. Fatal events of intracerebral hemorrhage in patients taking lecanemab have been observed.(1) In Study 2, baseline use of antithrombotic medications (aspirin, other antiplatelets, or anticoagulants) were allowed if patient was on a stable dose. Aspirin was the most common antithrombotic agent. The incidence of ICH was 0.9% (3/328 patients) in patients taking lecanemab with a concomitant antithrombotic medication at the time of the event compared to 0.6% (3/545 patients) in those who did not receive an antithrombotic. Patients taking lecanemab with an anticoagulant alone or combined with an antiplatelet medication or aspirin had an incidence of intracerebral hemorrhage of 2.5% (2/79 patients) compared to none in patients who received placebo. |
LEQEMBI, LEQEMBI IQLIK |
| NSAIDs; Aspirin (Non-Cardioprotective)/Metoprolol SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Unknown; however, possibly related to inhibition of prostaglandin by NSAIDs. CLINICAL EFFECTS: The antihypertensive action of metoprolol may be decreased. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Monitor patient's blood pressure and adjust the dose of metoprolol as needed. DISCUSSION: Concurrent administration of metoprolol and NSAIDs has been associated with a clinically significant loss in antihypertensive response. The magnitude of the effect of NSAIDs on control of blood pressure by beta-blockers needs to be determined for each anti-inflammatory agent. One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology. |
KAPSPARGO SPRINKLE, LOPRESSOR, METOPROLOL SUCCINATE, METOPROLOL TARTRATE, METOPROLOL-HYDROCHLOROTHIAZIDE, TOPROL XL |
| NSAIDs; Salicylates/Minoxidil SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Oral minoxidil functions as a direct-acting peripheral vasodilator, lowering elevated systolic and diastolic blood pressure by reducing resistance in peripheral blood vessels. This triggers a compensatory increase in cardiac output and renin secretion and results in sodium and water retention. NSAIDs inhibit prostaglandin synthesis and also result in sodium and water retention.(1,2) CLINICAL EFFECTS: The risk of heart failure may increase with oral minoxidil and NSAIDs due to their combined effects on blood vessel dilation, fluid retention, and altered sodium balance. Minoxidil efficacy may be compromised.(1,2) PREDISPOSING FACTORS: Higher doses of oral minoxidil have been associated with serious adverse events, including hypotensive syncope, pericarditis, pericardial effusion, and myocardial infarction.(1-5) PATIENT MANAGEMENT: Closely monitor body weight, fluid and electrolyte balance, and blood pressure when using oral minoxidil and NSAIDs concurrently. Minoxidil tablets should be co-administered with an appropriate diuretic to prevent fluid retention and potential congestive heart failure. A high-ceiling (loop) diuretic is often necessary alongside vigilant monitoring of body weight. Without concurrent diuretic use, minoxidil may lead to the retention of salt and water within a few days.(1,2) DISCUSSION: While the manufacturer of minoxidil does not provide specific recommendations regarding NSAID co-administration, it emphasizes the necessity of combining minoxidil with a beta-blocker to prevent tachycardia and increased myocardial workload. Additionally, concurrent use with a diuretic is recommended to avert serious fluid accumulation and potential congestive heart failure. NSAID labeling warns about fluid retention, edema, an elevated risk of heart failure, and potential drug interactions with beta-blockers and diuretics which can result in a blunting of the antihypertensive and cardiovascular effects of these agents.(1-5) |
MINOXIDIL |
| T Cell Immunotherapies/NSAIDs; Salicylates SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: NSAIDs augment the immune system. Concurrent use with NSAIDs may interfere with the activity of CAR-T cell immunotherapies.(1) CLINICAL EFFECTS: NSAIDs may decrease the efficacy of CAR-T cell immunotherapies.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: NSAIDs should be used with caution with or after CAR-T cell immunotherapy.(1) DISCUSSION: An in vitro study showed aspirin and celecoxib negatively affected CD19.CAR-T cells through their effects on the induction of apoptosis, reduction of activation, and impairment of proliferation.(1) |
ABECMA, AMTAGVI, AUCATZYL, BREYANZI, BREYANZI CD4 COMPONENT, BREYANZI CD8 COMPONENT, CARVYKTI, KYMRIAH, TECARTUS, TECELRA, YESCARTA |
| Donanemab/Antiplatelets SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Microhemorrhage has been reported with the use of donanemab. Radiographic changes on brain MRI have been noted as amyloid related imaging abnormalities-hemosiderin deposition (ARIA-H) which included microhemorrhage. In addition, intracerebral hemorrhages (ICH) greater than 1 cm in diameter have occurred in patients treated with donanemab.(1) CLINICAL EFFECTS: Concurrent use of donanemab with antiplatelets may increase the risk of hemorrhage.(1) PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: Donanemab should be used with extreme caution in patients treated with antiplatelets. Evaluate the risks and benefits of concurrent use of donanemab with antiplatelets.(1) The manufacturer of donanemab recommends testing for AP0E4 status prior to initiation of treatment.(1) Use of antiplatelet agents in patients who are homozygous for the APOE4 gene, may have an increased risk of ARIA with donanemab therapy.(1-3) Patients receiving concurrent therapy with donanemab and antiplatelets should be closely monitored for signs and symptoms of bleeding and changes in platelet count.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of microhemorrhage, including headache, nausea/vomiting, confusion, dizziness, visual disturbance, gait difficulties, and loss of coordination. General signs of blood loss include decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Instruct patients to report any signs and symptoms of bleeding, such as confusion, headache, dizziness, nausea, visual changes, unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. DISCUSSION: In a double-blind, placebo-controlled clinical study of 1736 participants randomized to receive donanemab (n = 860) or placebo (n = 876), donanemab was observed to increase amyloid related imaging abnormalities-hemosiderin deposition (ARIA-H), including microhemorrhage and intracerebral hemorrhage (ICH). Radiographic changes were classified as mild (<=4 new incidences), moderate (5 to 9 new incidences), or severe (10 or more new incidences). The maximum severity of ARIA-H microhemorrhage was observed as mild in 17% (143/853), moderate in 4% (34/853), and severe in 5% (40/853) of patients taking donanemab.(1) Baseline use of antithrombotic medications (aspirin, other antiplatelets, or anticoagulants) was allowed. The majority of exposures to antithrombotic medications were to aspirin. The incidence of ARIA-H was 30% (106/349) in patients taking donanemab with a concomitant antithrombotic medication within 30 days compared to 29% (148/504) who did not receive an antithrombotic within 30 days of an ARIA-H event.(1) The incidence of ICH greater than 1 cm in diameter was 0.6% (2/349 patients) in patients taking donanemab with a concomitant antithrombotic medication compared to 0.4% (2/504) in those who did not receive an antithrombotic. One fatal ICH occurred in a patient taking donanemab in the setting of focal neurologic symptoms of ARIA and the use of a thrombolytic agent.(1) |
KISUNLA |
| Obinutuzumab/Anticoagulants; Antiplatelets SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Severe and life-threatening thrombocytopenia has been reported during obinutuzumab therapy.(1) Anticoagulants and antiplatelets may have an additive risk of bleeding. CLINICAL EFFECTS: Concurrent use of obinutuzumab with anticoagulants or antiplatelet agents may result in additive or synergistic effects, including fatal and non-fatal hemorrhage.(1) PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: Monitor all patients frequently for thrombocytopenia and signs of bleeding. Consider withholding concomitant anticoagulants and antiplatelets, especially during the first cycle of obinutuzumab.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. DISCUSSION: Obinutuzumab with chemotherapy has been reported to cause severe and life-threatening thrombocytopenia. Fatal hemorrhagic events have occurred in patients with NHL and CLL during obinutuzumab therapy, including during Cycle 1.(1) |
GAZYVA |
| Angiotensin II Receptor Block (ARB)/High-Dose Aspirin SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Angiotensin II receptor blockers (ARBs) can cause vasodilation of the efferent renal arteriole which may result in decreased glomerular filtration rate. NSAIDs inhibit prostaglandin synthesis which can lead to afferent arteriolar vasoconstriction and may negate any decrease in blood pressure. CLINICAL EFFECTS: Concurrent use of aspirin may result in decreased antihypertensive effects of the ARB. In patients with existing renal impairment, the use of these agents may also result in further deterioration of renal clearance caused by renal hypoperfusion. Concurrent use of ARBs with aspirin and diuretics may result in increased risk of acute kidney injury (AKI). PREDISPOSING FACTORS: Low water intake/dehydration, drug sensitivity, greater than 75 years of age, and use of diuretics can lead to hypovolemia and increased risk of AKI. PATIENT MANAGEMENT: Monitor patients receiving doses of aspirin higher than 150 mg daily for decreased antihypertensive effects of their ARB. The use of alternative agents may need to be considered. Concurrent use of ARBs with aspirin and diuretics should be used with caution and monitored for signs of AKI. DISCUSSION: In a population based cohort study, the concurrent use of NSAIDs with renin-angiotensin system (RAS) inhibitors in 5,710 hypertensive patients stabilized on antihypertensive therapy required hypertension treatment intensification. Adjusted hazard ratios (HR) for hypertension treatment intensification were 1.34 [95% CI 1.05-1.71] for NSAIDs in general, 1.79 (95% CI 1.15-2.78) for diclofenac and 2.02 (95% CI 1.09-3.77) for piroxicam. There were significant interactions between NSAIDs and angiotensin converting enzyme inhibitors (ACE inhibitors; HR 4.09, 95% CI 2.02-8.27) or angiotensin receptor blockers (ARBs; HR 3.62, 95% CI 1.80-7.31), but not with other antihypertensive drugs. In a computational study, the risk of AKI using triple therapy (combination of a diuretic, renin-angiotensin system (RAS) inhibitor, and NSAID) was assessed. The study found the following factors may increase an individual's susceptibility to AKI: low water intake, drug sensitivity, greater than 75 years of age, and renal impairment.(4,5) In an observational study, current use of a triple therapy combination was associated with an increased rate of acute kidney injury (rate ratio (RR) 1.31, 95% confidence interval (CI) 1.12-1.53). The highest risk of AKI associated with triple therapy were observed in the first 30 days of use (RR 1.82, CI 1.35-2.46).(6) |
AMLODIPINE-OLMESARTAN, AMLODIPINE-VALSARTAN, AMLODIPINE-VALSARTAN-HCTZ, ARBLI, ATACAND, ATACAND HCT, AVALIDE, AVAPRO, AZOR, BENICAR, BENICAR HCT, CANDESARTAN CILEXETIL, CANDESARTAN-HYDROCHLOROTHIAZID, COZAAR, DIOVAN, DIOVAN HCT, EDARBI, EDARBYCLOR, ENTRESTO, ENTRESTO SPRINKLE, EPROSARTAN MESYLATE, EXFORGE, EXFORGE HCT, HYZAAR, IRBESARTAN, IRBESARTAN-HYDROCHLOROTHIAZIDE, LOSARTAN POTASSIUM, LOSARTAN-HYDROCHLOROTHIAZIDE, MICARDIS, MICARDIS HCT, OLMESARTAN MEDOXOMIL, OLMESARTAN-AMLODIPINE-HCTZ, OLMESARTAN-HYDROCHLOROTHIAZIDE, SACUBITRIL-VALSARTAN, TELMISARTAN, TELMISARTAN-AMLODIPINE, TELMISARTAN-HYDROCHLOROTHIAZID, TRIBENZOR, VALSARTAN, VALSARTAN-HYDROCHLOROTHIAZIDE |
| Gabapentinoids/Muscle Relaxants SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Concurrent use of gabapentinoids and muscle relaxants may result in additive CNS depression.(1) CLINICAL EFFECTS: Concurrent use of gabapentinoids and other CNS depressants, such as muscle relaxants, may result in profound sedation, respiratory depression, coma, and/or death.(1) PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. PATIENT MANAGEMENT: Limit prescribing muscle relaxants and gabapentinoids to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a gabapentinoid with a muscle relaxant, prescribe a lower initial dose of the gabapentinoid than indicated in the absence of a muscle relaxant and titrate based upon clinical response. If a muscle relaxant is indicated in a patient already taking a gabapentinoid, prescribe a lower dose of the muscle relaxant and titrate based upon clinical response.(1) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) DISCUSSION: Clinical trials have shown no pharmacokinetic interaction between pregabalin and muscle relaxants.(2) Among 49 case reports submitted to FDA over a 5 year period (2012-2017), 12 people died from respiratory depression with gabapentinoids. Two randomized, double-blind, placebo-controlled clinical trials in healthy people, three observational studies, and several studies in animals were reviewed. A trial showed that using pregabalin alone and using it with an opioid pain reliever can depress breathing function. Three observational studies showed a relationship between gabapentinoids given before surgery and respiratory depression occurring after surgery. Several animal studies also showed that pregabalin plus opioids can depress respiratory function. Muscle relaxants are expected to have a similar effect when used with gabapentinoids.(1) |
GABAPENTIN, GABAPENTIN ER, GABARONE, GRALISE, HORIZANT, LYRICA, LYRICA CR, NEURONTIN, PREGABALIN, PREGABALIN ER, RELGAABI |
The following contraindication information is available for CARISOPRODOL-ASPIRIN-CODEINE (carisoprodol/aspirin/codeine phosphate):
Drug contraindication overview.
*Children younger than 12 years of age. *Postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. *Significant respiratory depression.
*Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment. *Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days. *Known or suspected GI obstruction, including paralytic ileus. *Hypersensitivity to codeine or any components of the formulation.
*Children younger than 12 years of age. *Postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. *Significant respiratory depression.
*Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment. *Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days. *Known or suspected GI obstruction, including paralytic ileus. *Hypersensitivity to codeine or any components of the formulation.
There are 15 contraindications.
Absolute contraindication.
| Contraindication List |
|---|
| Acute asthma attack |
| Acute intermittent porphyria |
| Adenoidectomy in pediatric patient |
| Aspirin exacerbated respiratory disease |
| Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min |
| Chronic kidney disease stage 5 (failure) GFr<15 ml/min |
| Gastrointestinal hemorrhage |
| Hemolytic anemia from pyruvate kinase and g6PD deficiencies |
| Hemorrhage |
| Increased risk of bleeding due to coagulation disorder |
| Lactation |
| Paralytic ileus |
| Pregnancy |
| Reye's syndrome |
| Tonsillectomy in pediatric patient |
There are 24 severe contraindications.
Adequate patient monitoring is recommended for safer drug use.
| Severe List |
|---|
| Acute pancreatitis |
| Alcohol intoxication |
| Alcohol use disorder |
| CYp2d6 poor metabolizer |
| CYp2d6 ultrarapid metabolizer |
| Drug abuse |
| Drug dependence |
| Exacerbation of chronic obstructive pulmonary disease |
| Familial dysautonomia |
| Gastrointestinal obstruction |
| Gastrointestinal ulcer |
| History of opioid overdose |
| Hypoprothrombinemia |
| Intracranial hypertension |
| Kidney disease with likely reduction in glomerular filtration rate (GFr) |
| Respiratory depression |
| Salicylate intoxication |
| Sedation |
| Seizure disorder |
| Shock |
| Sleep apnea |
| Systemic mastocytosis |
| Thrombocytopenic disorder |
| Thrombotic thrombocytopenic purpura |
There are 19 moderate contraindications.
Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.
| Moderate List |
|---|
| Adrenocortical insufficiency |
| Alcohol intoxication |
| Anemia |
| Biliary tract disorder |
| Constipation |
| Cor pulmonale |
| CYp2c19 poor metabolizer |
| Debilitation |
| Disease of liver |
| Gout |
| Hypotension |
| Kidney disease with reduction in glomerular filtration rate (GFr) |
| Lower seizure threshold |
| Nasal polyp |
| Orthostatic hypotension |
| Seizure disorder |
| Untreated hypothyroidism |
| Urinary retention |
| Vitamin K deficiency |
The following adverse reaction information is available for CARISOPRODOL-ASPIRIN-CODEINE (carisoprodol/aspirin/codeine phosphate):
Adverse reaction overview.
The most common adverse reactions reported with codeine sulfate tablets include drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea, vomiting, and sweating.
The most common adverse reactions reported with codeine sulfate tablets include drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea, vomiting, and sweating.
There are 61 severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
| None. |
Allergic dermatitis Atelectasis Bronchospastic pulmonary disease CNS depression Dyspnea Hypotension Orthostatic hypotension Pruritus of skin Respiratory depression Skin rash Urticaria Wheezing |
| Rare/Very Rare |
|---|
|
Accidental fall Acute eruptions of skin Acute respiratory failure Adrenocortical insufficiency Allergic dermatitis Anaphylaxis Androgen deficiency Anemia Angioedema Blistering skin Bradycardia Bronchospastic pulmonary disease Bullous dermatitis Cardiac arrest DRESS syndrome Drug dependence Drug fever Drug-induced hepatitis Dyspnea Eosinophilia Erythema multiforme Exfoliative dermatitis Gastrointestinal hemorrhage Gastrointestinal perforation Gastrointestinal ulcer Hemolytic anemia Hemorrhage Ileus Interstitial nephritis Intracranial bleeding Leukopenia Opioid dependence Orthostatic hypotension Pancreatitis Pancytopenia Platelet aggregation inhibition Purpura Rectal bleeding Renal papillary necrosis Seizure disorder Shock Sleep apnea Stevens-johnson syndrome Syncope Tachycardia Thrombocytopenic disorder Toxic epidermal necrolysis Urticaria Wheezing |
There are 74 less severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Abdominal pain with cramps Constipation Dizziness Drowsy Gastric acid hypersecretory conditions Gastrointestinal irritation Headache disorder Heartburn Hyperhidrosis Nausea Sedation Vomiting |
Acute cognitive impairment Anorexia Dizziness Dysphoric mood Gastrointestinal irritation General weakness Headache disorder Hiccups Nervousness Oliguria Palpitations Pruritus of skin Sedation Skin rash Syncope Urticaria Visual changes Xerostomia |
| Rare/Very Rare |
|---|
|
Abnormal hepatic function tests Accidental fall Agitation Anorexia Ataxia Biliary spasm Black tarry stools Blurred vision Depression Diarrhea Diplopia Drowsy Dyspepsia Dysphagia Ecchymosis Epistaxis Erectile dysfunction Erythema Euphoria Fatigue Flushing Gastritis Gastrointestinal irritation Gingival bleeding Hematoma Infertility Insomnia Irritability Libido changes Nausea Non-cardiac chest pain Opioid induced allodynia Opioid induced hyperalgesia Pruritus of skin Skin rash Symptoms of anxiety Tinnitus Tremor Unsteady gait Upper abdominal pain Vasodilation of blood vessels Vertigo Visual changes Vomiting |
The following precautions are available for CARISOPRODOL-ASPIRIN-CODEINE (carisoprodol/aspirin/codeine phosphate):
Safety and effectiveness of codeine have not been established in pediatric patients. Pediatric patients receiving codeine for the management of pain, especially those who are obese, have obstructive sleep apnea or severe lung disease, or have evidence of ultrarapid metabolism of CYP2D6 substrates, are at increased risk of respiratory depression. Serious adverse events, including deaths, have been reported during postmarketing experience in pediatric patients receiving codeine.
Between January 1969 and May 2015, the FDA Adverse Event Reporting System (FAERS) received 64 reports of respiratory depression, including 24 reports of death, worldwide that were associated with codeine use in pediatric patients younger than 18 years of age. Ten of the 64 reports provided information about CYP2D6 metabolizer status. Seven of these patients were ultrarapid or extensive metabolizers of CYP2D6 substrates; 5 of which reported death.
Most of the cases of respiratory depression, including most of the deaths, occurred in children younger than 12 years of age. Respiratory depression may occur despite therapeutic serum concentrations of codeine or morphine; 1 patient who had concentrations within the therapeutic range died following use of codeine for management of pain after tonsillectomy and adenoidectomy. Codeine-containing preparations are contraindicated in children younger than 12 years of age and contraindicated for postoperative pain management following tonsillectomy and/or adenoidectomy in pediatric patients younger than 18 years of age.
Avoid the use of codeine in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of the drug unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression.
Contraindicated
Severe Precaution
Management or Monitoring Precaution
Between January 1969 and May 2015, the FDA Adverse Event Reporting System (FAERS) received 64 reports of respiratory depression, including 24 reports of death, worldwide that were associated with codeine use in pediatric patients younger than 18 years of age. Ten of the 64 reports provided information about CYP2D6 metabolizer status. Seven of these patients were ultrarapid or extensive metabolizers of CYP2D6 substrates; 5 of which reported death.
Most of the cases of respiratory depression, including most of the deaths, occurred in children younger than 12 years of age. Respiratory depression may occur despite therapeutic serum concentrations of codeine or morphine; 1 patient who had concentrations within the therapeutic range died following use of codeine for management of pain after tonsillectomy and adenoidectomy. Codeine-containing preparations are contraindicated in children younger than 12 years of age and contraindicated for postoperative pain management following tonsillectomy and/or adenoidectomy in pediatric patients younger than 18 years of age.
Avoid the use of codeine in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of the drug unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression.
Contraindicated
| None |
Severe Precaution
| None |
Management or Monitoring Precaution
| None |
A drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes has not been identified to date with use of carisoprodol or meprobamate (an active metabolite) in pregnant women. In an animal reproduction study, reduced fetal weights, postnatal weight gain, and postnatal survival were observed when pregnant mice were exposed to carisoprodol from gestation through weaning. Some experts recommend that the drug be avoided, if possible, during the first trimester of pregnancy.
Available data with codeine are insufficient to inform a drug-associated risk of major birth defects and miscarriage. In animal studies, embryolethal and fetotoxic effects were observed in animals administered codeine during the period of organogenesis. Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates.
An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Codeine is not recommended for use in women during and immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including codeine, can prolong labor through actions that temporarily reduce the strength, duration, and frequency of uterine contractions.
However, this effect is not consistent and may be offset by an increased rate of cervical dilatation, which may shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excessive sedation and respiratory depression. Use of opioid analgesics for an extended period during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.
Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly.
Available data with codeine are insufficient to inform a drug-associated risk of major birth defects and miscarriage. In animal studies, embryolethal and fetotoxic effects were observed in animals administered codeine during the period of organogenesis. Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates.
An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Codeine is not recommended for use in women during and immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including codeine, can prolong labor through actions that temporarily reduce the strength, duration, and frequency of uterine contractions.
However, this effect is not consistent and may be offset by an increased rate of cervical dilatation, which may shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excessive sedation and respiratory depression. Use of opioid analgesics for an extended period during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.
Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly.
Limited data indicate that carisoprodol is distributed into human milk and may reach concentrations that are 2-4 times maternal plasma concentrations. Other than mild sedation, no adverse effects have been observed in nursing infants exposed to carisoprodol; while the effects of the drug on milk production are not known, insufficient maternal milk production has been described in several case reports. The known benefits of breastfeeding should be considered along with the mother's clinical need for carisoprodol and any potential adverse effects on the breastfed infant from the drug or underlying maternal condition.
The nursing infant should be monitored for signs of sedation during breastfeeding. Breastfeeding is not recommended during treatment with codeine, especially in patients who have evidence of ultrarapid metabolism of CYP2D6 substrates. Serious adverse events (e.g., excessive sedation, difficulty nursing, respiratory depression), including death, have been reported in nursing infants exposed to codeine.
At least one case of opioid toxicity resulting in neonatal death has been reported in the nursing infant of a woman receiving codeine; genetic testing of the woman indicated that she was an ultrarapid metabolizer of codeine. Higher than expected concentrations of morphine were found in breast milk and in the blood of the infant. Somnolence has been reported more frequently in nursing infants whose mothers received codeine in combination with acetaminophen compared with those whose mothers received acetaminophen alone; evidence of ultrarapid metabolism of CYP2D6 substrates was identified in some of these women.
Concentrations of morphine in breast milk are low and dose-dependent in women who are normal metabolizers of codeine. FDA-approved tests (e.g., AmpliChip(R) CYP450 Test) are available to identify an individual's CYP2D6 genotype. Infants exposed to codeine through breast milk should be monitored closely for clinical manifestations of opioid toxicity (e.g., sedation, difficulty breastfeeding or breathing, hypotonia). Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic or breastfeeding is stopped.
The nursing infant should be monitored for signs of sedation during breastfeeding. Breastfeeding is not recommended during treatment with codeine, especially in patients who have evidence of ultrarapid metabolism of CYP2D6 substrates. Serious adverse events (e.g., excessive sedation, difficulty nursing, respiratory depression), including death, have been reported in nursing infants exposed to codeine.
At least one case of opioid toxicity resulting in neonatal death has been reported in the nursing infant of a woman receiving codeine; genetic testing of the woman indicated that she was an ultrarapid metabolizer of codeine. Higher than expected concentrations of morphine were found in breast milk and in the blood of the infant. Somnolence has been reported more frequently in nursing infants whose mothers received codeine in combination with acetaminophen compared with those whose mothers received acetaminophen alone; evidence of ultrarapid metabolism of CYP2D6 substrates was identified in some of these women.
Concentrations of morphine in breast milk are low and dose-dependent in women who are normal metabolizers of codeine. FDA-approved tests (e.g., AmpliChip(R) CYP450 Test) are available to identify an individual's CYP2D6 genotype. Infants exposed to codeine through breast milk should be monitored closely for clinical manifestations of opioid toxicity (e.g., sedation, difficulty breastfeeding or breathing, hypotonia). Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic or breastfeeding is stopped.
Geriatric patients may have increased sensitivity to codeine. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Respiratory depression is the main risk for geriatric patients treated with opioids and has occurred after large initial doses in patients who were not opioid-tolerant or when opioids were co-administered with other drugs that depress respiration.
Titrate the dosage of codeine slowly in geriatric patients and frequently re-evaluate for signs of CNS and respiratory depression. Codeine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Elderly patients are more likely to have decreased renal function; dosing should be selected with care and renal function should be regularly evaluated.
Titrate the dosage of codeine slowly in geriatric patients and frequently re-evaluate for signs of CNS and respiratory depression. Codeine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Elderly patients are more likely to have decreased renal function; dosing should be selected with care and renal function should be regularly evaluated.
The following prioritized warning is available for CARISOPRODOL-ASPIRIN-CODEINE (carisoprodol/aspirin/codeine phosphate):
WARNING: Codeine has a risk for abuse and addiction, which can lead to overdose and death. Codeine may also cause severe, possibly fatal, breathing problems. To lower your risk, your doctor should have you take the smallest dose of codeine that works, and take it for the shortest possible time.
See also How to Use section for more information about addiction. Ask your doctor or pharmacist if you should have medication available to treat opioid overdose (such as naloxone, nalmefene). Teach your family or household members about the signs of an opioid overdose and how to treat it.
The risk for severe breathing problems is higher when you start this medication and after a dose increase, or if you take the wrong dose/strength. Taking this medication with alcohol or other drugs that can cause drowsiness or breathing problems may cause very serious side effects, including death. Also, other medications can affect the removal of codeine from your body, which may affect how codeine works.
Be sure you know how to take this medication and what other drugs you should avoid taking with it. See also Drug Interactions section. Get medical help right away if any of these very serious side effects occur: slow/shallow breathing, unusual lightheadedness, severe drowsiness/dizziness, difficulty waking up.
Keep this medicine in a safe place to prevent theft, misuse, or abuse. If someone accidentally swallows this medication, get medical help right away. Children younger than 18 years should not use products that contain codeine.
Some children are more sensitive to codeine and have had very serious (rarely fatal) breathing problems such as slow/shallow breathing (see also Side Effects section). The risk is greater in children who are obese or have breathing problems, or after certain surgeries (including tonsil/adenoid removal). Talk with your doctor or pharmacist about the risks and benefits of this medication.
WARNING: Codeine has a risk for abuse and addiction, which can lead to overdose and death. Codeine may also cause severe, possibly fatal, breathing problems. To lower your risk, your doctor should have you take the smallest dose of codeine that works, and take it for the shortest possible time.
See also How to Use section for more information about addiction. Ask your doctor or pharmacist if you should have medication available to treat opioid overdose (such as naloxone, nalmefene). Teach your family or household members about the signs of an opioid overdose and how to treat it.
The risk for severe breathing problems is higher when you start this medication and after a dose increase, or if you take the wrong dose/strength. Taking this medication with alcohol or other drugs that can cause drowsiness or breathing problems may cause very serious side effects, including death. Also, other medications can affect the removal of codeine from your body, which may affect how codeine works.
Be sure you know how to take this medication and what other drugs you should avoid taking with it. See also Drug Interactions section. Get medical help right away if any of these very serious side effects occur: slow/shallow breathing, unusual lightheadedness, severe drowsiness/dizziness, difficulty waking up.
Keep this medicine in a safe place to prevent theft, misuse, or abuse. If someone accidentally swallows this medication, get medical help right away. Children younger than 18 years should not use products that contain codeine.
Some children are more sensitive to codeine and have had very serious (rarely fatal) breathing problems such as slow/shallow breathing (see also Side Effects section). The risk is greater in children who are obese or have breathing problems, or after certain surgeries (including tonsil/adenoid removal). Talk with your doctor or pharmacist about the risks and benefits of this medication.
The following icd codes are available for CARISOPRODOL-ASPIRIN-CODEINE (carisoprodol/aspirin/codeine phosphate)'s list of indications:
| Muscle spasm | |
| M62.83 | Muscle spasm |
| M62.830 | Muscle spasm of back |
| M62.831 | Muscle spasm of calf |
| M62.838 | Other muscle spasm |
| R25.2 | Cramp and spasm |
Formulary Reference Tool