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Drug overview for ALKA-SELTZER PLUS NIGHT (ASA) (doxylamine succinate/phenylephrine/dextromethorphan hbr/asa):
Generic name: doxylamine succinate/phenylephrine/dextromethorphan HBr/ASA
Drug class: Amphetamines/Anorexiants/Stimulants
Therapeutic class: Respiratory Therapy Agents
Aspirin (the prototype of the salicylates) is a nonsteroidal Dextromethorphan, a derivative of levorphanol, is an antitussive agent. Doxylamine is an ethanolamine-derivative, first generation antihistamine. Phenylephrine hydrochloride is a sympathomimetic amine that predominantly acts by a direct effect on alpha1-adrenergic receptors. anti-inflammatory agent (NSAIA) and also exhibits antithrombotic, analgesic, and antipyretic activity.
Aspirin is used extensively in the treatment of mild to moderate pain, Dextromethorphan is used for the temporary relief of coughs caused by minor Doxylamine succinate shares the actions and uses of other antihistamines. fever, and inflammatory diseases. Aspirin is also used in the prevention of throat and bronchial irritation such as may occur with common colds or with arterial and venous thrombosis.
Aspirin, however, should be used with inhaled irritants. Dextromethorphan is most effective in the treatment of chronic, nonproductive cough. The drug is a common ingredient in commercial extreme caution, if at all, in patients in whom urticaria, angioedema, bronchospasm, severe rhinitis, or shock is precipitated by other cough mixtures available without prescription.
salicylates or other NSAIAs. (See Cautions: Sensitivity Reactions in the Although cough and cold preparations that contain cough suppressants Salicylates General Statement 28:08.04.24.) (including dextromethorphan), nasal decongestants, antihistamines, and/or expectorants commonly are used in pediatric patients younger than 2 years of age, systematic reviews of controlled trials have concluded that nonprescription (over-the-counter, OTC) cough and cold preparations are not more effective than placebo in reducing acute cough and other symptoms of upper respiratory tract infection in these patients. Furthermore, adverse events, including deaths, have been (and continue to be) reported in pediatric patients younger than 2 years of age receiving these preparations.
(See Cautions: Pediatric Precautions and see Acute Toxicity: Manifestations.) For information on abuse of dextromethorphan, see Cautions. For use of dextromethorphan hydrobromide in fixed combination with quinidine sulfate in the treatment of pseudobulbar affect (PBA), see Dextromethorphan Hydrobromide and Quinidine Sulfate 28:92.
Generic name: doxylamine succinate/phenylephrine/dextromethorphan HBr/ASA
Drug class: Amphetamines/Anorexiants/Stimulants
Therapeutic class: Respiratory Therapy Agents
Aspirin (the prototype of the salicylates) is a nonsteroidal Dextromethorphan, a derivative of levorphanol, is an antitussive agent. Doxylamine is an ethanolamine-derivative, first generation antihistamine. Phenylephrine hydrochloride is a sympathomimetic amine that predominantly acts by a direct effect on alpha1-adrenergic receptors. anti-inflammatory agent (NSAIA) and also exhibits antithrombotic, analgesic, and antipyretic activity.
Aspirin is used extensively in the treatment of mild to moderate pain, Dextromethorphan is used for the temporary relief of coughs caused by minor Doxylamine succinate shares the actions and uses of other antihistamines. fever, and inflammatory diseases. Aspirin is also used in the prevention of throat and bronchial irritation such as may occur with common colds or with arterial and venous thrombosis.
Aspirin, however, should be used with inhaled irritants. Dextromethorphan is most effective in the treatment of chronic, nonproductive cough. The drug is a common ingredient in commercial extreme caution, if at all, in patients in whom urticaria, angioedema, bronchospasm, severe rhinitis, or shock is precipitated by other cough mixtures available without prescription.
salicylates or other NSAIAs. (See Cautions: Sensitivity Reactions in the Although cough and cold preparations that contain cough suppressants Salicylates General Statement 28:08.04.24.) (including dextromethorphan), nasal decongestants, antihistamines, and/or expectorants commonly are used in pediatric patients younger than 2 years of age, systematic reviews of controlled trials have concluded that nonprescription (over-the-counter, OTC) cough and cold preparations are not more effective than placebo in reducing acute cough and other symptoms of upper respiratory tract infection in these patients. Furthermore, adverse events, including deaths, have been (and continue to be) reported in pediatric patients younger than 2 years of age receiving these preparations.
(See Cautions: Pediatric Precautions and see Acute Toxicity: Manifestations.) For information on abuse of dextromethorphan, see Cautions. For use of dextromethorphan hydrobromide in fixed combination with quinidine sulfate in the treatment of pseudobulbar affect (PBA), see Dextromethorphan Hydrobromide and Quinidine Sulfate 28:92.
DRUG IMAGES
ALKA-SELTZER PLUS NIGHT TB EFF
The following indications for ALKA-SELTZER PLUS NIGHT (ASA) (doxylamine succinate/phenylephrine/dextromethorphan hbr/asa) have been approved by the FDA:
Indications:
Cold symptoms
Cough
Fever
Flu-like symptoms
Headache disorder
Nasal congestion
Rhinorrhea
Professional Synonyms:
Cephalgia
Cephalodynia
Febrile reaction
Febrile
Nasal stuffiness
Pyrexia
Indications:
Cold symptoms
Cough
Fever
Flu-like symptoms
Headache disorder
Nasal congestion
Rhinorrhea
Professional Synonyms:
Cephalgia
Cephalodynia
Febrile reaction
Febrile
Nasal stuffiness
Pyrexia
The following dosing information is available for ALKA-SELTZER PLUS NIGHT (ASA) (doxylamine succinate/phenylephrine/dextromethorphan hbr/asa):
Dosages of dextromethorphan hydrobromide and dextromethorphan polistirex are expressed in terms of dextromethorphan hydrobromide.
The usual dosage of dextromethorphan hydrobromide for adults and children 12 years of age or older is 10-20 mg every 4 hours or 30 mg every 6-8 hours, not to exceed 120 mg daily, or as directed by a clinician. The usual dosage for children 6 to younger than 12 years of age is 5-10 mg every 4 hours or 15 mg every 6-8 hours, not to exceed 60 mg daily, or as directed by a clinician. Children 2 to younger than 6 years of age may receive 2.5-5
mg every 4 hours or 7.5 mg every 6-8 hours, not to exceed 30 mg daily, or as directed by a clinician. Dosage in children younger than 2 years of age must be individualized.
Suggested dosages for children younger than 2 years of age+ for some cough and cold preparations have been published in various references for prescribing and parenting. Using recommended dosages for adults and older children, some clinicians have extrapolated dosages for these preparations based on the weight or age of children younger than 2 years of age. However, these extrapolations were based on assumptions that pathology of the disease and pharmacology of the drugs are similar in adults and pediatric patients.
There currently are no specific dosage recommendations (i.e., approved by the US Food and Drug Administration (FDA)) for cough and cold preparations for this patient population. (See Cautions: Pediatric Precautions.)
The usual dosage of dextromethorphan hydrobromide as the extended-release oral suspension containing the polistirex for adults and children 12 years of age or older is 60 mg twice daily. The usual dosage as the extended-release oral suspension for children 6 to younger than 12 years of age is 30 mg twice daily; children 2 to younger than 6 years of age may receive 15 mg twice daily.
Phenylephrine hydrochloride should be administered in the lowest effective dosage for the shortest possible time. When used to increase blood pressure in patients with acute hypotensive states, dosage should be individualized based on the pressor response.
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.
The usual dosage of dextromethorphan hydrobromide for adults and children 12 years of age or older is 10-20 mg every 4 hours or 30 mg every 6-8 hours, not to exceed 120 mg daily, or as directed by a clinician. The usual dosage for children 6 to younger than 12 years of age is 5-10 mg every 4 hours or 15 mg every 6-8 hours, not to exceed 60 mg daily, or as directed by a clinician. Children 2 to younger than 6 years of age may receive 2.5-5
mg every 4 hours or 7.5 mg every 6-8 hours, not to exceed 30 mg daily, or as directed by a clinician. Dosage in children younger than 2 years of age must be individualized.
Suggested dosages for children younger than 2 years of age+ for some cough and cold preparations have been published in various references for prescribing and parenting. Using recommended dosages for adults and older children, some clinicians have extrapolated dosages for these preparations based on the weight or age of children younger than 2 years of age. However, these extrapolations were based on assumptions that pathology of the disease and pharmacology of the drugs are similar in adults and pediatric patients.
There currently are no specific dosage recommendations (i.e., approved by the US Food and Drug Administration (FDA)) for cough and cold preparations for this patient population. (See Cautions: Pediatric Precautions.)
The usual dosage of dextromethorphan hydrobromide as the extended-release oral suspension containing the polistirex for adults and children 12 years of age or older is 60 mg twice daily. The usual dosage as the extended-release oral suspension for children 6 to younger than 12 years of age is 30 mg twice daily; children 2 to younger than 6 years of age may receive 15 mg twice daily.
Phenylephrine hydrochloride should be administered in the lowest effective dosage for the shortest possible time. When used to increase blood pressure in patients with acute hypotensive states, dosage should be individualized based on the pressor response.
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.
Dextromethorphan preparations are administered orally. Lozenges containing dextromethorphan hydrobromide should not be used in children younger than 6 years of age and liquid-filled capsules containing the drug should not be used in children younger than 12 years of age, unless otherwise directed by a clinician. Doxylamine succinate is administered orally.
The fixed combination of doxylamine/pyridoxine delayed-release Diclegis(R) and extended-release Bonjesta(R) tablets should be taken on an empty stomach with a glass of water; the tablets should be swallowed whole and should not be crushed, chewed, or split. 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.
The fixed combination of doxylamine/pyridoxine delayed-release Diclegis(R) and extended-release Bonjesta(R) tablets should be taken on an empty stomach with a glass of water; the tablets should be swallowed whole and should not be crushed, chewed, or split. 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.
No dosing information available.
No generic dosing information available.
The following drug interaction information is available for ALKA-SELTZER PLUS NIGHT (ASA) (doxylamine succinate/phenylephrine/dextromethorphan hbr/asa):
There are 9 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 |
|---|---|
| Sympathomimetics (Indirect & Mixed Acting)/MAOIs 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: Catecholamine stores increased by MAOIs can be released by indirect acting sympathomimetics such as ephedrine and amphetamine. MAO inhibitors also interfere with gut and liver metabolism of direct acting sympathomimetics (e.g oral phenylephrine). CLINICAL EFFECTS: Concurrent use of MAOIs may result in potentiation of sympathomimetic effects, which may result in headaches, hypertensive crisis, toxic neurological effects, and malignant hyperpyrexia. Fatalities have occurred. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Concurrent use of monoamine oxidase inhibitors and sympathomimetics is contraindicated. The manufacturers of sympathomimetic agents recommend waiting 14 days after discontinuation of MAO inhibitors before initiating the sympathomimetic. DISCUSSION: Indirect acting sympathomimetic amines may cause abrupt elevation of blood pressure when administered to patients taking monoamine oxidase inhibitors, resulting in a potentially fatal hypertensive crisis. Mixed (direct and indirect) acting sympathomimetics have also been shown to interact with monoamine oxidase inhibitors depending on their degree of indirect action. The direct-acting sympathomimetics have not been reported to interact. Dopamine is metabolized by monoamine oxidase, and its pressor effect is enhanced by monoamine oxidase inhibitors. Since procarbazine, an antineoplastic agent, is a weak monoamine oxidase inhibitor, hypertensive reactions may result from its concurrent use with indirect and mixed acting sympathomimetics. Furazolidone, an antibacterial with monoamine oxidase inhibitor action, has also been shown to interact with indirect acting sympathomimetics. Linezolid is another antibacterial with monoamine oxidase inhibitor properties. Metaxalone is a weak inhibitor of MAO. Foods containing large amounts of tyramine have also been implicated in this interaction. Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A. At recommended dosages, rasagiline, oral selegiline, and transdermal selegiline up to 6mg/day are selective for MAO-B; however, at higher dosages they have been shown to lose their selectivity. One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated 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. |
EMSAM, FURAZOLIDONE, MARPLAN, MATULANE, METAXALONE, METHYLENE BLUE, NARDIL, PARNATE, PHENELZINE SULFATE, PROCARBAZINE HCL, PROVAYBLUE, SELEGILINE HCL, TRANYLCYPROMINE SULFATE |
| Selected Opioids; Dextromethorphan/Selected MAOIs 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: Selected opioids inhibit neural reuptake of serotonin. MAOIs may increase neuronal serotonin concentrations via inhibition of MAO-A.(26) CLINICAL EFFECTS: The concurrent use of selected opioids with MAOIs has resulted in hypotension, hyperpyrexia, sedation, somnolence, and death. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(26) PREDISPOSING FACTORS: Higher opioid concentrations as may occur due to inhibition of opioid clearance, patient specific genomic factors (e.g. poor metabolizer status for a P450 enzyme), or high opioid dosage may increase the risk for a severe interaction. PATIENT MANAGEMENT: Dextromethorphan, diamorphine, meperidine, and tapentadol should not be used in patients taking MAOIs. Use alternative agents for cough or pain. The US manufacturer of Nuedexta(dextromethorphan-quinidine) states Nuedexta is contraindicated within 14 days of MAOI administration.(28) Quinidine increases systemic dextromethorphan concentrations 10 to 20-fold. Other strong CYP2D6 inhibitors such as bupropion, fluoxetine and paroxetine could similarly increase dextromethorphan levels. The US manufacturer of selegiline states that concurrent use with dextromethorphan or meperidine is contraindicated. The US manufacturers of meperidine and tapentadol and the UK manufacturer of diamorphine state that they should not be used concurrently with or within 14 days of taking an MAOI. DISCUSSION: The interaction between meperidine and MAOIs has been well documented. There are at least two reports of potential interactions between MAOIs and dextromethorphan. Concomitant use of quinidine, a strong CYP2D6 inhibitor, increases systemic dextromethorphan concentrations 10 to 20-fold. Other strong CYP2D6 inhibitors such as bupropion, fluoxetine and paroxetine could similarly increase dextromethorphan levels and risk for serotonin toxicity in patients also receiving MAOIs. Furazolidone is known to be a monoamine oxidase inhibitor. Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A. One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated 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. |
AZILECT, EMSAM, FURAZOLIDONE, MARPLAN, MATULANE, METHYLENE BLUE, NARDIL, PARNATE, PHENELZINE SULFATE, PROCARBAZINE HCL, PROVAYBLUE, RASAGILINE MESYLATE, SELEGILINE HCL, TRANYLCYPROMINE SULFATE, XADAGO, ZELAPAR |
| 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 |
| Selected Antihistamines/Selected MAOIs 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: MAOIs prolong and intensify the effects of antihistamines.(1-6) CLINICAL EFFECTS: Concurrent use of antihistamines and a MAOI may result in severe hypotension.(1-6) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Concurrent use of antihistamines and a MAOI is contraindicated.(1-6) DISCUSSION: MAOIs may prolong and intensify the effects of antihistamines, resulting in severe hypotension.(1-6) A case report describes a patient having cyproheptadine added to their phenelzine therapy in an attempt to relieve the patients anorgasmia. The patient began to suddenly experience visual hallucination after taking the cyproheptadine for two months. Once the medication was terminated, the hallucinations stopped occurring within 48 hours.(7) Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A.(8,9) |
AZILECT, EMSAM, FURAZOLIDONE, MARPLAN, MATULANE, METHYLENE BLUE, NARDIL, PARNATE, PHENELZINE SULFATE, PROCARBAZINE HCL, PROVAYBLUE, RASAGILINE MESYLATE, SELEGILINE HCL, TRANYLCYPROMINE SULFATE, XADAGO, ZELAPAR |
| 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 |
| Dichlorphenamide/Aspirin (Greater Than 325 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: Dichlorphenamide 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 dichlorphenamide 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 |
| Dextromethorphan/Metaxalone 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: Dextromethorphan inhibits neural reuptake of serotonin. Metaxalone, a weak inhibitor of MAO, may increase neuronal serotonin concentrations.(1) CLINICAL EFFECTS: The concurrent use of dextromethorphan with MAOIs may result in hypotension, hyperpyrexia, sedation, somnolence, and death. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(1) PREDISPOSING FACTORS: Higher opioid concentrations as may occur due to inhibition of opioid clearance, patient specific genomic factors (e.g. poor metabolizer status for a P450 enzyme), or high opioid dosage may increase the risk for a severe interaction. PATIENT MANAGEMENT: Dextromethorphan should not be used in patients taking MAOIs such as metaxalone. Use alternative agents for cough. The US manufacturer of Nuedexta (dextromethorphan-quinidine) states Nuedexta is contraindicated within 14 days of MAOI administration.(1) Quinidine increases systemic dextromethorphan concentrations 10 to 20-fold. DISCUSSION: Metaxalone is a weak inhibitor of MAO.(2,3) There are at least two reports of potential interactions between MAOIs and dextromethorphan. Concomitant use of quinidine, a strong CYP2D6 inhibitor, increases systemic dextromethorphan concentrations 10 to 20-fold. Other strong CYP2D6 inhibitors such as bupropion, fluoxetine and paroxetine could similarly increase dextromethorphan levels and risk for serotonin toxicity in patients also receiving MAOIs.(4,5) |
METAXALONE |
| Selected CYP2D6 Substrates/Mavorixafor 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: Mavorixafor is a strong inhibitor of CYP2D6 and is expected to inhibit the metabolism of agents through this pathway.(1) CLINICAL EFFECTS: Concurrent use of mavorixafor may result in elevated levels of and toxicity from agents metabolized by CYP2D6.(1) PREDISPOSING FACTORS: With tricyclic antidepressants, the risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids). With anticholinergic agents, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(2) PATIENT MANAGEMENT: The US manufacturer of mavorixafor states concurrent use with CYP2D6 substrate that are highly dependent on CYP2D6 metabolism is contraindicated.(1) DISCUSSION: Mavorixafor (400 mg) increased dextromethorphan (CYP2D6 substrate) maximum concentration (Cmax) and area-under-curve (AUC) by 6-fold and 9-fold, respectively.(1) Selected CYP2D6 substrates linked to this monograph include: aripiprazole, brexpiprazole, desipramine, deutetrabenazine, dextromethorphan, doxepin, encainide, fenfluramine, metoclopramide, methoxyphenamine, metoprolol, mexiletine, nebivolol, paroxetine, perphenazine, risperidone, tetrabenazine, trimipramine, venlafaxine, and yohimbine. |
XOLREMDI |
There are 32 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). 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, OTREXUP, RASUVO, TREXALL, XATMEP |
| Ergot Alkaloids/Sympathomimetics SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Concurrent use of ergot alkaloids and sympathomimetics may result in additive or synergistic effect on peripheral blood vessels. CLINICAL EFFECTS: Concurrent use of ergot alkaloids and sympathomimetics may result in increased blood pressure due to peripheral vasoconstriction. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: When possible, avoid the concurrent use of ergot alkaloids and sympathomimetics. If concurrent use is warranted, monitor blood pressure and for signs of vasoconstriction. Decreasing the dose of one or both drugs may be necessary. DISCUSSION: There have been reports of severe vasoconstriction resulting in gangrene in patients receiving intravenous ergonovine with dopamine or norepinephrine. |
DIHYDROERGOTAMINE MESYLATE, ERGOLOID MESYLATES, ERGOMAR, ERGOTAMINE TARTRATE, ERGOTAMINE-CAFFEINE, METHYLERGONOVINE MALEATE, METHYSERGIDE MALEATE, MIGERGOT, MIGRANAL, TRUDHESA |
| 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 |
| Selected Inhalation Anesthetic Agents/Sympathomimetics SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: The exact mechanism is unknown. The anesthetics produce conduction changes that increase impulse re-entry into the myocardial tissue.(1) The anesthetics' ability to precipitate arrhythmias is enhanced by elevated arterial blood pressure, tachycardia, hypercapnia, and/or hypoxia, events that stimulate the release of endogenous catecholamines.(1) CLINICAL EFFECTS: Concurrent use of inhalation anesthetic agents and sympathomimetics may result in ventricular arrhythmias or sudden blood pressure and heart rate increase during surgery.(2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Monitor blood pressure and avoid use of sympathomimetics in patients being treated with anesthetics on the day of surgery.(2) Intravenous use of epinephrine during surgery with halothane and related halogenated general anesthetics should be strongly discouraged. When intravenous epinephrine is necessary, nitrous oxide anesthesia supplemented with ether, muscle relaxants, or opioids should be used instead of halothane.(3,4) Epinephrine may safely be used subcutaneously with the following precautions: the patient is adequately ventilated to prevent hypoxia or respiratory acidosis; the total dose of epinephrine is limited to 100 mcg/10 minute period or 300 mcg/hour in adults, 3.5 mcg/Kg in infants, 2.5 mcg/Kg in children up to two years of age, and 1.45 mcg/Kg in children over two years of age; a minimum effective concentration of anesthetic is maintained; the drugs are not co-administered in patients with hypertension or other cardiovascular disorders; and the cardiac rhythm is continuously monitored during and after injection.(3-10) If arrhythmias occur after the administration of the epinephrine, the drugs of choice are lidocaine or propranolol, depending on the type of arrhythmia.(1) DISCUSSION: Administration of epinephrine during halothane anesthesia may may lead to serious ventricular arrhythmias.(3-6,11-18) This has occurred when epinephrine was administered intravenously,(6) when it was administered with lidocaine as a dental block,(11,14) or when it was administered supraperiosteally.(5) Norepinephrine has been shown to interact with halothane in a manner similar to epinephrine.(1) In two case reports, patients were given terbutaline (0.25 to 0.35 mg) for wheezing following induction of anesthesia with halothane. One patient's heart rate increased from 68 to 100 beats/minute, and the ECG showed premature ventricular contractions and bigeminy, while the other patient developed multiple unifocal premature ventricular contractions and bigeminy. The arrhythmias resolved in both patients following lidocaine administration.(19) Although not documented, isoproterenol causes effects on the heart similar to terbutaline(20) and would probably interact with halothane in a similar manner. Other inhalation anesthetics that increase the incidence of arrhythmias with epinephrine include chloroform,(20) methoxyflurane,(20) and enflurane.(12) A similar interaction may be expected between the other inhalation anesthetics and sympathomimetics. |
DESFLURANE, FORANE, ISOFLURANE, SEVOFLURANE, SUPRANE, TERRELL, ULTANE |
| 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 TRIVALENT 2024-2025 |
| 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 (creatine 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. |
ALIMTA, AXTLE, PEMETREXED, PEMETREXED DISODIUM, PEMFEXY, PEMRYDI RTU |
| Solid Oral Potassium Tablets/Anticholinergics SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Concentrated potassium may damage the lining of the GI tract. Anticholinergics delay gastric emptying, resulting in the potassium product remaining in the gastrointestinal tract for a longer period of time.(1-16) CLINICAL EFFECTS: Use of solid oral dosage forms of potassium in patients treated with anticholinergics may result in gastrointestinal erosions, ulcers, stenosis and bleeding.(1-16) PREDISPOSING FACTORS: Diseases or conditions which may increase risk for GI damage include: preexisting dysphagia, strictures, cardiomegaly, diabetic gastroparesis, elderly status, or insufficient oral intake to allow dilution of potassium.(1-10,21) Other drugs which may add to risk for GI damage include: nonsteroidal anti-inflammatory drugs (NSAIDs), bisphosphonates, or tetracyclines.(21) PATIENT MANAGEMENT: Regulatory agency and manufacturer recommendations regarding this interaction: - In the US, all solid oral dosage forms (including tablets and extended release capsules) of potassium are contraindicated in patients receiving anticholinergics at sufficient dosages to result in systemic effects.(2-8) Patients receiving such anticholinergic therapy should use a liquid form of potassium chloride.(2) - In Canada, solid oral potassium is contraindicated in any patient with a cause for arrest or delay in tablet/capsule passage through the gastrointestinal tract and the manufacturers recommend caution with concurrent anticholinergic medications.(1,9-10) Evaluate each patient for predisposing factors which may increase risk for GI damage. In patients with multiple risk factors for harm, consider use of liquid potassium supplements, if tolerated. For patients receiving concomitant therapy, assure any potassium dose form is taken after meals with a large glass of water or other fluid. To decrease potassium concentration in the GI tract, limit each dose to 20 meq; if more than 20 meq daily is required, give in divided doses.(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. Patients should be instructed to immediately report any difficulty swallowing, abdominal pain, distention, severe vomiting, or gastrointestinal 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 clinical trials, there was a higher incidence of gastric and duodenal lesions in patients receiving a high dose of a wax-matrix controlled-release formulation with a concurrent anticholinergic agent. Some lesions were asymptomatic and not accompanied by bleeding, as shown by a lack of positive Hemoccult tests.(1-17) Several studies suggest that the incidence of gastric and duodenal lesions may be less with the microencapsulated formulation of potassium chloride.(14-17) |
KLOR-CON 10, KLOR-CON 8, KLOR-CON M10, KLOR-CON M15, KLOR-CON M20, POTASSIUM CHLORIDE, POTASSIUM CITRATE ER, UROCIT-K |
| 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 |
| Solid Oral Potassium Capsules/Anticholinergics SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Concentrated potassium may damage the lining of the GI tract. Anticholinergics delay gastric emptying, resulting in the potassium product remaining in the gastrointestinal tract for a longer period of time.(1-16)) CLINICAL EFFECTS: Use of solid oral dosage forms of potassium in patients treated with anticholinergics may result in gastrointestinal erosions, ulcers, stenosis and bleeding.(1-16) PREDISPOSING FACTORS: Diseases or conditions which may increase risk for GI damage include: preexisting dysphagia, strictures, cardiomegaly, diabetic gastroparesis, elderly status, or insufficient oral intake to allow dilution of potassium.(1-10,21) Other drugs which may add to risk for GI damage include: nonsteroidal anti-inflammatory drugs (NSAIDs), bisphosphonates, or tetracyclines.(21) PATIENT MANAGEMENT: Regulatory agency and manufacturer recommendations regarding this interaction: - In the US, all solid oral dosage forms (including tablets and extended release capsules) of potassium are contraindicated in patients receiving anticholinergics at sufficient dosages to result in systemic effects.(2-8) Patients receiving such anticholinergic therapy should use a liquid form of potassium chloride.(2) - In Canada, solid oral potassium is contraindicated in any patient with a cause for arrest or delay in tablet/capsule passage through the gastrointestinal tract and the manufacturers recommend caution with concurrent anticholinergic medications.(1,9-10) Evaluate each patient for predisposing factors which may increase risk for GI damage. In patients with multiple risk factors for harm, consider use of liquid potassium supplements, if tolerated. For patients receiving concomitant therapy, assure any potassium dose form is taken after meals with a large glass of water or other fluid. To decrease potassium concentration in the GI tract, limit each dose to 20 meq; if more than 20 meq daily is required, give in divided doses.(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. Patients should be instructed to immediately report any difficulty swallowing, abdominal pain, distention, severe vomiting, or gastrointestinal 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 clinical trials, there was a higher incidence of gastric and duodenal lesions in patients receiving a high dose of a wax-matrix controlled-release formulation with a concurrent anticholinergic agent. The lesions were asymptomatic and not accompanied by bleeding, as shown by a lack of positive Hemoccult tests.(1-17) Several studies suggest that the incidence of gastric and duodenal lesions may be less with the microencapsulated formulation of potassium chloride.(14-17) |
POTASSIUM CHLORIDE |
| Mixed;Indirect Sympathomimetics/Selected MAOIs SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Catecholamine stores increased by MAOIs can be released by indirect acting sympathomimetics such as ephedrine and amphetamine. MAO inhibitors also interfere with gut and liver metabolism of direct acting sympathomimetics (e.g oral phenylephrine). CLINICAL EFFECTS: Concurrent use of MAOIs may result in potentiation of sympathomimetic effects, which may result in headaches, hypertensive crisis, toxic neurological effects, and malignant hyperpyrexia. Fatalities have occurred with combinations of sympathomimetics and MAO-A inhibitors. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Concurrent use of MAO-A inhibitors and sympathomimetics is contraindicated. The manufacturers of sympathomimetic agents recommend waiting 14 days after discontinuation of MAO inhibitors before initiating the sympathomimetic. Patients receiving direct or indirect acting sympathomimetics should not receive linezolid unless they are monitored for potential increases in blood pressure. Initial dosages of dopamine and epinephrine should be reduced. At recommended dosages, oral selegiline and transdermal selegiline up to 6mg/day are selective for MAO-B; however, at higher dosages they have been shown to lose their selectivity. Patients receiving higher dosages of selegiline should be considered susceptive to this interaction. DISCUSSION: Indirect acting sympathomimetic amines may cause abrupt elevation of blood pressure when administered to patients taking monoamine oxidase inhibitors, resulting in a potentially fatal hypertensive crisis. Mixed (direct and indirect) acting sympathomimetics have also been shown to interact with monoamine oxidase inhibitors depending on their degree of indirect action. The direct-acting sympathomimetics have not been reported to interact. Dopamine is metabolized by monoamine oxidase, and its pressor effect is enhanced by monoamine oxidase inhibitors. Furazolidone, an antibacterial with monoamine oxidase inhibitor action, has also been shown to interact with indirect acting sympathomimetics. Foods containing large amounts of tyramine have also been implicated in this interaction. A significant pressor response was observed in normal subjects receiving linezolid and tyramine doses of more than 100 mg. Administration of linezolid (600 mg BID for 3 days) with pseudoephedrine (60 mg q 4 hours for 2 doses) increased blood pressure by 32 mmHg. Administration of linezolid (600 mg BID for 3 days) with phenylpropanolamine (25 mg q 4 hours for 2 doses) increased blood pressure by 38 mmHg. One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated 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. |
EMSAM, LINEZOLID, LINEZOLID-0.9% NACL, LINEZOLID-D5W, SELEGILINE HCL, XADAGO, ZELAPAR, ZYVOX |
| 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 |
| 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 |
| Radioactive Iodide/Agents that Affect Iodide SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Many compounds can affect iodide protein binding and alter iodide pharmacokinetics and pharmacodynamics.(1) CLINICAL EFFECTS: Compounds that affect iodide pharmacokinetics and pharmacodynamics may impact the effectiveness of radioactive iodide.(1) PREDISPOSING FACTORS: Compounds that affect iodide pharmacokinetics and pharmacodynamics are expected to have the most impact during therapy using radioactive iodide. Diagnostic procedures would be expected to be impacted less. PATIENT MANAGEMENT: Discuss the use of agents that affect iodide pharmacokinetics and pharmacodynamics with the patient's oncologist.(1) Because indocyanine green contains sodium iodide, the iodine-binding capacity of thyroid tissue may be reduced for at least one week following administration. Do not perform radioactive iodine uptake studies for at least one week following administration of indocyanine green.(2) The manufacturer of iopamidol states administration may interfere with thyroid uptake of radioactive iodine and decrease therapeutic and diagnostic efficacy. Avoid thyroid therapy or testing for up to 6 weeks post administration of iopamidol.(3) DISCUSSION: Many agents interact with radioactive iodine. The average duration of effect is: anticoagulants - 1 week antihistamines - 1 week anti-thyroid drugs, e.g: carbimazole, methimazole, propylthiouracil - 3-5 days corticosteroids - 1 week iodide-containing medications, e.g: amiodarone - 1-6 months expectorants - 2 weeks Lugol solution - 3 weeks saturated solution of potassium iodine - 3 weeks vitamins - 10-14 days iodide-containing X-ray contrast agents - up to 1 year lithium - 4 weeks phenylbutazone - 1-2 weeks sulfonamides - 1 week thyroid hormones (natural or synthetic), e.g.: thyroxine - 4 weeks tri-iodothyronine - 2 weeks tolbutamide - 1 week topical iodide - 1-9 months (1) |
ADREVIEW, JEANATOPE, MEGATOPE, SODIUM IODIDE I-123 |
| 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). 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 |
| Selected Direct-Acting Sympathomimetics/Tricyclic Compounds SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Unknown. However, it is speculated that direct-acting sympathomimetic amines have an enhanced effect due to tricyclic blockage of norepinephrine reuptake. CLINICAL EFFECTS: Increased effect of direct acting sympathomimetics. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Consider avoiding the concurrent use of direct-acting sympathomimetics and tricyclic compounds. If concurrent use of direct-acting sympathomimetics and tricyclic compounds is warranted, the initial dose of the sympathomimetic should be lowered and the patient should be monitored for adverse cardiovascular effects. Use of tricyclic compounds and other sympathomimetics should be approached with caution. DISCUSSION: Epinephrine and other direct-acting sympathomimetic amines exert enhanced cardiovascular effects (e.g., arrhythmias, hypertension, and tachycardia) in individuals concurrently receiving or previously treated with tricyclic antidepressants. Other direct and mixed acting sympathomimetic amines have also been reported to interact with tricyclic antidepressants. These include norepinephrine, phenylephrine, dopamine, and methoxamine. Protriptyline, amitriptyline, and desipramine have also been reported to interact with direct-acting sympathomimetics. |
AMITRIPTYLINE HCL, AMOXAPINE, ANAFRANIL, CHLORDIAZEPOXIDE-AMITRIPTYLINE, CLOMIPRAMINE HCL, DESIPRAMINE HCL, DOXEPIN HCL, IMIPRAMINE HCL, IMIPRAMINE PAMOATE, NORPRAMIN, NORTRIPTYLINE HCL, PAMELOR, PERPHENAZINE-AMITRIPTYLINE, PROTRIPTYLINE HCL, SILENOR, TRIMIPRAMINE MALEATE |
| Iobenguane I 123/Agents that Affect Catecholamines SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Many compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with iobenguane uptake into cells.(1) CLINICAL EFFECTS: Compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with imaging completed with iobenguane.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Discuss the use of agents that affect catecholamines. Discontinue drugs that reduce catecholamine uptake or deplete catecholamine stores prior to imaging with iobenguane. Before imaging with iobenguane, discontinue agents that affect catecholamines for at least 5 biological half-lives, as clinically tolerated.(1) DISCUSSION: Many agents may reduce catecholamine uptake or deplete catecholamine stores.(1) Examples include: - CNS stimulants or amphetamines (e.g. cocaine, methylphenidate, dextroamphetamine) - norepinephrine and dopamine reuptake inhibitors (e.g. phentermine) - norepinephrine and serotonin reuptake inhibitors (e.g. tramadol) - monoamine oxidase inhibitors (e.g. phenelzine, linezolid) - central monoamine depleting drugs (e.g. reserpine) - non-select beta adrenergic blocking drugs (e.g. labetalol) - alpha agonists or alpha/beta agonists (e.g. pseudoephedrine, phenylephrine, ephedrine, phenylpropanolamine, naphazoline) - tricyclic antidepressants or norepinephrine reuptake inhibitors (e.g. amitriptyline, bupropion, duloxetine, mirtazapine, venlafaxine) - botanicals that may inhibit reuptake of norepinephrine, serotonin or dopamine (e.g. ephedra, ma huang, St. John's Wort, yohimbine) |
ADREVIEW |
| Selected CYP2D6 Substrates/Panobinostat SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Panobinostat is a moderate inhibitor of CYP2D6 and is expected to inhibit the metabolism of agents through this pathway.(1) CLINICAL EFFECTS: Concurrent use of panobinostat may result in elevated levels of and toxicity from agents metabolized by CYP2D6.(1) PREDISPOSING FACTORS: With tricyclic antidepressants, the risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids). With anticholinergic agents, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(4) PATIENT MANAGEMENT: Avoid the concurrent use of panobinostat with agents that are sensitive CYP2D6 or CYP2D6 substrates with a narrow therapeutic index. If concurrent use is warranted, monitor patients for toxicity.(1) DISCUSSION: In a study in 14 subjects with advanced cancer, panobinostat (20 mg daily on Days 3, 5, and 8) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of dextromethorphan (60 mg) by 20-200% and 20-130%, respectively. Dextromethorphan exposures were extremely variable.(1) Selected CYP2D6 substrates linked to this monograph include: desipramine, deutetrabenazine, dextromethorphan, doxepin, encainide, methoxyphenamine, metoprolol, nebivolol, paroxetine, perphenazine, risperidone, tetrabenazine, trimipramine, venlafaxine, and yohimbine. |
FARYDAK |
| Selected CYP1A2 or CYP2D6 Substrates/Givosiran SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Givosiran interferes with the first and rate-limiting step in hepatic heme biosynthesis, which may lower hepatic heme levels and decrease production and/or activity of cytochrome P450 enzymes.(1,2) CLINICAL EFFECTS: Concurrent use of givosiran may result in elevated levels of and toxicity from agents metabolized by CYP1A2 or CYP2D6.(1) PREDISPOSING FACTORS: With tricyclic antidepressants, the risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids). With anticholinergic agents, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(3) PATIENT MANAGEMENT: Avoid the concurrent use of givosiran with agents that are sensitive substrates of CYP1A2 or CYP2D6, or CYP1A2 or CYP2D6 substrates with a narrow therapeutic index. If concurrent use is unavoidable, decrease the dose of the CYP1A2 or CYP2D6 substrate and monitor patients for toxicity. DISCUSSION: A study of 9 patients with acute intermittent porphyria found that givosiran decreased the maximum concentration (Cmax) and area-under-curve (AUC) of caffeine (a CYP1A2 substrate) by 1.3- and 3.1-fold, respectively, compared to caffeine alone. Givosiran also decreased the Cmax and AUC of dextromethorphan (a CYP2D6 substrate) by 2- and 2.4-fold, respectively, compared to dextromethorphan alone.(1,2) Selected CYP2D6 substrates linked to this monograph include: desipramine, deutetrabenazine, dextromethorphan, doxepin, encainide, methoxyphenamine, metoprolol, nebivolol, nefazodone, paroxetine, perphenazine, risperidone, tetrabenazine, trimipramine, and venlafaxine. Selected CYP1A2 substrates linked to this monograph include: agomelatine, aminophylline, rasagiline, tacrine, theophylline, tizanidine, and yohimbine. |
GIVLAARI |
| Clozapine/Anticholinergics SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Clozapine has potent anticholinergic properties and inhibits serotonin receptors, including 5-HT3.(1-4) Both of these properties may cause inhibition of gastrointestinal (GI) smooth muscle contraction, resulting in decreased peristalsis.(3,4) These effects may be compounded by concurrent use of anticholinergic agents.(1-6) CLINICAL EFFECTS: Concurrent use of clozapine with other anticholinergic agents may increase the risk of constipation (common) and serious bowel complications (uncommon), including complete bowel obstruction, fecal impaction, paralytic ileus and intestinal ischemia or infarction.(1-6) PREDISPOSING FACTORS: The risk for serious bowel complications is higher with increasing age, higher frequency of constipation, and in patients on higher doses of clozapine or multiple anticholinergic agents.(1,5) PATIENT MANAGEMENT: Avoid the use of other anticholinergic agents with clozapine.(1-6) 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.(2) Consider a prophylactic laxative in those with a history of constipation or bowel obstruction.(2) Review patient medication list for other anticholinergic agents. When possible, decrease the dosage or number of prescribed anticholinergic agents, particularly in the elderly. Counsel the patient about the importance of maintaining adequate hydration. Encourage regular exercise and eating a high-fiber diet.(2) DISCUSSION: In a prospective cohort study of 26,720 schizophrenic patients in the Danish Central Psychiatric Research Registry, the odds ratio (OR) for ileus was 1.99 with clozapine and 1.48 with anticholinergics. The OR for fatal ileus was 6.73 with clozapine and 5.88 with anticholinergics. Use of anticholinergics with 1st generation antipsychotics (FGA) increased the risk of ileus compare to FGA alone, but this analysis was not done with clozapine.(5) A retrospective cohort study of 24,970 schizophrenic patients from the Taiwanese National Health Insurance Research Database found that the hazard ratio (HR) for clozapine-induced constipation increased from 1.64 when clozapine is used alone, to 2.15 when used concomitantly with anticholinergics. However, there was no significant difference in the HR for ileus when clozapine is used with and without anticholinergics (1.95 and 2.02, respectively).(6) In the French Pharmacovigilance Database, 7 of 38 cases of antipsychotic-associated ischemic colitis or intestinal necrosis involved clozapine, and 5 of these cases involved use of concomitant anticholinergic agents. Three patients died, one of whom was on concomitant anticholinergics.(3) In a case series, 4 of 9 cases of fatal clozapine-associated GI dysfunction involved concurrent anticholinergic agents.(4) |
CLOZAPINE, CLOZAPINE ODT, CLOZARIL, VERSACLOZ |
| 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 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 either anticoagulants or 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. 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 and antiplatelets. 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 |
| Mixed;Indirect Sympathomimetics/Rasagiline SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Catecholamine stores increased by MAOIs can be released by indirect acting sympathomimetics such as ephedrine and amphetamine. MAO inhibitors also interfere with gut and liver metabolism of direct acting sympathomimetics (e.g oral phenylephrine). CLINICAL EFFECTS: Concurrent use of MAOIs may result in potentiation of sympathomimetic effects, which may result in headaches, hypertensive crisis, toxic neurological effects, and malignant hyperpyrexia. Hypertensive crisis has been reported in patients taking recommended doses of rasagiline with sympathomimetic agents. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: At recommended dosages, rasagiline is selective for MAO-B; however, at higher dosages it has been shown to lose its selectivity. Patients receiving higher dosages of rasagiline should be considered susceptive to this interaction. Concurrent use should be approached with caution. DISCUSSION: Indirect acting sympathomimetic amines may cause abrupt elevation of blood pressure when administered to patients taking monoamine oxidase inhibitors, resulting in a potentially fatal hypertensive crisis. Mixed (direct and indirect) acting sympathomimetics have also been shown to interact with monoamine oxidase inhibitors depending on their degree of indirect action. The direct-acting sympathomimetics have not been reported to interact. Dopamine is metabolized by monoamine oxidase, and its pressor effect is enhanced by monoamine oxidase inhibitors. |
AZILECT, RASAGILINE MESYLATE |
| Glucagon (Diagnostic)/Anticholinergics SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Glucagon and anticholinergic agents may have additive effects on inhibition of gastrointestinal motility.(1) CLINICAL EFFECTS: Concurrent use of glucagon with anticholinergic agents may increase the risk of gastrointestinal hypomotility, including constipation and bowel complications.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Concurrent use of glucagon as a diagnotic aid is not recommended with the use of anticholinergic agents.(1) If concurrent use is necessary, evaluate the patient's bowel function. Monitor for symptoms of constipation and gastrointestinal hypomotility. DISCUSSION: Both glucagon and anticholinergic agents may have additive effects on inhibition of gastrointestinal motility and increase the risk of gastrointestinal adverse effects.(1) |
GLUCAGON HCL |
| Sodium Iodide I 131/Agents that Affect Iodide SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Many compounds can affect iodide protein binding and alter iodide pharmacokinetics and pharmacodynamics.(1,2) CLINICAL EFFECTS: Compounds that affect iodide pharmacokinetics and pharmacodynamics may impact the effectiveness of radioactive iodide.(1,2) PREDISPOSING FACTORS: Compounds that affect iodide pharmacokinetics and pharmacodynamics are expected to have the most impact during therapy using radioactive iodide. Diagnostic procedures would be expected to be impacted less. PATIENT MANAGEMENT: Discuss the use of agents that affect iodide pharmacokinetics and pharmacodynamics with the patient's oncologist.(1,2) Because indocyanine green contains sodium iodide, the iodine-binding capacity of thyroid tissue may be reduced for at least one week following administration. Do not perform radioactive iodine uptake studies for at least one week following administration of indocyanine green.(3) The manufacturer of iopamidol states administration may interfere with thyroid uptake of radioactive iodine and decrease therapeutic and diagnostic efficacy. Avoid thyroid therapy or testing for up to 6 weeks post administration of iopamidol.(4) DISCUSSION: Many agents interact with radioactive iodine. The average duration of effect is: anticoagulants - 1 week antihistamines - 1 week anti-thyroid drugs, e.g: carbimazole, methimazole, propylthiouracil - 3-5 days corticosteroids - 1 week iodide-containing medications, e.g: amiodarone - 1-6 months expectorants - 2 weeks Lugol solution - 3 weeks saturated solution of potassium iodine - 3 weeks vitamins - 10-14 days iodide-containing X-ray contrast agents - up to 1 year lithium - 4 weeks phenylbutazone - 1-2 weeks sulfonamides - 1 week thyroid hormones (natural or synthetic), e.g.: thyroxine - 4 weeks tri-iodothyronine - 2 weeks tolbutamide - 1 week topical iodide - 1-9 months (1,2) |
HICON, SODIUM IODIDE I-131 |
There are 37 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. |
DUZALLO, 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, ETHACRYNATE SODIUM, ETHACRYNIC ACID, FUROSCIX, FUROSEMIDE, FUROSEMIDE-0.9% NACL, LASIX, 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, GLUCOTROL XL, GLYBURIDE, GLYBURIDE MICRONIZED, 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 |
| Angiotensin II Receptor Blocker (ARB)/NSAIDs; Salicylates 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 ARBs 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. Concurrent use of ARBs with NSAIDs 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: Patients maintained on ARBs 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 ARBs. 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 ARB therapy. Concurrent use of ARBs with NSAIDs and diuretics should be used with caution and monitored for signs of AKI. 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.(22,23) 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).(24) 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. |
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, TELMISARTAN, TELMISARTAN-AMLODIPINE, TELMISARTAN-HYDROCHLOROTHIAZID, TRIBENZOR, VALSARTAN, VALSARTAN-HYDROCHLOROTHIAZIDE |
| Sympathomimetics (Direct, Mixed-Acting)/Guanethidine SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Direct or mixed-acting sympathomimetics may inhibit uptake of guanethidine at the adrenergic neuron. CLINICAL EFFECTS: Decreased antihypertensive effectiveness. Effects may be seen for several days after discontinuation of the direct or mixed-acting sympathomimetic. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Avoid concomitant administration of these drugs. If both drugs are administered, adjust the guanethidine dose as needed based on blood pressure. DISCUSSION: Documentation supports routine monitoring of this interaction. It should be noted that this interaction can occur quickly. |
GUANETHIDINE HEMISULFATE |
| 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, CORGARD, 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 |
| Sympathomimetics/Rauwolfia Alkaloids SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Reserpine depletes catecholamine stores within the peripheral vascular adrenergic nerve endings, thus indirect acting sympathomimetics are unable to trigger the release of catecholamines. The reserpine-induced catecholamine release increases sensitivity to the effects of direct acting sympathomimetics. CLINICAL EFFECTS: Increased effects of direct acting sympathomimetics. Decreased effects of indirect acting sympathomimetics. Mixed acting sympathomimetics will show effects based on the predominance of either direct or indirect activity. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: If these agents are administered concurrently, monitor blood pressure. The dose of the sympathomimetic may need to be adjusted. DISCUSSION: This interaction has been well documented in animal studies and human case reports have confirmed the interaction. Reserpine has been shown to decrease the response to epinephrine administered for hypotension. Reserpine has also been shown to decrease the effectiveness of ophthalmic epinephrine, a direct acting sympathomimetic. Ophthalmic phenylephrine has been shown to decrease the hypotensive effects of reserpine. |
RESERPINE |
| 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 |
| Sympathomimetics (Direct, Mixed-Acting)/Methyldopa SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Unknown. CLINICAL EFFECTS: The pressor response to sympathomimetics may be increased. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Start with low doses of sympathomimetics and monitor blood pressure of patients during concurrent administration of sympathomimetics and methyldopa. DISCUSSION: The pressor response to sympathomimetics has been reported to be increased during methyldopa administration. In addition to increased duration of pressor response, severe hypertension has been reported. |
METHYLDOPA, METHYLDOPA-HYDROCHLOROTHIAZIDE, METHYLDOPATE HCL |
| 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 |
| 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, CYMBALTA, 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, 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: Aspirin's inhibition of prostaglandin synthesis may inhibit the release of vasodilating prostaglandins by ACE inhibitors. CLINICAL EFFECTS: Concurrent use of aspirin may result in decreased antihypertensive effects of the ACE inhibitor. PREDISPOSING FACTORS: None determined. 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. 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. 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. |
ACCUPRIL, ACCURETIC, 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, VESTURA, YASMIN 28, YAZ, ZARAH, ZUMANDIMINE |
| Dextromethorphan/Selected SSRIs that Inhibit CYP2D6 SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Fluoxetine and paroxetine, strong inhibitors of CYP2D6, may inhibit the metabolism of dextromethorphan.(1-4) CLINICAL EFFECTS: Patients may experience increased adverse effects of dextromethorphan due to elevated systemic concentrations. Concomitant use of two or more serotonergic agents increases the risk for serotonin syndrome. Serotonin syndrome constitutes a range of toxicities from mild to life threatening.(5) Mild serotonin symptoms may include: shivering, diaphoresis, mydriasis, intermittent tremor, and/or myoclonus.(5) Moderate serotonin symptoms may include: tachycardia, hypertension, hyperthermia, mydriasis, diaphoresis, hyperactive bowel sounds, hyperreflexia, and/OR clonus.(5) Severe serotonin symptoms may include: severe hypertension and tachycardia, shock, agitated delirium, muscular rigidity, and/or hypertonicity.(5) PREDISPOSING FACTORS: Concurrent use of additional drugs which increase CNS serotonin levels would be expected to further increase risk for serotonin syndrome.(5) PATIENT MANAGEMENT: Monitor patients on multiple serotonergic agents for symptoms of serotonin toxicity. Patients in whom serotonin syndrome is suspected should receive immediate medical attention. If the interacting agents are prescribed by different providers, it would be prudent to assure that both are aware of concomitant therapy and monitoring the patient for serotonin toxicities. Advise patients not to exceed recommended dosages of dextromethorphan. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea. DISCUSSION: An open label parallel group trial evaluated the interaction between dextromethorphan-quinidine 30 mg-30 mg (higher than marketed strength of 20 mg-10 mg) and paroxetine 20 mg in 27 healthy volunteers with a mean age of 33.6 years. Subjects were randomly divided into 2 groups: - Group 1 received paroxetine 20 mg once daily for 12 days, followed by the addition of dextromethorphan-quinidine twice daily for 8 days. - Group 2 received dextromethorphan-quinidine twice daily for 8 days, followed by paroxetine 20 mg daily for 12 days. Results: overall, adverse effects were reported in 19 of 26 subjects who received combination therapy (73%) and 15 of 27 subjects who received monotherapy (56%). Adverse effects from the combination differed somewhat between groups and were more closely associated with the second drug product administered. Group 1 reported dizziness, headache, somnolence, euphoria, nausea, and vomiting after the addition of dextromethorphan-quinidine to paroxetine. Group 2 adverse events were dizziness, headache, nausea, vomiting, insomnia, anxiety, and hyperhidrosis after the addition of paroxetine to dextromethorphan.(1) Two weeks of fluoxetine therapy increased the area-under-curve (AUC) of dextromethorphan by 27-fold.(4) Serotonin syndrome has been reported in patients following the addition of dextromethorphan containing cough syrups to fluoxetine(6,7) and paroxetine.(8) |
FLUOXETINE DR, FLUOXETINE HCL, OLANZAPINE-FLUOXETINE HCL, PAROXETINE CR, PAROXETINE ER, PAROXETINE HCL, PAROXETINE MESYLATE, PAXIL, PAXIL CR, PROZAC |
| 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 |
| 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 |
| Selected CYP2D6 Substrates/Desvenlafaxine SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Desvenlafaxine is considered a weak inhibitor of CYP2D6.(1) CLINICAL EFFECTS: Concurrent use of desvenlafaxine may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP2D6 pathway.(1) Agents linked to this monograph are: atomoxetine, dapoxetine, deutetrabenazine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine, and yohimbine. PREDISPOSING FACTORS: With perphenazine and tolterodine, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(2) PATIENT MANAGEMENT: Reduce the dose of CYP2D6 substrates by up to one-half when coadministered with desvenlafaxine 400 mg.(1) Studies have shown that desvenlafaxine does not have a clinically relevant effect on CYP2D6 metabolism at the dose of 100 mg daily. CYP2D6 substrates should be dosed at the original level when coadministered with desvenlafaxine 100 mg or lower or when desvenlafaxine is discontinued.(1) DISCUSSION: In a study, coadministration of desvenlafaxine 100 mg daily with desipramine (single dose 50 mg) increased desipramine's maximum concentration (Cmax) and area-under-the-curve (AUC)by 25% and 17%.(1) In a study, coadministration of desvenlafaxine 400 mg daily with desipramine (single dose 50 mg) increased desipramine's maximum concentration (Cmax) and area-under-the-curve (AUC)by 50% and 90%.(1) Selected CYP2D6 substrates linked to this monograph are: atomoxetine, dapoxetine, deutetrabenazine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine, and yohimbine. |
DESVENLAFAXINE ER, DESVENLAFAXINE SUCCINATE ER, PRISTIQ |
| 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 |
| 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 |
| Zonisamide/Anticholinergics SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Zonisamide can cause decreased sweating and elevated body temperature. Agents with anticholinergic activity can predispose patients to heat-related disorders.(1-2) CLINICAL EFFECTS: Concurrent use of zonisamide with agents with anticholinergic activity may increase the incidence of oligohidrosis and hyperthermia, especially in pediatric or adolescent patients.(1-2) Overheating and dehydration can lead to brain damage and death. PREDISPOSING FACTORS: Pediatric and adolescent patients and patients with dehydration may be more likely to experience heat-related disorders.(1) PATIENT MANAGEMENT: The UK and US manufacturers of zonisamide state that caution should be used in adults when zonisamide is prescribed with other medicinal products that predispose to heat-related disorders, such as agents with anticholinergic activity.(1-2) Pediatric and adolescent patients must not take anticholinergic agents (e.g. clomipramine, hydroxyzine, diphenhydramine, haloperidol, imipramine, and oxybutynin) concurrently with zonisamide.(1) Monitor for signs and symptoms of heat stroke: skin feels very hot with little or no sweating, confusion, muscle cramps, rapid heartbeat, or rapid breathing. Monitor for signs and symptoms of dehydration: dry mouth, urinating less than usual, dark-colored urine, dry skin, feeling tired, dizziness, or irritability. If signs or symptoms of dehydration, oligohidrosis, or elevated body temperature occur, discontinuation of zonisamide should be considered. DISCUSSION: Case reports of decreased sweating and elevated temperature have been reported, especially in pediatric patients. Some cases resulted in heat stroke that required hospital treatment and resulted in death.(1) |
ZONEGRAN, ZONISADE, ZONISAMIDE |
| Topiramate/Anticholinergics SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Topiramate can cause decreased sweating and elevated body temperature. Agents with anticholinergic activity can predispose patients to heat-related disorders.(1-2) CLINICAL EFFECTS: Concurrent use of topiramate with agents with anticholinergic activity may increase the incidence of oligohidrosis and hyperthermia, especially in pediatric or adolescent patients.(1-2) Overheating and dehydration can lead to brain damage and death. PREDISPOSING FACTORS: Pediatric and adolescent patients and patients with dehydration may be more likely to experience heat-related disorders.(1) PATIENT MANAGEMENT: The manufacturer of topiramate states that caution should be used when topiramate is prescribed with other medicinal products that predispose to heat-related disorders, such as agents with anticholinergic activity (e.g. clomipramine, hydroxyzine, diphenhydramine, haloperidol, imipramine, and oxybutynin) concurrently with zonisamide.(1) Monitor for signs and symptoms of heat stroke: skin feels very hot with little or no sweating, confusion, muscle cramps, rapid heartbeat, or rapid breathing. Monitor for signs and symptoms of dehydration: dry mouth, urinating less than usual, dark-colored urine, dry skin, feeling tired, dizziness, or irritability. If signs or symptoms of dehydration, oligohidrosis, or elevated body temperature occur, discontinuation of zonisamide should be considered. DISCUSSION: Case reports of decreased sweating and elevated temperature have been reported, especially in pediatric patients. Some cases resulted in heat stroke that required hospital treatment.(1) A 64-year old woman developed non-exertional hyperthemia while taking multiple psychiatric medications with topiramate.(2) |
EPRONTIA, PHENTERMINE-TOPIRAMATE ER, QSYMIA, TOPAMAX, TOPIRAMATE, TOPIRAMATE ER, TOPIRAMATE ER SPRINKLE, TROKENDI XR |
| 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 |
| Dextromethorphan/Selected Serotonergic Agents SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Dextromethorphan inhibits neuronal reuptake of serotonin. Concurrent administration with one or more serotonergic agents may increase serotonin effects, leading to serotonin toxicity.(1-11) CLINICAL EFFECTS: The concurrent use of dextromethorphan with serotonergic agents may increase the risk for serotonin syndrome. Serotonin syndrome constitutes a range of toxicities from mild to life threatening.(3) Mild serotonin symptoms may include: shivering, diaphoresis, mydriasis, intermittent tremor, and/or myoclonus.(3) Moderate serotonin symptoms may include: tachycardia, hypertension, hyperthermia, mydriasis, diaphoresis, hyperactive bowel sounds, hyperreflexia, and/OR clonus.(3) Severe serotonin symptoms may include: severe hypertension and tachycardia, shock, agitated delirium, muscular rigidity, and/or hypertonicity.(3) PREDISPOSING FACTORS: Concurrent use of additional drugs which increase CNS serotonin levels would be expected to further increase risk for serotonin syndrome.(1-11) PATIENT MANAGEMENT: Monitor patients on multiple serotonergic agents for symptoms of serotonin toxicity. Patients in whom serotonin syndrome is suspected should receive immediate medical attention. If the interacting agents are prescribed by different providers, it would be prudent to assure that both are aware of concomitant therapy and monitoring the patient for serotonin toxicities. Advise patients not to exceed recommended dosages of dextromethorphan. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea. DISCUSSION: Dextromethorphan inhibits neuronal reuptake of serotonin and may potentially precipitate dose-dependant serotonin toxicity in conjunction with other serotonergic agents.(4,5) Serotonin syndrome has been reported in patients following the addition of dextromethorphan containing cough syrups to duloxetine,(6) escitalopram,(7) fluoxetine,(8,9) paroxetine,(10) and sertraline.(11) Selected serotonergic agents linked to this monograph include: citalopram, clomipramine, duloxetine, escitalopram, fluvoxamine, imipramine, levomilnacipran, milnacipran, sertraline, venlafaxine, vilazodone and vortioxetine. |
ANAFRANIL, CELEXA, CITALOPRAM HBR, CLOMIPRAMINE HCL, CYMBALTA, DRIZALMA SPRINKLE, DULOXETINE HCL, DULOXICAINE, EFFEXOR XR, ESCITALOPRAM OXALATE, FETZIMA, FLUVOXAMINE MALEATE, FLUVOXAMINE MALEATE ER, IMIPRAMINE HCL, IMIPRAMINE PAMOATE, LEXAPRO, SAVELLA, SERTRALINE HCL, TRINTELLIX, VENLAFAXINE BESYLATE ER, VENLAFAXINE HCL, VENLAFAXINE HCL ER, VIIBRYD, VILAZODONE HCL, ZOLOFT |
| Dextromethorphan/Selected 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 dextromethorphan.(1-4) CLINICAL EFFECTS: Patients may experience increased adverse effects of dextromethorphan due to elevated systemic concentrations. Elevated levels of dextromethorphan or concomitant use of two or more serotonergic agents increases the risk for serotonin syndrome. Serotonin syndrome constitutes a range of toxicities from mild to life threatening.(5) Mild serotonin symptoms may include: shivering, diaphoresis, mydriasis, intermittent tremor, and/or myoclonus.(5) Moderate serotonin symptoms may include: tachycardia, hypertension, hyperthermia, mydriasis, diaphoresis, hyperactive bowel sounds, hyperreflexia, and/OR clonus.(5) Severe serotonin symptoms may include: severe hypertension and tachycardia, shock, agitated delirium, muscular rigidity, and/or hypertonicity.(5) PREDISPOSING FACTORS: Concurrent use of additional drugs which increase CNS serotonin levels would be expected to further increase risk for serotonin syndrome.(5) PATIENT MANAGEMENT: Monitor patients for elevated dextromethorphan levels or on multiple serotonergic agents for symptoms of serotonin toxicity. Patients in whom serotonin syndrome is suspected should receive immediate medical attention. If the interacting agents are prescribed by different providers, it would be prudent to assure that both are aware of concomitant therapy and monitoring the patient for serotonin toxicities. Advise patients not to exceed recommended dosages of dextromethorphan. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea. DISCUSSION: An open label parallel group trial evaluated the interaction between dextromethorphan-quinidine 30 mg-30 mg (higher than marketed strength of 20 mg-10 mg) and paroxetine 20 mg in 27 healthy volunteers with a mean age of 33.6 years. Subjects were randomly divided into 2 groups: - Group 1 received paroxetine 20 mg once daily for 12 days, followed by the addition of dextromethorphan-quinidine twice daily for 8 days. - Group 2 received dextromethorphan-quinidine twice daily for 8 days, followed by paroxetine 20 mg daily for 12 days. Results: overall, adverse effects were reported in 19 of 26 subjects who received combination therapy (73%) and 15 of 27 subjects who received monotherapy (56%). Adverse effects from the combination differed somewhat between groups and were more closely associated with the second drug product administered. Group 1 reported dizziness, headache, somnolence, euphoria, nausea, and vomiting after the addition of dextromethorphan-quinidine to paroxetine. Group 2 adverse events were dizziness, headache, nausea, vomiting, insomnia, anxiety, and hyperhidrosis after the addition of paroxetine to dextromethorphan.(1) Two weeks of fluoxetine therapy increased the area-under-curve (AUC) of dextromethorphan by 27-fold.(4) Serotonin syndrome has been reported in patients following the addition of dextromethorphan containing cough syrups to fluoxetine(6,7) and paroxetine.(8) Selected strong CYP2D6 inhibitors linked to this monograph include: bupropion, dacomitinib, hydroquinidine, quinidine, and terbinafine.(8) |
APLENZIN, AUVELITY, BUPROPION HCL, BUPROPION HCL SR, BUPROPION XL, CONTRAVE, FORFIVO XL, NUEDEXTA, QUINIDINE GLUCONATE, QUINIDINE SULFATE, TERBINAFINE HCL, VIZIMPRO, WELLBUTRIN SR, WELLBUTRIN XL |
| 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 |
| 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 |
| Ziprasidone/Serotonergic Agents SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Ziprasidone is a 5-HT1A agonist and serotonin and norepinephrine reuptake inhibitor. Concurrent administration with one or more serotonergic agents may increase serotonin effects, resulting in serotonin toxicity.(1,2) CLINICAL EFFECTS: Concurrent use of ziprasidone and other serotonergic agents may result in serotonin syndrome, a potentially life-threatening condition with symptoms including altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, and tremor.(1) PREDISPOSING FACTORS: Serotonin syndrome risk is dose-related. Higher systemic concentrations of either drug would be predicted to increase risk for serotonin toxicity.(2) Concomitant therapy with multiple agents which increase brain serotonin concentrations may also increase risk for serotonin syndrome.(2) PATIENT MANAGEMENT: Caution patients about the risk of serotonin syndrome with the concomitant use of ziprasidone with other serotonergic drugs. Instruct patients to contact their healthcare provider, or report to the emergency room, should they experience signs or symptoms of serotonin syndrome.(1) DISCUSSION: Several cases of serotonin syndrome have been reported in patients receiving ziprasidone.(4-6) |
GEODON, ZIPRASIDONE HCL, ZIPRASIDONE MESYLATE |
The following contraindication information is available for ALKA-SELTZER PLUS NIGHT (ASA) (doxylamine succinate/phenylephrine/dextromethorphan hbr/asa):
Drug contraindication overview.
Doxylamine succinate is contraindicated in patients with known hypersensitivity to doxylamine, other ethanolamine derivative antihistamines, or any ingredient in the formulation. Doxylamine in fixed combination with pyridoxine is contraindicated in patients receiving monoamine oxidase (MAO) inhibitors.
Doxylamine succinate is contraindicated in patients with known hypersensitivity to doxylamine, other ethanolamine derivative antihistamines, or any ingredient in the formulation. Doxylamine in fixed combination with pyridoxine is contraindicated in patients receiving monoamine oxidase (MAO) inhibitors.
There are 9 contraindications.
Absolute contraindication.
| Contraindication List |
|---|
| Aspirin exacerbated respiratory disease |
| Gastrointestinal hemorrhage |
| Hemolytic anemia from pyruvate kinase and g6PD deficiencies |
| Hemorrhage |
| Increased risk of bleeding due to coagulation disorder |
| Lactation |
| Pregnancy |
| Reye's syndrome |
| Severe uncontrolled hypertension |
There are 16 severe contraindications.
Adequate patient monitoring is recommended for safer drug use.
| Severe List |
|---|
| Alcohol use disorder |
| Angle-closure glaucoma |
| Benign prostatic hyperplasia |
| Bladder outflow obstruction |
| Chronic idiopathic constipation |
| Coronary artery disease |
| Gastrointestinal ulcer |
| Hypertension |
| Hyperthyroidism |
| Hypoprothrombinemia |
| Salicylate intoxication |
| Stenosing peptic ulcer |
| Systemic mastocytosis |
| Thrombocytopenic disorder |
| Thrombotic thrombocytopenic purpura |
| Urinary retention |
There are 13 moderate contraindications.
Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.
| Moderate List |
|---|
| Anemia |
| Chronic heart failure |
| Coronary artery disease |
| Disease of liver |
| Gout |
| Hypertension |
| Hyperthyroidism |
| Kidney disease with reduction in glomerular filtration rate (GFr) |
| Nasal polyp |
| Ocular hypertension |
| Pyloroduodenal obstruction |
| Seizure disorder |
| Vitamin K deficiency |
The following adverse reaction information is available for ALKA-SELTZER PLUS NIGHT (ASA) (doxylamine succinate/phenylephrine/dextromethorphan hbr/asa):
Adverse reaction overview.
No enhanced Common Adverse Effects information available for this drug.
No enhanced Common Adverse Effects information available for this drug.
There are 45 severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
| None. | None. |
| Rare/Very Rare |
|---|
|
Acute eruptions of skin Allergic dermatitis Anaphylaxis Anemia Angioedema Blistering skin Blood dyscrasias Bronchospastic pulmonary disease Bullous dermatitis Cardiac arrhythmia Dizziness DRESS syndrome Drug-induced hepatitis Dyspnea Exfoliative dermatitis Extrasystoles Gastrointestinal hemorrhage Gastrointestinal perforation Gastrointestinal ulcer Hallucinations Headache disorder Hemolytic anemia Hemorrhage Hyperhidrosis Hypersensitivity drug reaction Hypotension Insomnia Interstitial nephritis Intracranial bleeding Leukopenia Nervousness Pallor Platelet aggregation inhibition Purpura Rectal bleeding Renal papillary necrosis Seizure disorder Stevens-johnson syndrome Tachycardia Thrombocytopenic disorder Toxic epidermal necrolysis Tremor Urticaria Vomiting Wheezing |
There are 71 less severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Abdominal pain with cramps Anticholinergic toxicity Dizziness Drowsy Gastric acid hypersecretory conditions Gastrointestinal irritation Heartburn Nausea Thick bronchial secretions Vomiting |
Muscle weakness Sedation |
| Rare/Very Rare |
|---|
|
Abdominal distension Abdominal pain with cramps Abnormal hepatic function tests Accidental fall Acute abdominal pain Acute cognitive impairment Agitation Anorexia Anticholinergic toxicity Ataxia Black tarry stools Blurred vision Chest discomfort Chills Constipation Diarrhea Diplopia Dizziness Drowsy Dry nose Dry throat Dyspepsia Dyspnea Dysuria Ecchymosis Epistaxis Erythema Euphoria Excitement Fatigue Gastritis Gingival bleeding Headache disorder Hematoma Hyperhidrosis Insomnia Irritability Maculopapular rash Malaise Migraine Nausea Nervousness Nightmares Palpitations Paresthesia Pruritus of skin Skin photosensitivity Skin rash Symptoms of anxiety Tachycardia Tinnitus Tremor Urinary retention Urticaria Vertigo Visual changes Vomiting Wheezing Xerostomia |
The following precautions are available for ALKA-SELTZER PLUS NIGHT (ASA) (doxylamine succinate/phenylephrine/dextromethorphan hbr/asa):
No enhanced Pediatric Use information available for this drug.
Contraindicated
Severe Precaution
Management or Monitoring Precaution
Contraindicated
| None |
Severe Precaution
| None |
Management or Monitoring Precaution
| None |
Doxylamine succinate in fixed combination with pyridoxine hydrochloride is intended for use in the management of nausea and vomiting of pregnancy. Numerous epidemiologic studies (including cohort studies, case-control studies, and meta-analyses) have been performed to investigate possible teratogenic effects of doxylamine in fixed combination with pyridoxine in pregnant women. A meta-analysis of 16 cohort and 11 case-control studies published between 1963 and 1991 reported no increased risk for malformations from first trimester exposures to doxylamine succinate and pyridoxine hydrochloride in fixed combination, with or without dicyclomine hydrochloride (a drug included in a combination product that was previously commercially available for nausea and vomiting of pregnancy).
Another meta-analysis of 12 cohort and 5 case-control studies published between 1963 and 1985 reported no clinically important associations between fetal abnormalities and first trimester exposure to doxylamine succinate and pyridoxine hydrochloride with or without dicyclomine hydrochloride. A reanalysis of data from another meta-analysis supporting the safety of doxylamine during pregnancy found that the strength of the data had been overstated, both in terms of the numbers of patients exposed to doxylamine succinate and the reported odds ratio, which suggested a potential protective effect of antihistamines with regard to fetal malformations. However, the reanalysis did not find evidence of an increased risk of fetal malformations associated with doxylamine use.
Historically, there was considerable controversy regarding the teratogenic potential, if any, of doxylamine; however, after evaluating extensive data and information concerning the possible teratogenicity of the drug, FDA concluded that it is unlikely that doxylamine is teratogenic. FDA recognized, however, that despite the large number of pregnancies evaluated to date the possibility that doxylamine may be weakly teratogenic cannot be excluded. Doxylamine was commercially available in the US for the treatment of nausea and vomiting associated with pregnancy in combination with dicyclomine and pyridoxine until 1976, and then in combination with only pyridoxine until 1983 when the manufacturer voluntarily discontinued manufacturing and distributing the combination.
FDA stated that the removal of products containing doxylamine and pyridoxine that previously were commercially available for the management of nausea and vomiting of pregnancy was not for reasons of safety or effectiveness. Most epidemiologic studies (case-control and cohort) in which fixed combinations of doxylamine and pyridoxine with or without dicyclomine were used during pregnancy indicate that an association between use of these combinations and adverse fetal effects does not appear to exist. In a few studies, a weak association between use of the fixed combinations during pregnancy and specific fetal abnormalities (e.g., pyloric stenosis, cardiac defects, oral clefts) was reported, but a causal relationship with the drugs was not established and these findings have not been confirmed by many other studies.
Women considering self-medication with doxylamine during pregnancy should consult a health professional for advice regarding the relative risks and benefits of such therapy. Most reproduction studies in various animal species using doxylamine and pyridoxine alone or in fixed combination have not revealed evidence of harm to the fetus. Studies in rats and mice using doxylamine succinate dosages up to 125 times the maximum human dosage did not reveal evidence of observable congenital abnormalities, but wavy ribs and diaphragmatic hernias occurred in rats at dosages 125-375 times the maximum human dosage; an overall increase in fetal wastage, varying from zero to threefold, occurred in most rodents receiving dosages 125 or more times greater than the maximum human dosage.
Once daily administration of doxylamine succinate and pyridoxine hydrochloride in pregnant rats during organogenesis (gestational day 6-15) resulted in increased fetal resorptions, decreased fetal body weight, and increased skeletal variations with reduced ossification at dosages 60-100 times the highest clinical dosage based on body surface area. In a study in pregnant cynomolgus monkeys receiving doxylamine succinate and pyridoxine hydrochloride once daily during organogenesis (gestational day 22-50) at dosages up to 3.2 times the highest proposed clinical dosage based on body surface area, there were no observed malformations and no evidence of embryo, fetal, or maternal toxicity.
In another study in pregnant cynomolgus and rhesus monkeys and baboons receiving doxylamine succinate and pyridoxine hydrochloride at dosages 0.5-20 times higher than the clinical dosage based on body surface area, ventricular septal defects were observed in preterm (gestational day 100) fetuses; no relationship between dosage and incidence of ventricular septal defects was observed, and no ventricular septal defects were observed in infant monkeys at term. In addition, no ventricular septal defects were observed at gestational day 100 in cynomolgus monkeys administered the combination of doxylamine succinate and pyridoxine hydrochloride for 4-day periods between 22 and 41 days of gestation.
In a small study in monkeys receiving a fixed combination of doxylamine succinate and pyridoxine hydrochloride throughout fetal organogenesis at dosages 10-20 times the maximum human dosage, intraventricular septal defects were present in 4 of 7 fetuses delivered on day 100 of gestation (full-term gestation is about 160 days), while 2 fetuses aborted on the 46th and 56th day of gestation appeared to be developing normally and 3 other fetuses allowed to develop to term were normal. The importance of septal defects in these monkeys is not known, since an opening in the septum is usually present early during fetal development in monkeys. In other studies in monkeys receiving the fixed combination for shorter periods of time, there was no evidence of fetal toxicity.
It is not known whether phenylephrine hydrochloride can cause fetal harm when administered to pregnant women; the drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal studies suggest a potential for adverse cardiovascular effects to the fetus if the drug is administered IV during pregnancy. Administration of phenylephrine to patients in late pregnancy or labor may cause fetal anoxia and bradycardia by increasing contractility of the uterus and decreasing uterine blood flow.
In studies of IV phenylephrine in pregnant women undergoing cesarean delivery with neuraxial anesthesia, common adverse effects reported in the mother included nausea and vomiting, bradycardia, reactive hypertension, and transient arrhythmias. The drug did not appear to affect neonatal Apgar scores or umbilical artery blood-gas status. If a vasopressor is used in conjunction with oxytocic drugs, the vasopressor effect is potentiated and may result in potentially serious adverse effects. (See Drug Interactions: Oxytocic Drugs.)
Another meta-analysis of 12 cohort and 5 case-control studies published between 1963 and 1985 reported no clinically important associations between fetal abnormalities and first trimester exposure to doxylamine succinate and pyridoxine hydrochloride with or without dicyclomine hydrochloride. A reanalysis of data from another meta-analysis supporting the safety of doxylamine during pregnancy found that the strength of the data had been overstated, both in terms of the numbers of patients exposed to doxylamine succinate and the reported odds ratio, which suggested a potential protective effect of antihistamines with regard to fetal malformations. However, the reanalysis did not find evidence of an increased risk of fetal malformations associated with doxylamine use.
Historically, there was considerable controversy regarding the teratogenic potential, if any, of doxylamine; however, after evaluating extensive data and information concerning the possible teratogenicity of the drug, FDA concluded that it is unlikely that doxylamine is teratogenic. FDA recognized, however, that despite the large number of pregnancies evaluated to date the possibility that doxylamine may be weakly teratogenic cannot be excluded. Doxylamine was commercially available in the US for the treatment of nausea and vomiting associated with pregnancy in combination with dicyclomine and pyridoxine until 1976, and then in combination with only pyridoxine until 1983 when the manufacturer voluntarily discontinued manufacturing and distributing the combination.
FDA stated that the removal of products containing doxylamine and pyridoxine that previously were commercially available for the management of nausea and vomiting of pregnancy was not for reasons of safety or effectiveness. Most epidemiologic studies (case-control and cohort) in which fixed combinations of doxylamine and pyridoxine with or without dicyclomine were used during pregnancy indicate that an association between use of these combinations and adverse fetal effects does not appear to exist. In a few studies, a weak association between use of the fixed combinations during pregnancy and specific fetal abnormalities (e.g., pyloric stenosis, cardiac defects, oral clefts) was reported, but a causal relationship with the drugs was not established and these findings have not been confirmed by many other studies.
Women considering self-medication with doxylamine during pregnancy should consult a health professional for advice regarding the relative risks and benefits of such therapy. Most reproduction studies in various animal species using doxylamine and pyridoxine alone or in fixed combination have not revealed evidence of harm to the fetus. Studies in rats and mice using doxylamine succinate dosages up to 125 times the maximum human dosage did not reveal evidence of observable congenital abnormalities, but wavy ribs and diaphragmatic hernias occurred in rats at dosages 125-375 times the maximum human dosage; an overall increase in fetal wastage, varying from zero to threefold, occurred in most rodents receiving dosages 125 or more times greater than the maximum human dosage.
Once daily administration of doxylamine succinate and pyridoxine hydrochloride in pregnant rats during organogenesis (gestational day 6-15) resulted in increased fetal resorptions, decreased fetal body weight, and increased skeletal variations with reduced ossification at dosages 60-100 times the highest clinical dosage based on body surface area. In a study in pregnant cynomolgus monkeys receiving doxylamine succinate and pyridoxine hydrochloride once daily during organogenesis (gestational day 22-50) at dosages up to 3.2 times the highest proposed clinical dosage based on body surface area, there were no observed malformations and no evidence of embryo, fetal, or maternal toxicity.
In another study in pregnant cynomolgus and rhesus monkeys and baboons receiving doxylamine succinate and pyridoxine hydrochloride at dosages 0.5-20 times higher than the clinical dosage based on body surface area, ventricular septal defects were observed in preterm (gestational day 100) fetuses; no relationship between dosage and incidence of ventricular septal defects was observed, and no ventricular septal defects were observed in infant monkeys at term. In addition, no ventricular septal defects were observed at gestational day 100 in cynomolgus monkeys administered the combination of doxylamine succinate and pyridoxine hydrochloride for 4-day periods between 22 and 41 days of gestation.
In a small study in monkeys receiving a fixed combination of doxylamine succinate and pyridoxine hydrochloride throughout fetal organogenesis at dosages 10-20 times the maximum human dosage, intraventricular septal defects were present in 4 of 7 fetuses delivered on day 100 of gestation (full-term gestation is about 160 days), while 2 fetuses aborted on the 46th and 56th day of gestation appeared to be developing normally and 3 other fetuses allowed to develop to term were normal. The importance of septal defects in these monkeys is not known, since an opening in the septum is usually present early during fetal development in monkeys. In other studies in monkeys receiving the fixed combination for shorter periods of time, there was no evidence of fetal toxicity.
It is not known whether phenylephrine hydrochloride can cause fetal harm when administered to pregnant women; the drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal studies suggest a potential for adverse cardiovascular effects to the fetus if the drug is administered IV during pregnancy. Administration of phenylephrine to patients in late pregnancy or labor may cause fetal anoxia and bradycardia by increasing contractility of the uterus and decreasing uterine blood flow.
In studies of IV phenylephrine in pregnant women undergoing cesarean delivery with neuraxial anesthesia, common adverse effects reported in the mother included nausea and vomiting, bradycardia, reactive hypertension, and transient arrhythmias. The drug did not appear to affect neonatal Apgar scores or umbilical artery blood-gas status. If a vasopressor is used in conjunction with oxytocic drugs, the vasopressor effect is potentiated and may result in potentially serious adverse effects. (See Drug Interactions: Oxytocic Drugs.)
Doxylamine succinate is expected to be distributed into human milk, because of its low molecular weight. Adverse effects (e.g., excitement, irritability, and sedation) have been reported in infants presumably exposed to doxylamine through human milk. Infants with apnea or other respiratory syndromes may be particularly vulnerable to the sedative effects of doxylamine.
Because of the potential for serious adverse reactions to antihistamines in nursing infants, a decision should be made whether to discontinue nursing or doxylamine, taking into account the importance of the drug to the woman. The manufacturer of doxylamine/pyridoxine in fixed combination states that this preparation should notbe used in nursing women. It is not known whether phenylephrine is distributed into human milk following parenteral administration. The drug should be used with caution in nursing women.
Because of the potential for serious adverse reactions to antihistamines in nursing infants, a decision should be made whether to discontinue nursing or doxylamine, taking into account the importance of the drug to the woman. The manufacturer of doxylamine/pyridoxine in fixed combination states that this preparation should notbe used in nursing women. It is not known whether phenylephrine is distributed into human milk following parenteral administration. The drug should be used with caution in nursing women.
No enhanced Geriatric Use information available for this drug.
The following prioritized warning is available for ALKA-SELTZER PLUS NIGHT (ASA) (doxylamine succinate/phenylephrine/dextromethorphan hbr/asa):
No warning message for this drug.
No warning message for this drug.
The following icd codes are available for ALKA-SELTZER PLUS NIGHT (ASA) (doxylamine succinate/phenylephrine/dextromethorphan hbr/asa)'s list of indications:
| Cold symptoms | |
| J00 | Acute nasopharyngitis [common cold] |
| Cough | |
| R05 | Cough |
| R05.1 | Acute cough |
| R05.2 | Subacute cough |
| R05.3 | Chronic cough |
| R05.9 | Cough, unspecified |
| Fever | |
| R50 | Fever of other and unknown origin |
| R50.2 | Drug induced fever |
| R50.8 | Other specified fever |
| R50.81 | Fever presenting with conditions classified elsewhere |
| R50.82 | Postprocedural fever |
| R50.83 | Postvaccination fever |
| R50.84 | Febrile nonhemolytic transfusion reaction |
| R50.9 | Fever, unspecified |
| Flu-like symptoms | |
| J02.9 | Acute pharyngitis, unspecified |
| R05 | Cough |
| R05.1 | Acute cough |
| R05.2 | Subacute cough |
| R05.9 | Cough, unspecified |
| R09.81 | Nasal congestion |
| R50.9 | Fever, unspecified |
| R53.1 | Weakness |
| R53.81 | Other malaise |
| R53.83 | Other fatigue |
| R68.83 | Chills (without fever) |
| Headache disorder | |
| G43 | Migraine |
| G43.0 | Migraine without aura |
| G43.00 | Migraine without aura, not intractable |
| G43.009 | Migraine without aura, not intractable, without status migrainosus |
| G43.01 | Migraine without aura, intractable |
| G43.019 | Migraine without aura, intractable, without status migrainosus |
| G43.1 | Migraine with aura |
| G43.10 | Migraine with aura, not intractable |
| G43.109 | Migraine with aura, not intractable, without status migrainosus |
| G43.11 | Migraine with aura, intractable |
| G43.119 | Migraine with aura, intractable, without status migrainosus |
| G43.4 | Hemiplegic migraine |
| G43.40 | Hemiplegic migraine, not intractable |
| G43.409 | Hemiplegic migraine, not intractable, without status migrainosus |
| G43.41 | Hemiplegic migraine, intractable |
| G43.419 | Hemiplegic migraine, intractable, without status migrainosus |
| G43.5 | Persistent migraine aura without cerebral infarction |
| G43.50 | Persistent migraine aura without cerebral infarction, not intractable |
| G43.509 | Persistent migraine aura without cerebral infarction, not intractable, without status migrainosus |
| G43.51 | Persistent migraine aura without cerebral infarction, intractable |
| G43.519 | Persistent migraine aura without cerebral infarction, intractable, without status migrainosus |
| G43.6 | Persistent migraine aura with cerebral infarction |
| G43.60 | Persistent migraine aura with cerebral infarction, not intractable |
| G43.609 | Persistent migraine aura with cerebral infarction, not intractable, without status migrainosus |
| G43.61 | Persistent migraine aura with cerebral infarction, intractable |
| G43.619 | Persistent migraine aura with cerebral infarction, intractable, without status migrainosus |
| G43.7 | Chronic migraine without aura |
| G43.70 | Chronic migraine without aura, not intractable |
| G43.709 | Chronic migraine without aura, not intractable, without status migrainosus |
| G43.71 | Chronic migraine without aura, intractable |
| G43.719 | Chronic migraine without aura, intractable, without status migrainosus |
| G43.8 | Other migraine |
| G43.80 | Other migraine, not intractable |
| G43.809 | Other migraine, not intractable, without status migrainosus |
| G43.81 | Other migraine, intractable |
| G43.819 | Other migraine, intractable, without status migrainosus |
| G43.82 | Menstrual migraine, not intractable |
| G43.829 | Menstrual migraine, not intractable, without status migrainosus |
| G43.83 | Menstrual migraine, intractable |
| G43.839 | Menstrual migraine, intractable, without status migrainosus |
| G43.9 | Migraine, unspecified |
| G43.90 | Migraine, unspecified, not intractable |
| G43.909 | Migraine, unspecified, not intractable, without status migrainosus |
| G43.91 | Migraine, unspecified, intractable |
| G43.919 | Migraine, unspecified, intractable, without status migrainosus |
| G43.B | Ophthalmoplegic migraine |
| G43.B0 | Ophthalmoplegic migraine, not intractable |
| G43.B1 | Ophthalmoplegic migraine, intractable |
| G43.C | Periodic headache syndromes in child or adult |
| G43.C0 | Periodic headache syndromes in child or adult, not intractable |
| G43.C1 | Periodic headache syndromes in child or adult, intractable |
| G43.D | Abdominal migraine |
| G43.D0 | Abdominal migraine, not intractable |
| G43.D1 | Abdominal migraine, intractable |
| G43.E | Chronic migraine with aura |
| G43.E0 | Chronic migraine with aura, not intractable |
| G43.E09 | Chronic migraine with aura, not intractable, without status migrainosus |
| G43.E1 | Chronic migraine with aura, intractable |
| G43.E19 | Chronic migraine with aura, intractable, without status migrainosus |
| G44 | Other headache syndromes |
| G44.0 | Cluster headaches and other trigeminal autonomic cephalgias (TAc) |
| G44.00 | Cluster headache syndrome, unspecified |
| G44.001 | Cluster headache syndrome, unspecified, intractable |
| G44.009 | Cluster headache syndrome, unspecified, not intractable |
| G44.01 | Episodic cluster headache |
| G44.011 | Episodic cluster headache, intractable |
| G44.019 | Episodic cluster headache, not intractable |
| G44.02 | Chronic cluster headache |
| G44.021 | Chronic cluster headache, intractable |
| G44.029 | Chronic cluster headache, not intractable |
| G44.03 | Episodic paroxysmal hemicrania |
| G44.031 | Episodic paroxysmal hemicrania, intractable |
| G44.039 | Episodic paroxysmal hemicrania, not intractable |
| G44.04 | Chronic paroxysmal hemicrania |
| G44.041 | Chronic paroxysmal hemicrania, intractable |
| G44.049 | Chronic paroxysmal hemicrania, not intractable |
| G44.05 | Short lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCt) |
| G44.051 | Short lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCt), intractable |
| G44.059 | Short lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCt), not intractable |
| G44.09 | Other trigeminal autonomic cephalgias (TAc) |
| G44.091 | Other trigeminal autonomic cephalgias (TAc), intractable |
| G44.099 | Other trigeminal autonomic cephalgias (TAc), not intractable |
| G44.1 | Vascular headache, not elsewhere classified |
| G44.2 | Tension-type headache |
| G44.20 | Tension-type headache, unspecified |
| G44.201 | Tension-type headache, unspecified, intractable |
| G44.209 | Tension-type headache, unspecified, not intractable |
| G44.21 | Episodic tension-type headache |
| G44.211 | Episodic tension-type headache, intractable |
| G44.219 | Episodic tension-type headache, not intractable |
| G44.22 | Chronic tension-type headache |
| G44.221 | Chronic tension-type headache, intractable |
| G44.229 | Chronic tension-type headache, not intractable |
| G44.3 | Post-traumatic headache |
| G44.30 | Post-traumatic headache, unspecified |
| G44.301 | Post-traumatic headache, unspecified, intractable |
| G44.309 | Post-traumatic headache, unspecified, not intractable |
| G44.31 | Acute post-traumatic headache |
| G44.311 | Acute post-traumatic headache, intractable |
| G44.319 | Acute post-traumatic headache, not intractable |
| G44.32 | Chronic post-traumatic headache |
| G44.321 | Chronic post-traumatic headache, intractable |
| G44.329 | Chronic post-traumatic headache, not intractable |
| G44.4 | Drug-induced headache, not elsewhere classified |
| G44.40 | Drug-induced headache, not elsewhere classified, not intractable |
| G44.41 | Drug-induced headache, not elsewhere classified, intractable |
| G44.5 | Complicated headache syndromes |
| G44.51 | Hemicrania continua |
| G44.52 | New daily persistent headache (NDPh) |
| G44.53 | Primary thunderclap headache |
| G44.59 | Other complicated headache syndrome |
| G44.8 | Other specified headache syndromes |
| G44.81 | Hypnic headache |
| G44.82 | Headache associated with sexual activity |
| G44.83 | Primary cough headache |
| G44.84 | Primary exertional headache |
| G44.85 | Primary stabbing headache |
| G44.89 | Other headache syndrome |
| R51 | Headache |
| R51.9 | Headache, unspecified |
| Nasal congestion | |
| R09.81 | Nasal congestion |
| Rhinorrhea | |
| R09.82 | Postnasal drip |
Formulary Reference Tool