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Drug overview for HYDROCODONE-ACETAMINOPHEN (hydrocodone bitartrate/acetaminophen):
Generic name: HYDROCODONE BITARTRATE/ACETAMINOPHEN (HYE-droe-KOE-done/a-SEET-a-MIN-oh-fen)
Drug class: Non-Opioid Analgesic/Antipyretic, Non-Salicylate
Therapeutic class: Analgesic, Anti-inflammatory or Antipyretic
Acetaminophen is a synthetic nonopiate derivative of p-aminophenol that produces analgesia and antipyresis. Hydrocodone bitartrate is a phenanthrene-derivative opiate agonist Hydrocodone bitartrate is a phenanthrene-derivative opiate agonist that is antitussive and analgesic agent. used as an analgesic and antitussive agent.
Acetaminophen is used extensively in the treatment of mild to moderate pain and fever. Extended-release hydrocodone bitartrate is used for the relief of pain that is severe enough to require long-term, daily, around-the-clock use of an opiate analgesic. Because of the risks of addiction, abuse, and misuse associated with opiates, even at recommended dosages, and because of the greater risks of overdose and death associated with extended-release opiate formulations, extended-release hydrocodone bitartrate should be reserved for use in patients for whom alternative treatment options (e.g., nonopiate analgesics or immediate-release opiates) are inadequate or not tolerated.
Extended-release hydrocodone bitartrate is not indicated for use on an as-needed (''prn'') basis. Efficacy of hydrocodone bitartrate extended-release capsules (Zohydro(R) ER) was established in patients with moderate to severe chronic low back pain requiring chronic opiate therapy; the currently prescribed opiate was switched to the extended-release hydrocodone bitartrate capsules and the dosage was titrated to a stable level (up to 100 mg twice daily) during an initial open-label phase of the study; over a subsequent 12-week, randomized, placebo-controlled withdrawal phase, hydrocodone was associated with reductions in pain intensity compared with placebo. Efficacy of extended-release tablets of hydrocodone bitartrate (Hysingla(R) ER) also was established in patients with moderate to severe chronic low back pain.
The currently prescribed opiate and/or nonopiate analgesic(s) were switched to extended-release hydrocodone bitartrate tablets and the dosage was titrated to a stable level (20-120 mg once daily) during an initial open-label phase of the study; over a subsequent 12-week, randomized, placebo-controlled withdrawal phase, hydrocodone provided greater analgesia compared with placebo. Hydrocodone bitartrate in fixed combination with acetaminophen is used for the relief of moderate to moderately severe pain. Hydrocodone bitartrate in fixed combination with ibuprofen is used short term (generally for less than 10 days) for the relief of acute pain.
Efficacy was established in single-dose studies in patients with postoperative (abdominal, gynecologic, orthopedic) pain. Hydrocodone bitartrate in fixed combination with ibuprofen is not indicated for the management of pain associated with such chronic conditions as osteoarthritis or rheumatoid arthritis. For further information on the role of opiate analgesics in the management of acute or chronic pain, see Uses: Pain, in the Opiate Agonists General Statement 28:08.08. For use of hydrocodone as an antitussive agent, see 48:08.
Generic name: HYDROCODONE BITARTRATE/ACETAMINOPHEN (HYE-droe-KOE-done/a-SEET-a-MIN-oh-fen)
Drug class: Non-Opioid Analgesic/Antipyretic, Non-Salicylate
Therapeutic class: Analgesic, Anti-inflammatory or Antipyretic
Acetaminophen is a synthetic nonopiate derivative of p-aminophenol that produces analgesia and antipyresis. Hydrocodone bitartrate is a phenanthrene-derivative opiate agonist Hydrocodone bitartrate is a phenanthrene-derivative opiate agonist that is antitussive and analgesic agent. used as an analgesic and antitussive agent.
Acetaminophen is used extensively in the treatment of mild to moderate pain and fever. Extended-release hydrocodone bitartrate is used for the relief of pain that is severe enough to require long-term, daily, around-the-clock use of an opiate analgesic. Because of the risks of addiction, abuse, and misuse associated with opiates, even at recommended dosages, and because of the greater risks of overdose and death associated with extended-release opiate formulations, extended-release hydrocodone bitartrate should be reserved for use in patients for whom alternative treatment options (e.g., nonopiate analgesics or immediate-release opiates) are inadequate or not tolerated.
Extended-release hydrocodone bitartrate is not indicated for use on an as-needed (''prn'') basis. Efficacy of hydrocodone bitartrate extended-release capsules (Zohydro(R) ER) was established in patients with moderate to severe chronic low back pain requiring chronic opiate therapy; the currently prescribed opiate was switched to the extended-release hydrocodone bitartrate capsules and the dosage was titrated to a stable level (up to 100 mg twice daily) during an initial open-label phase of the study; over a subsequent 12-week, randomized, placebo-controlled withdrawal phase, hydrocodone was associated with reductions in pain intensity compared with placebo. Efficacy of extended-release tablets of hydrocodone bitartrate (Hysingla(R) ER) also was established in patients with moderate to severe chronic low back pain.
The currently prescribed opiate and/or nonopiate analgesic(s) were switched to extended-release hydrocodone bitartrate tablets and the dosage was titrated to a stable level (20-120 mg once daily) during an initial open-label phase of the study; over a subsequent 12-week, randomized, placebo-controlled withdrawal phase, hydrocodone provided greater analgesia compared with placebo. Hydrocodone bitartrate in fixed combination with acetaminophen is used for the relief of moderate to moderately severe pain. Hydrocodone bitartrate in fixed combination with ibuprofen is used short term (generally for less than 10 days) for the relief of acute pain.
Efficacy was established in single-dose studies in patients with postoperative (abdominal, gynecologic, orthopedic) pain. Hydrocodone bitartrate in fixed combination with ibuprofen is not indicated for the management of pain associated with such chronic conditions as osteoarthritis or rheumatoid arthritis. For further information on the role of opiate analgesics in the management of acute or chronic pain, see Uses: Pain, in the Opiate Agonists General Statement 28:08.08. For use of hydrocodone as an antitussive agent, see 48:08.
DRUG IMAGES
HYDROCODONE-ACETAMIN 7.5-325
HYDROCODONE-ACETAMIN 10-300 MG
HYDROCODONE-ACETAMIN 7.5-300
HYDROCODONE-ACETAMIN 5-300 MG
HYDROCODONE-ACETAMIN 5-325 MG
The following indications for HYDROCODONE-ACETAMINOPHEN (hydrocodone bitartrate/acetaminophen) have been approved by the FDA:
Indications:
Pain
Professional Synonyms:
None.
Indications:
Pain
Professional Synonyms:
None.
The following dosing information is available for HYDROCODONE-ACETAMINOPHEN (hydrocodone bitartrate/acetaminophen):
Hydrocodone bitartrate should be given at the lowest effective dosage and for the shortest duration of therapy consistent with the treatment goals of the patient. Reduced dosage is indicated in poor-risk and geriatric patients. If concomitant therapy with other CNS depressants is required, the lowest effective dosages and shortest possible duration of concomitant therapy should be used.
For acute pain not related to trauma or surgery, the prescribed quantity should be limited to the amount needed for the expected duration of pain severe enough to require opiate analgesia (generally 3 days or less and rarely more than 7 days). When opiate analgesics are used for the management of chronic noncancer pain, the US Centers for Disease Control and Prevention (CDC) recommends that primary care clinicians carefully reassess individual benefits and risks before prescribing dosages equivalent to 50 mg or more of morphine sulfate daily (approximately 50 mg or more of hydrocodone bitartrate daily) and avoid dosages equivalent to 90 mg or more of morphine sulfate daily (approximately 90 mg or more of hydrocodone bitartrate daily) or carefully justify their decision to titrate the dosage to such levels. Other experts recommend consulting a pain management specialist before exceeding a dosage equivalent to 80-120 mg of morphine sulfate daily.
For further information on the management of opiate analgesic therapy, see Dosage and Administration: Dosage, in the Opiate Agonists General Statement 28:08.08.
No adjustment of initial hydrocodone bitartrate dosage is required in patients with mild or moderate hepatic impairment. Because of the potential for increased drug exposure, the manufacturer states that therapy with hydrocodone bitartrate extended-release capsules should be initiated at a dosage of 10 mg every 12 hours in patients with severe hepatic impairment. The manufacturer of hydrocodone bitartrate extended-release tablets states that dosage of this formulation should be reduced by 50% in patients with severe hepatic impairment.
Patients with severe hepatic impairment should be monitored closely for adverse effects (e.g., respiratory depression, sedation).
Because of the potential for increased drug exposure, the manufacturer states that therapy with hydrocodone bitartrate extended-release capsules should be initiated at a low dose in patients with renal impairment. The manufacturer of hydrocodone bitartrate extended-release tablets states that dosage of this formulation should be reduced by 50% in patients with moderate or severe renal impairment (including end-stage renal disease); the manufacturer states that the extended-release tablets may be used without dosage adjustment in patients with mild renal impairment. Patients with renal impairment should be monitored closely for adverse effects (e.g., respiratory depression, sedation).
Acetaminophen is relatively safe when used at recommended dosages. However, acetaminophen overdosage has been the leading cause of acute liver failure in the US, United Kingdom, and most of Europe, with about 50% of US cases in recent years resulting from inadvertent overdosage (e.g., in patients not recognizing the presence of the drug in multiple over-the-counter (OTC) and/or prescription products that they may be taking). Therefore, patients should be warned about the importance of determining whether acetaminophen is present in their medications (e.g., by examining labels carefully, by consulting their clinician and pharmacist) and of not exceeding recommended dosages or combining acetaminophen-containing preparations.
Acetaminophen should not be used for self-medication of pain for longer than 10 days (in adults or children 12 years of age and older) or 5 days (in children 2-11 years of age), unless directed by a clinician because pain of such intensity and duration may indicate a pathologic condition requiring medical evaluation and supervised treatment.
Acetaminophen should not be used in adults or children for self-medication of marked fever (greater than 39.5degreesC), fever persisting longer than 3 days, or recurrent fever, unless directed by a clinician because such fevers may indicate serious illness requiring prompt medical evaluation.
Acetaminophen should not be used in adults or children for self-medication of sore throat pain (pharyngitis, laryngitis, tonsillitis) for longer than 2 days.
To minimize the risk of overdosage, recommended age-appropriate daily dosages of acetaminophen should not be exceeded. Because severe liver toxicity and death have occurred in children who received multiple excessive doses of acetaminophen as part of therapeutic administration, parents or caregivers should be instructed to use weight-based dosing for acetaminophen, to use only the calibrated measuring device provided with the particular acetaminophen formulation for measuring dosage, to ensure that the correct number of tablets required for the intended dose is removed from the package, and not to exceed the recommended daily dosage because serious adverse effects could result. In addition, patients should be warned that the risk of overdosage and severe liver damage is increased if more than one preparation containing acetaminophen are used concomitantly.
Pharmacists have an important role in preventing acetaminophen-induced hepatotoxicity by advising consumers about the risk of failing to recognize that a wide variety of OTC and prescription preparations contain acetaminophen. Failure to recognize acetaminophen as an ingredient may be particularly likely with prescription drugs because the label of the dispensed drug may not clearly state its presence. Educating consumers about the risk of exceeding recommended acetaminophen dosages also is important.
The US Food and Drug Administration (FDA) recommends that pharmacists receiving prescriptions for fixed-combination preparations containing more than 325 mg of acetaminophen per dosage unit contact the prescriber to discuss use of a preparation containing no more than 325 mg of the drug per dosage unit. (See Preparations.)
Clinicians should exercise caution when prescribing, preparing, and administering IV acetaminophen to avoid dosing errors that could result in accidental overdosage and death. In particular, clinicians should ensure that the dose (in mg) and the volume (in mL) are not confused, the dose for patients weighing less than 50 kg is based on body weight, the infusion pump is programmed correctly, and the total daily dosage of acetaminophen from all sources does not exceed the maximum recommended daily dosage.
In patients with hepatic impairment or active liver disease, reduction of the total daily dosage of acetaminophen may be warranted. In patients with severe renal impairment (creatinine clearance of 30 mL/minute or less), longer dosing intervals and a reduced total daily dosage of acetaminophen may be warranted. (See Cautions: Precautions and Contraindications.)
For acute pain not related to trauma or surgery, the prescribed quantity should be limited to the amount needed for the expected duration of pain severe enough to require opiate analgesia (generally 3 days or less and rarely more than 7 days). When opiate analgesics are used for the management of chronic noncancer pain, the US Centers for Disease Control and Prevention (CDC) recommends that primary care clinicians carefully reassess individual benefits and risks before prescribing dosages equivalent to 50 mg or more of morphine sulfate daily (approximately 50 mg or more of hydrocodone bitartrate daily) and avoid dosages equivalent to 90 mg or more of morphine sulfate daily (approximately 90 mg or more of hydrocodone bitartrate daily) or carefully justify their decision to titrate the dosage to such levels. Other experts recommend consulting a pain management specialist before exceeding a dosage equivalent to 80-120 mg of morphine sulfate daily.
For further information on the management of opiate analgesic therapy, see Dosage and Administration: Dosage, in the Opiate Agonists General Statement 28:08.08.
No adjustment of initial hydrocodone bitartrate dosage is required in patients with mild or moderate hepatic impairment. Because of the potential for increased drug exposure, the manufacturer states that therapy with hydrocodone bitartrate extended-release capsules should be initiated at a dosage of 10 mg every 12 hours in patients with severe hepatic impairment. The manufacturer of hydrocodone bitartrate extended-release tablets states that dosage of this formulation should be reduced by 50% in patients with severe hepatic impairment.
Patients with severe hepatic impairment should be monitored closely for adverse effects (e.g., respiratory depression, sedation).
Because of the potential for increased drug exposure, the manufacturer states that therapy with hydrocodone bitartrate extended-release capsules should be initiated at a low dose in patients with renal impairment. The manufacturer of hydrocodone bitartrate extended-release tablets states that dosage of this formulation should be reduced by 50% in patients with moderate or severe renal impairment (including end-stage renal disease); the manufacturer states that the extended-release tablets may be used without dosage adjustment in patients with mild renal impairment. Patients with renal impairment should be monitored closely for adverse effects (e.g., respiratory depression, sedation).
Acetaminophen is relatively safe when used at recommended dosages. However, acetaminophen overdosage has been the leading cause of acute liver failure in the US, United Kingdom, and most of Europe, with about 50% of US cases in recent years resulting from inadvertent overdosage (e.g., in patients not recognizing the presence of the drug in multiple over-the-counter (OTC) and/or prescription products that they may be taking). Therefore, patients should be warned about the importance of determining whether acetaminophen is present in their medications (e.g., by examining labels carefully, by consulting their clinician and pharmacist) and of not exceeding recommended dosages or combining acetaminophen-containing preparations.
Acetaminophen should not be used for self-medication of pain for longer than 10 days (in adults or children 12 years of age and older) or 5 days (in children 2-11 years of age), unless directed by a clinician because pain of such intensity and duration may indicate a pathologic condition requiring medical evaluation and supervised treatment.
Acetaminophen should not be used in adults or children for self-medication of marked fever (greater than 39.5degreesC), fever persisting longer than 3 days, or recurrent fever, unless directed by a clinician because such fevers may indicate serious illness requiring prompt medical evaluation.
Acetaminophen should not be used in adults or children for self-medication of sore throat pain (pharyngitis, laryngitis, tonsillitis) for longer than 2 days.
To minimize the risk of overdosage, recommended age-appropriate daily dosages of acetaminophen should not be exceeded. Because severe liver toxicity and death have occurred in children who received multiple excessive doses of acetaminophen as part of therapeutic administration, parents or caregivers should be instructed to use weight-based dosing for acetaminophen, to use only the calibrated measuring device provided with the particular acetaminophen formulation for measuring dosage, to ensure that the correct number of tablets required for the intended dose is removed from the package, and not to exceed the recommended daily dosage because serious adverse effects could result. In addition, patients should be warned that the risk of overdosage and severe liver damage is increased if more than one preparation containing acetaminophen are used concomitantly.
Pharmacists have an important role in preventing acetaminophen-induced hepatotoxicity by advising consumers about the risk of failing to recognize that a wide variety of OTC and prescription preparations contain acetaminophen. Failure to recognize acetaminophen as an ingredient may be particularly likely with prescription drugs because the label of the dispensed drug may not clearly state its presence. Educating consumers about the risk of exceeding recommended acetaminophen dosages also is important.
The US Food and Drug Administration (FDA) recommends that pharmacists receiving prescriptions for fixed-combination preparations containing more than 325 mg of acetaminophen per dosage unit contact the prescriber to discuss use of a preparation containing no more than 325 mg of the drug per dosage unit. (See Preparations.)
Clinicians should exercise caution when prescribing, preparing, and administering IV acetaminophen to avoid dosing errors that could result in accidental overdosage and death. In particular, clinicians should ensure that the dose (in mg) and the volume (in mL) are not confused, the dose for patients weighing less than 50 kg is based on body weight, the infusion pump is programmed correctly, and the total daily dosage of acetaminophen from all sources does not exceed the maximum recommended daily dosage.
In patients with hepatic impairment or active liver disease, reduction of the total daily dosage of acetaminophen may be warranted. In patients with severe renal impairment (creatinine clearance of 30 mL/minute or less), longer dosing intervals and a reduced total daily dosage of acetaminophen may be warranted. (See Cautions: Precautions and Contraindications.)
Hydrocodone bitartrate is administered orally. Patients receiving hydrocodone should avoid alcohol; concomitant use may result in profound sedation, respiratory depression, coma, or death. Hydrocodone bitartrate extended-release capsules are administered twice daily (every 12 hours).
The extended-release capsules must be taken whole; crushing, breaking, cutting, chewing, or dissolving the capsules will result in uncontrolled delivery of hydrocodone and can result in overdosage and death. Patients should be advised that they must not consume alcoholic beverages or take prescription or nonprescription preparations containing alcohol during therapy, since concomitant ingestion of alcohol with hydrocodone bitartrate extended-release capsules may result in increased plasma concentrations of the drug and a potentially fatal overdose. (See Drug Interactions: Alcohol.) Hydrocodone bitartrate extended-release tablets are administered once daily (every 24 hours) without regard to meals.
Multiple tablets of lower-dose strengths that provide the desired total daily dosage can be taken as a once-daily dose. If a dose is missed, the next dose should be taken at the scheduled time on the following day. The extended-release tablets must be taken whole, one tablet at a time, with enough water to ensure complete swallowing of the tablet immediately after it is placed in the mouth.
The tablets should not be wet (e.g., soaked, licked) before they are placed in the mouth for swallowing, since wetting the tablets results in formation of a gelatinous mass that may be difficult to swallow. (See Cautions.) Crushing, chewing, or dissolving the tablets will result in uncontrolled delivery of hydrocodone and can result in overdosage and death. Hydrocodone bitartrate and hydrocodone polistirex are administered orally.
When the extended-release oral suspension containing hydrocodone polistirex and chlorpheniramine polistirex (e.g., Tussionex(R) Pennkinetic(R)) is used, patients and caregivers should be strongly advised to use an accurate, calibrated dosing device to measure doses of the suspension. Use of a household teaspoon as a measuring device could result in overdosage. The extended-release oral suspension should not be diluted with other liquids or mixed with other drugs, since this may alter resin binding, thereby altering the rate of hydrocodone absorption and possibly resulting in toxicity.
The extended-release oral suspension should not be given more frequently than every 12 hours; if cough is not controlled, the clinician should be contacted. The extended-release oral suspension should be shaken well before each use. Acetaminophen is administered orally, rectally as suppositories, and by IV infusion over 15 minutes. Acetaminophen preparations for self-medication should not be used unless seals on the tamper-resistant packaging are intact.
The extended-release capsules must be taken whole; crushing, breaking, cutting, chewing, or dissolving the capsules will result in uncontrolled delivery of hydrocodone and can result in overdosage and death. Patients should be advised that they must not consume alcoholic beverages or take prescription or nonprescription preparations containing alcohol during therapy, since concomitant ingestion of alcohol with hydrocodone bitartrate extended-release capsules may result in increased plasma concentrations of the drug and a potentially fatal overdose. (See Drug Interactions: Alcohol.) Hydrocodone bitartrate extended-release tablets are administered once daily (every 24 hours) without regard to meals.
Multiple tablets of lower-dose strengths that provide the desired total daily dosage can be taken as a once-daily dose. If a dose is missed, the next dose should be taken at the scheduled time on the following day. The extended-release tablets must be taken whole, one tablet at a time, with enough water to ensure complete swallowing of the tablet immediately after it is placed in the mouth.
The tablets should not be wet (e.g., soaked, licked) before they are placed in the mouth for swallowing, since wetting the tablets results in formation of a gelatinous mass that may be difficult to swallow. (See Cautions.) Crushing, chewing, or dissolving the tablets will result in uncontrolled delivery of hydrocodone and can result in overdosage and death. Hydrocodone bitartrate and hydrocodone polistirex are administered orally.
When the extended-release oral suspension containing hydrocodone polistirex and chlorpheniramine polistirex (e.g., Tussionex(R) Pennkinetic(R)) is used, patients and caregivers should be strongly advised to use an accurate, calibrated dosing device to measure doses of the suspension. Use of a household teaspoon as a measuring device could result in overdosage. The extended-release oral suspension should not be diluted with other liquids or mixed with other drugs, since this may alter resin binding, thereby altering the rate of hydrocodone absorption and possibly resulting in toxicity.
The extended-release oral suspension should not be given more frequently than every 12 hours; if cough is not controlled, the clinician should be contacted. The extended-release oral suspension should be shaken well before each use. Acetaminophen is administered orally, rectally as suppositories, and by IV infusion over 15 minutes. Acetaminophen preparations for self-medication should not be used unless seals on the tamper-resistant packaging are intact.
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| HYDROCODONE-ACETAMIN 5-300 MG | Maintenance | Adults take 1 tablet by oral route every 4-6 hours as needed for pain |
| HYDROCODONE-ACETAMIN 7.5-300 | Maintenance | Adults take 1 tablet by oral route every 6 hours as needed |
| HYDROCODONE-ACETAMIN 5-325 MG | Maintenance | Adults take 1 tablet by oral route every 6 hours as needed for pain |
| HYDROCODONE-ACETAMIN 7.5-325 | Maintenance | Adults take 1 tablet by oral route every 6 hours as needed for pain |
| HYDROCODONE-ACETAMIN 10-325 MG | Maintenance | Adults take 1 tablet by oral route every 4-6 hours as needed for pain |
| HYDROCODONE-ACETAMIN 10-300 MG | Maintenance | Adults take 1 tablet by oral route every 6 hours as needed |
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| HYDROCODONE-ACETAMIN 5-325 MG | Maintenance | Adults take 1 tablet by oral route every 6 hours as needed for pain |
| HYDROCODONE-ACETAMIN 7.5-325 | Maintenance | Adults take 1 tablet by oral route every 6 hours as needed for pain |
| HYDROCODONE-ACETAMIN 10-325 MG | Maintenance | Adults take 1 tablet by oral route every 4-6 hours as needed for pain |
| HYDROCODONE-ACETAMIN 5-300 MG | Maintenance | Adults take 1 tablet by oral route every 4-6 hours as needed for pain |
| HYDROCODONE-ACETAMIN 7.5-300 | Maintenance | Adults take 1 tablet by oral route every 6 hours as needed |
| HYDROCODONE-ACETAMIN 10-300 MG | Maintenance | Adults take 1 tablet by oral route every 6 hours as needed |
The following drug interaction information is available for HYDROCODONE-ACETAMINOPHEN (hydrocodone bitartrate/acetaminophen):
There are 2 contraindications.
These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.
| Drug Interaction | Drug Names |
|---|---|
| Opioid Antagonists/Opioid Analgesics SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Naltrexone, nalmefene, and samidorphan are opioid antagonists and thus inhibit the effects of opioid analgesics.(1-3) CLINICAL EFFECTS: Concurrent administration or the administration of naltrexone within 7-10 days of opioids may induce acute abstinence syndrome or exacerbate a pre-existing subclinical abstinence syndrome.(1,4) Patients taking naltrexone may not experience beneficial effects of opioid-containing medications.(4) Samidorphan can precipitate opioid withdrawal in patients who are dependent on opioids. In patients who use opioids, delay initiation of samidorphan for a minimum of 7 days after last use of short-acting opioids and 14 days after last use of long-acting opioids.(3) Concurrent use of nalmefene tablets with opioid agonists may prevent the beneficial effects of the opioid.(2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of naltrexone states that the administration of naltrexone concurrently with opioids or to patients dependent on opioids is contraindicated.(1,4) Patients previously dependent on short-acting opioids should be opioid-free for a minimum of seven to ten days before beginning naltrexone therapy. Patients previously on buprenorphine or methadone may be vulnerable to withdrawal symptoms for as long as 2 weeks.(1,4) The manufacturer of naltrexone states that the naloxone challenge test, described in the naltrexone prescribing information, can be administered to determine if patients are opioid free.(1) The manufacturer of samidorphan states the concurrent use of samidorphan in patients using opioids or undergoing acute opioid withdrawal is contraindicated. Prior to initiating samidorphan, there should be at least a 7-day opioid free interval from the last use of short-acting opioids, and at least a 14-day opioid free interval from the last use of long-acting opioids.(3) The UK manufacturer of nalmefene tablets (for reduction of alcohol consumption) states the concurrent use of opioid analgesics is contraindicated.(2) Suspend the use of nalmefene tablets for 7 days prior to the anticipated use of opioids (e.g., elective surgery).(2) DISCUSSION: A double-blind, randomized, placebo-control study evaluated pain relief and side effects of 35 opioid-naive patients undergoing cesarean section. All patients received spinal anesthesia (bupivacaine and morphine) and were randomized to also receive placebo, naltrexone 3 mg, or naltrexone 6 mg. Patients treated with naltrexone experienced shorter duration of pain relief (not statistically significant), however incidence of opioid-induced side effects was reduced. Patients in the naltrexone 6 mg group had lower rates of pruritus, vomiting, and somnolence (all statistically significant) compared to the placebo group.(5) In a double-blind, randomized, placebo-control trial ten recreational opioid users were studied to determine the effects of hydromorphone (4 mg and 16 mg), tramadol (87.5 mg, 175 mg, and 350 mg), and placebo after pretreatment with naltrexone (50 mg) or placebo. Results show that lower doses of hydromorphone and tramadol acted similar to placebo. Hydromorphone 16 mg alone caused euphoria and miosis which were blocked by naltrexone. Tramadol 350 mg produced a lower magnitude of euphoria and miosis compared to hydromorphone. Naltrexone partially diminished the euphoria caused by tramadol, while it enhanced some of the unpleasant monoaminergic effects (flushing, malaise, vomiting).(6) A case report describes a 28 year-old ex-heroin addict who was stable on methadone 100 mg daily and simultaneously stopped using heroin and began drinking alcohol. He was admitted to the hospital for alcohol detoxification and, by mistake, was given naltrexone 100 mg instead of methadone 100 mg. The patient experienced withdrawal symptoms including chills, agitation, muscle and abdominal pain, generalized piloerection, and dilated pupils. Treatment of withdrawal was titrated to treat symptoms and required administration 78 mg of parenteral hydromorphone, after which the patient experienced relief for the following six hours.(8) Intentional administration of an opioid antagonist, naloxone, with opioid analgesics has been performed with close monitoring to lower required opioid dose by inducing withdrawal. Three case reports describe patients who had improved pain relief on significantly reduced doses of opioid analgesics.(8) In a double-blind controlled trial, 267 trauma patients were randomized to receive 0.05 mg/kg intravenous morphine either alone or in combination with 5 mg naltrexone oral suspension. Evaluated endpoints include reduction of pain and incidence of side effects. Results indicate that ultra-low dose naltrexone does not alter opioid requirements for pain control, but does lower incidence of nausea [2 (1.16%) vs 16 (11.6%), p<0.001].(9) |
CONTRAVE, LOTREXONE, LYBALVI, NALTREX, NALTREXONE BASE MONOHYDRATE, NALTREXONE HCL, NALTREXONE HCL DIHYDRATE, NALTREXONE HCL MICRONIZED, OPVEE, VIVITROL |
| Selected Opioids/Mifepristone 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: Mifepristone is an inhibitor of CYP3A4 and may increase levels and effects of drugs metabolized by this enzyme, including alfentanil, benzhydrocodone, fentanyl, hydrocodone, meperidine, oxycodone, and sufentanil.(1) CLINICAL EFFECTS: Alfentanil, benzhydrocodone, fentanyl, hydrocodone, meperidine, oxycodone, and sufentanil are particularly susceptible to significant toxicity, including profound sedation, respiratory depression, coma, and/or death.(1,2) PREDISPOSING FACTORS: Due to the need for continuous therapy and mifepristone's long half-life of 85 hours(1) which leads to accumulation, patients with endogenous Cushing's syndrome may be at an increased risk for toxicity. PATIENT MANAGEMENT: The US manufacturer of mifepristone for hypercortisolism due to endogenous Cushing's syndrome states use with CYP3A4 substrates with a narrow therapeutic range, including alfentanil, benzhydrocodone, fentanyl, hydrocodone, meperidine, oxycodone, and sufentanil, is contraindicated.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. Consider this risk when using concurrently with agents that may increase opioid drug levels.(3) If concomitant use is unavoidable, monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness. Discuss naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(4) DISCUSSION: Administration of mifepristone 1200 mg daily for 10 days followed by a single dose of simvastatin 80 mg led to an increase of simvastatin and simvastatin acid (active metabolite) area-under-curve (AUC) of 10.4-fold and 15.7-fold, respectively.(1) |
KORLYM, MIFEPREX, MIFEPRISTONE |
There are 5 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 Opioids/Selected CYP3A4 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: CYP3A4 inhibitors may inhibit the metabolism of alfentanil,(1,2) benzhydrocodone,(3) fentanyl,(1,2) hydrocodone,(4) oxycodone,(5) and sufentanil.(6) Benzhydrocodone is a prodrug of hydrocodone.(3) CLINICAL EFFECTS: The concurrent administration of a CYP3A4 inhibitor may result in elevated levels of and toxicity from alfentanil,(1,2) benzhydrocodone,(3) fentanyl,(1,2) hydrocodone,(4) oxycodone,(5) and sufentanil,(6) including profound sedation, respiratory depression, coma, and/or death. PREDISPOSING FACTORS: Heat. PATIENT MANAGEMENT: Monitor patients receiving potent or moderate CYP3A4 inhibitors for an extended period of time. Dosage adjustments should be made if warranted. The manufacturer of itraconazole states that concomitant administration of fentanyl is not recommended during and 2 weeks after itraconazole treatment.(7) Avoid exposing the fentanyl patch application site and surrounding area to direct external heat sources as there have been reports of overdose and death as a result of exposure to heat. The manufacturer of sufentanil sublingual tablets states that if concomitant use with CYP3A4 inhibitors is necessary, consider use of an alternate agent that allows dose adjustment.(6) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. Consider this risk when using concurrently with agents that may increase opioid drug levels.(8) Discuss naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(9) DISCUSSION: In a randomized, placebo-controlled trial in 20 healthy subjects, clarithromycin (500 mg twice daily) increased the area-under-curve (AUC) of a single oral dose of oxycodone (10 mg) by 2-fold and 2.3-fold in young and elderly subjects, respectively.(10) In a controlled cross-over study in 6 subjects, 7 days of pretreatment with erythromycin decreased the clearance of alfentanil by 25%. Alfentanil half-life increased by 56%.(11) Erythromycin has been shown to inhibit fentanyl metabolism in vitro.(12) In a randomized, double-blind, placebo-controlled crossover study in 9 subjects, single doses of intravenous fluconazole (400 mg) and oral fluconazole (400 mg) decreased the clearance of a single dose of alfentanil (20 mcg/kg) by 58% and 55%, respectively. Alfentanil half-life almost doubled after both intravenous and oral fluconazole. Both intravenous and oral fluconazole increased subjective effects of alfentanil and increased alfentanil-induced respiratory depression.(13) In a cross-over study, pretreatment with itraconazole (200 mg daily for 4 days) had no effect on a single dose of intravenous fentanyl (3 mcg/kg).(14) In a cross-over study in 12 healthy subjects, itraconazole (200 mg daily for 5 days) increased the AUC and Cmax of a single oral dose of oxycodone (10 mg) by 144% and 45%, respectively. The AUC of noroxycodone decreased 49% and the AUC of oxymorphone increased 359% with concurrent itraconazole and oral oxycodone. Itraconazole increased the AUC of a single intravenous dose of oxycodone (0.1 mg/kg) by 51%.(15) In a randomized cross-over study in 12 healthy subjects, ketoconazole increased the AUC of oxycodone by 2-fold to 3-fold and also increased oxycodone-related nausea, drowsiness, and pruritus.(16) In a randomized cross-over study in 10 healthy subjects, ketoconazole increased the AUC of oxymorphone by 3-fold following a single dose of oxycodone (0.2 mg/kg). Increased side effects were also noted.(17,18) Ketoconazole has been shown to inhibit the metabolism of alfentanil,(19) fentanyl,(12) and oxycodone(20) in vitro. In a study of 11 subjects, ritonavir reduced the clearance of fentanyl 67% and increased the AUC 174%. Eight subjects reported nausea during the study.(21) In a randomized cross-over study in 16 healthy subjects, ritonavir (300 mg twice daily for 4 days) and lopinavir/ritonavir (400/100 mg twice daily for 4 days) increased the AUC of a single dose of oxycodone (10 mg) by 3.0-fold and 2.6-fold, respectively. Oxycodone half-life increased 55% and 58%, respectively, with concurrent ritonavir or lopinavir/ritonavir. Both regimens also increased self-reported oxycodone effects.(22) The Australian manufacturer of ritonavir states that the AUC of fentanyl may be potentially increased 3-fold with concurrent ritonavir.(23) In a randomized cross-over study in 11 healthy subjects, telithromycin (800 mg daily for 4 days) increased the AUC of a single dose of oxycodone (10 mg immediate-release) by 80%. The AUC of noroxycodone was decreased by 46%. There was a modest increase in the pharmacodynamic effects of oxycodone.(24) In a randomized cross-over study in 10 healthy subjects, troleandomycin increased the AUC of alfentanil by 135%.(25) In a randomized cross-over study in 12 healthy subjects, troleandomycin increased the AUC of a single dose of fentanyl (oral transmucosal, 10 mcg/kg) by 76%.(26) Troleandomycin has been shown to inhibit alfentanil(18) and fentanyl(27) metabolism in vitro. In a randomized, cross-over study in 12 healthy subjects, concurrent use of voriconazole and alfentanil increased the AUC of alfentanil 6-fold and decreased its clearance by 85%.(23,28) In a randomized, cross-over study in 12 healthy subjects, voriconazole (400 mg twice daily, Day 1; 200 mg twice daily, Day 2) and fluconazole (400 mg daily, Day 1; 200 mg daily, Day 2) decreased the clearance of a single dose of intravenous fentanyl (5 mcg/kg) by 23% and 16%, respectively.(29) In a randomized cross-over study in 12 healthy subjects, pretreatment with voriconazole for 4 days increased the AUC, Cmax, and half-life of a single dose of oxycodone (10 mg) by 3.6-fold, 1.7-fold, 2.0-fold, respectively.(30) There are case reports of interactions between alfentanil and erythromycin,(31) fentanyl and clarithromycin,(32) fentanyl and fluconazole,(33) fentanyl and itraconazole,(34) and oxycodone and voriconazole.(35) In the case report with fentanyl and fluconazole, the patient died of respiratory depression.(33) A study in healthy subjects shown that the application of heat over the fentanyl patch system increased mean overall fentanyl exposure by 120% and average maximum fentanyl level by 61%.(2) In a single dose study of sufentanil sublingual tablet 15 mcg with a strong CYP3A4 inhibitor, ketoconazole, resulted in 77% and 19% greater AUC and Cmax values of sufentanil, respectively, compared to its administration alone.(6) Strong CYP3A4 inhibitors that have been documented to interact with alfentanil, benzhydrocodone, fentanyl, hydrocodone, and/or oxycodone or would be expected to interact with these agents include: boceprevir, clarithromycin, cobicistat, elvitegravir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, voriconazole.(36) Moderate CYP3A4 inhibitors that have been documented to interact with alfentanil, benzhydrocodone, fentanyl, hydrocodone, and/or oxycodone include: erythromycin and fluconazole.(36) |
APTIVUS, CLARITHROMYCIN, CLARITHROMYCIN ER, DIFLUCAN, E.E.S. 200, E.E.S. 400, ERY-TAB, ERYPED 200, ERYPED 400, ERYTHROCIN LACTOBIONATE, ERYTHROCIN STEARATE, ERYTHROMYCIN, ERYTHROMYCIN ESTOLATE, ERYTHROMYCIN ETHYLSUCCINATE, ERYTHROMYCIN LACTOBIONATE, EVOTAZ, FLUCONAZOLE, FLUCONAZOLE-NACL, GENVOYA, ITRACONAZOLE, ITRACONAZOLE MICRONIZED, KALETRA, KETOCONAZOLE, KISQALI, KRAZATI, LANSOPRAZOL-AMOXICIL-CLARITHRO, LOPINAVIR-RITONAVIR, NEFAZODONE HCL, NOXAFIL, OMECLAMOX-PAK, PAXLOVID, POSACONAZOLE, PREZCOBIX, RECORLEV, SPORANOX, STRIBILD, SYMTUZA, TOLSURA, TUKYSA, TYBOST, VFEND, VFEND IV, VIRACEPT, VOQUEZNA TRIPLE PAK, VORICONAZOLE, ZOKINVY, ZYDELIG |
| Sodium Oxybate/Agents that May Cause Respiratory Depression SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Oxybate by itself may be associated with severe somnolence or respiratory depression. Concurrent use with other CNS depressants may further increase the risk for respiratory depression or loss of consciousness.(1-3) CLINICAL EFFECTS: Concurrent use of sodium oxybate and sedative hypnotics or alcohol may further increase the risk for profound sedation, respiratory depression, coma, and/or death.(1,2) Fatalities have been reported.(3) PREDISPOSING FACTORS: Based upon FDA evaluation of deaths in patients taking sodium oxybate, risk factors may include: use of multiple drugs which depress the CNS, more rapid than recommended oxybate dose titration, exceeding the maximum recommended oxybate dose, and prescribing for unapproved uses such as fibromyalgia, insomnia or migraine. Note that in oxybate clinical trials for narcolepsy 78% - 85% of patients were also receiving concomitant CNS stimulants.(1-3) PATIENT MANAGEMENT: Avoid use of concomitant opioids, benzodiazepines, sedating antidepressants, sedating antipsychotics, general anesthetics, or muscle relaxants, particularly when predisposing risk factors are present. If combination use is required, dose reduction or discontinuation of one or more CNS depressants should be considered. If short term use of an opioid or general anesthetic is required, consider interruption of sodium oxybate treatment.(1,2) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. Consider this risk when using concurrently with other agents that may cause CNS depression.(4) Discuss naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(5) DISCUSSION: The FDA evaluated sodium oxybate postmarket fatal adverse event reports from the FDA Adverse Event Reporting System(AERS)and from the manufacturer. Although report documentation was not always optimal or complete, useful information was obtained. Factors which may have contributed to fatal outcome: concomitant use of one or more drugs which depress the CNS, more rapid than recommended oxybate dose titration, exceeding the maximum recommended oxybate dose, and prescribing for unapproved uses such as fibromyalgia, insomnia or migraine. Many deaths occurred in patients with serious psychiatric disorders such as depression and substance abuse. Other concomitant diseases may have also contributed to respiratory and CNS depressant effects of oxybate.(3) |
LUMRYZ, LUMRYZ STARTER PACK, SODIUM OXYBATE, XYREM, XYWAV |
| Selected Opioids/Ceritinib; Crizotinib SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Ceritinib(1) and crizotinib(2) inhibit CYP3A4, and thus may inhibit the metabolism of agents processed by this isoenzyme, including alfentanil, benzhydrocodone, fentanyl, hydrocodone, meperidine, oxycodone, and sufentanil. CLINICAL EFFECTS: Concurrent use of ceritinib(1) or crizotinib(2) with alfentanil, benzhydrocodone, fentanyl, hydrocodone, meperidine, oxycodone, or sufentanil may lead to elevated drug levels and increased side effects of the opioid, including profound sedation, respiratory depression, coma, and/or death.(1-3) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Avoid coadministration of sensitive or narrow therapeutic window CYP3A4 substrates such as alfentanil, benzhydrocodone, fentanyl, hydrocodone, meperidine, oxycodone, or sufentanil with ceritinib and crizotinib. If concomitant use is unavoidable, dosage adjustments of the opioid should be considered when initiating or discontinuing ceritinib(1) or crizotinib.(2) Patients maintained on ceritinib or crizotinib may need lower initial doses of opioid medications. Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. Consider this risk when using concurrently with agents that may increase opioid drug levels.(5) Monitor patients receiving concurrent therapy for adverse affects, including unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness. Discuss naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(6) DISCUSSION: In a study, ceritinib (750 mg daily for 3 weeks) increased the area-under-curve (AUC) and maximum concentration (Cmax) of midazolam (a CYP3A4 substrate) by 5.4-fold and 1.8-fold, respectively, compared to midazolam alone.(1) Crizotinib (250 mg twice daily for 28 days) increased the AUC of oral midazolam by 3.7-fold.(2) Thus, ceritinib(1) and crizotinib(2) are expected to increase levels of opioids metabolized by CYP3A4. |
XALKORI, ZYKADIA |
| VIBERZI | |
| ALPROSTADIL, PROSTAGLANDIN E1, PROSTIN VR PEDIATRIC |
There are 20 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 |
|---|---|
| Selected Opioids/Selected Strong CYP3A4 Inducers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of alfentanil, benzhydrocodone, buprenorphine,(1) fentanyl, hydrocodone, meperidine,(2-4) morphine,(5) oxycodone, papaveretum, and sufentanil.(6) CLINICAL EFFECTS: Concurrent use of a strong CYP3A4 inducer may result in decreased levels of alfentanil, benzhydrocodone, buprenorphine, fentanyl, hydrocodone, meperidine, morphine, oxycodone, papaveretum, and sufentanil, which may result in decreased effectiveness and may precipitate withdrawal symptoms.(1-6) Induction of meperidine metabolism may result in an increase in levels of normeperidine, the toxic metabolite of meperidine, resulting in a higher risk of excitatory effects, including hallucinations, tremors, and seizures.(2,3) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Patients maintained on alfentanil, benzhydrocodone, buprenorphine, fentanyl, hydrocodone, meperidine, morphine, oxycodone, papaveretum, and sufentanil may require dosage adjustments if a strong CYP3A4 inducer is initiated or discontinued. The effects of the interaction may last for several weeks after the discontinuation of the inducer. Patients who transfer to Sublocade (extended release subcutaneous syringe buprenorphine) from transmucosal buprenorphine used concomitantly with CYP3A4 inducers should be monitored to ensure that the plasma buprenorphine level produced by Sublocade is adequate. If patients already on Sublocade require newly-initiated treatment with CYP3A4 inducer, the patient should be monitored for withdrawal. If the dose of Sublocade is not adequate in the absence of the concomitant medication, and the concomitant medication cannot be reduced or discontinued, the patient should be transitioned back to a formulation of buprenorphine that permits dose adjustment. If a patient has been stabilized on Sublocade with a CYP3A4 inducer and the concomitant medication is discontinued, the patient should be monitored for signs and symptoms of over-medication. Within 2 weeks of Sublocade administration, if the dose provided by Sublocade is excessive in the absence of the concomitant inducer, it may be necessary to remove the Sublocade and treat the patient with a formulation of buprenorphine that permits dose adjustments.(15) The manufacturer of sufentanil sublingual tablets states that if concomitant use with CYP3A4 inducers is necessary, consider use of an alternate agent that allows dose adjustment.(6) DISCUSSION: In a study in 12 opoid-dependent patients, rifampin (600 mg daily) decreased the area-under-curve (AUC) of buprenorphine by 70%. Half of the subjects experienced withdrawal symptoms. When compared to historical values, there was no effect on rifampin levels.(1) In a study of four healthy volunteers, phenytoin increased meperidine clearance from 1017 +/- 225 ml/min (mean +/- SD) to 1280 +/- 130 ml/min and decreased half-life from 6.4 hours to 4.3 hours. Phenytoin also increased normeperidine AUC by 1.53-fold after IV meperidine and by 1.25-fold after oral meperidine.(3) In a study in 10 healthy subjects, pretreatment with rifampin (600 mg daily) for 13 days decreased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of morphine by 28% and 41%, respectively. The AUCs of morphine-3-glucuronide and morphine-6-glucuronide were proportionally decreased as well. Following rifampin pretreatment, no analgesic effects of morphine were seen.(5) In a randomized controlled trial of 12 healthy participants St. John's wort decreased the oxycodone AUC by 50%, shortened the oxycodone elimination half-life, and decreased the self-reported drug effect of oxycodone compared to placebo.(7) In a study in 12 healthy subjects, pretreatment with rifampin had no effect on fentanyl Cmax or time to Cmax (Tmax) after administration of oral transmucosal fentanyl. However, fentanyl AUC decreased 62%.(8) In a study in 9 healthy subjects, rifampin increased the clearance of alfentanil by 169%. Alfentanil half-life decreased 61%.(9) In a study of patients undergoing craniotomy, higher fentanyl maintenance doses were required in patients receiving carbamazepine and phenytoin compared to control subjects not receiving enzyme-inducing agents.(10) There are case reports of decreased levels and effectiveness of oxycodone with concurrent phenytoin(11) and rifampin(12) and with concurrent fentanyl and rifampin.(13-14) Selected strong CYP3A4 inducers linked to this monograph include: apalutamide, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenytoin, rifampin, rifapentine, and St. John's Wort. |
BRAFTOVI, CARBAMAZEPINE, CARBAMAZEPINE ER, CARBATROL, CEREBYX, DILANTIN, DILANTIN-125, EPITOL, EQUETRO, ERLEADA, FOSPHENYTOIN SODIUM, LYSODREN, MITOTANE, ORKAMBI, PHENYTEK, PHENYTOIN, PHENYTOIN SODIUM, PHENYTOIN SODIUM EXTENDED, PRIFTIN, RIFADIN, RIFAMPIN, TEGRETOL, TEGRETOL XR, TIBSOVO, XTANDI |
| Selected Opioid Analgesics/Cimetidine SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The metabolism of selected opioid analgesics may be inhibited by cimetidine.(1-15) At doses of 800-2400 mg daily, cimetidine is a moderate inhibitor of CYP3A4 and a weak inhibitor of CYP1A2, CYP2C19, CYP2C9, and CYP2D6.(16) Benzhydrocodone is a prodrug of hydrocodone.(12) CLINICAL EFFECTS: The effect of selected opioid analgesics may be increased including profound sedation, respiratory depression, coma, and/or death. Opioid analgesics have been associated with histamine release and is dependent on dose, route of administration, and rate of administration. Histamine release can cause arteriole dilation and contribute to a profound decrease in systemic blood pressure. The cardiovascular effects of histamine release occurring with the opioid analgesics may be decreased by giving cimetidine concurrently.() PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Cimetidine use at higher doses of 200-400 mg four times daily would have an increased risk of inhibiting the metabolism of opioid analgesics. Lower doses and over-the-counter doses of cimetidine would be expected to have a diminished effect. Consider using alternative H2 antagonists when long-term concurrent therapy with opioid analgesics is indicated. The manufacturer of sufentanil sublingual tablets states that if concomitant use with CYP3A4 inhibitors is necessary, consider use of an alternate agent that allows dose adjustment.(15) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. Consider this risk when using concurrently with agents that may increase opioid drug levels.(17) Monitor the patient for increased adverse effects of the opioid analgesic including respiratory and central nervous system depression, unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness. Discuss naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(18) DISCUSSION: Severe respiratory depression has been reported with the concurrent administration of opioid analgesics and cimetidine. Systemic levels of opioid analgesics metabolized by CYP3A4 may be increased during concurrent use with cimetidine, a CYP3A4 inhibitor.(1-15) In a study of 6 healthy subjects, the effects of ketoconazole (a strong CYP3A4 inhibitor) 400 mg daily for 3 days on alfentanil were studied. The maximum concentration (Cmax) and area-under-curve (AUC) of alfentanil were increased with both sequential and simultaneous dosing of alfentanil with concurrent ketoconazole.(19) In a study of 16 healthy subjects, the effects of ketoconazole 300 mg twice daily for 2 days on fentanyl 5 mcg/kg single dose were examined. Fentanyl AUC was increased by 133% and clearance was reduced to 78%. The metabolism of fentanyl to norfentanyl by CYP3A4 was delayed and partial metabolic clearance decreased by 18% with concurrent ketoconazole.(20) In vitro results of the effects of ketoconazole on hydrocodone confirmed CYP3A4 is responsible for the metabolism of hydrocodone to norhydrocodone.(21) A review discussed the metabolism of hydrocodone by CYP2D6 to O-demethylated hydromorphone and by CYP3A4 to N-demethylated norhydrocodone. CYP3A4 activity is reported as higher in women resulting in higher fractions of the norhydrocodone metabolite in women than in men.(22) A case report of a 46 year old hemodialysis patient was on routine therapy with phenytoin 100 mg three times daily and cimetidine 300 mg three times daily. Four days after starting cimetidine, morphine 15 mg IM every 4 hours was initiated for pain. After the sixth dose of morphine, the patient was apneic with a respiratory rate of 3 breaths/minute and had a grand mal seizure. The patient responded to naloxone 0.4 mg IV single dose with improvement in respiratory rate to 12 breaths/minute. Cimetidine was stopped and phenytoin decreased to 100 mg twice daily with improvement after 80 hours from initial episode. A month later the patient required surgery and was given cimetidine 150 mg twice daily followed by Pantopon 15 mg IM every 3-6 hours postoperatively for pain. The patient again became apneic, confused, and developed muscle twitching which responded to naloxone 0.4 mg for 4 doses over the next 24 hours with complete recovery.(23) In a study of 8 healthy subjects, the effects of cimetidine on morphine were studied. Subjects were evaluated in three study periods: morphine 10 mg IM single dose; cimetidine 600 mg oral given one hour before morphine 10 mg IM single dose; and cimetidine 600 mg oral single dose. Morphine reduced resting ventilation and increased end-tidal CO2 with peak effects at 120 minutes and resolution at 12 hours. Morphine with cimetidine pretreatment had similar effects on resting ventilation and end-tidal CO2, however the recovery ratio from 120 to 720 minutes was significantly different than morphine alone (p<0.05).(24) In a study of 7 healthy subjects, the effects of cimetidine 300 mg oral four times daily for 4 days on morphine 10 mg IV single dose were evaluated. No significant differences were found in morphine concentrations at any time point from zero to ten hours after dose administration with and without cimetidine. Morphine elimination half-life (t1/2), systemic clearance, volume of distribution, and AUC with and without cimetidine had no statistical differences.(25) In a study of 40 patients undergoing elective coronary artery bypass graft surgery were randomized to receive either cimetidine 4 mg/kg, diphenhydramine 1 mg/kg, a combination of both cimetidine and diphenhydramine, or placebo, followed by morphine 1 mg/kg. Patients were randomized to one of four groups: 1. placebo plus morphine; 2. cimetidine plus morphine; 3. diphenhydramine plus morphine; or 4. cimetidine plus diphenhydramine plus morphine. Patients in group 1 had a 10-fold increase in plasma histamine levels within 2 minutes of morphine with a decrease in mean BP, diastolic BP, and systemic vascular resistance (SVR). Group 2 has similar effects with a peak change in SVR and plasma histamine rise within 2 minutes of morphine. The change in SVR was significant when compared to placebo but less than group 1. Group 3 patients had an increase in heart rate (HR) from diphenhydramine alone as well as peak effects within 2 minutes of morphine with decreases in BP and SVR but were less than morphine alone. Group 4 patients had a 7-fold increase in histamine with a significant increase in HR, diastolic BP, and BP. When group 4 is compared to group 1, patients had a decrease in SVR and diastolic BP that was significantly less despite comparable increases in plasma histamine.(26) In vitro testing of oxycodone and methadone, cimetidine caused a greater than 50% inhibition in all pathways: CYP2B6, CYP3A4, CYP2C18, and CYP2D6. Cimetidine was found to be a weak reversible inhibitor in vitro. Extrapolation of the data to in vivo inhibition is unlikely to produce significant inhibition unless concentrations exceed normal doses by 10-fold.(27) Two studies examined the effects of CYP2D6 and CYP3A4 on the metabolism of oxycodone as well as genetic polymorphism influences. After concurrent administration of oxycodone with ketoconazole, the Cmax of the metabolites noroxycodone and noroxymorphone were decreased by 80% from baseline.(28,29) A review discussed the metabolism of oxycodone by CYP3A4 to noroxycodone, the major metabolite with weak antinociceptive properties, and by CYP2D6 to the active minor metabolite oxymorphone.() In a study of 8 male subjects, effects of cimetidine 600 mg twice daily for seven days on pethidine 70 mg IV single dose was evaluated. Concurrent use with cimetidine was associated with a 22% decrease in clearance, 11% decrease in elimination rate, and a 13% decrease in volume of distribution of pethidine. Changes were also seen in norpethidine, the primary metabolite, with a 23% decrease in AUC and 29% decrease in Cmax.(30) Opioid analgesics linked to this monograph include: alfentanil, benzhydrocodone, dihydrocodeine, fentanyl, hydrocodone, meperidine, meptazinol, nalbuphine, oxycodone, oxymorphone, pentazocine, propoxyphene, and sufentanil. |
CIMETIDINE |
| Opioids/Buprenorphine; Pentazocine SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Buprenorphine is a partial agonist at mu-opiate receptors, exhibiting a ceiling effect at which higher doses produce no further effect. Pentazocine is a mixed agonist-antagonist at opiate receptors.(1) Full mu-opioid agonists (e.g., morphine, methadone) continue to have increased effects at higher doses without ceiling effects.(2) CLINICAL EFFECTS: Concurrent use of buprenorphine or pentazocine with other opioids in opioid dependent patients may result in withdrawal symptoms. Concurrent use in other patients may result in additive or decreased analgesia and decreased opioid side effects. PREDISPOSING FACTORS: Patients dependent on opioids or who take higher dosages of opioids may be more likely to experience withdrawal symptoms with concurrent use. PATIENT MANAGEMENT: Use buprenorphine and pentazocine with caution in patients maintained or dependent on other opioids and monitor for signs of withdrawal. In other patients, also monitor for changes in analgesic effects. The manufacturer of Sublocade states buprenorphine may precipitate opioid withdrawal in patients who are currently physically dependent on full opioid agonists. The risk of withdrawal may be increased if buprenorphine is given less than 6 hours after short-acting opioids (such as heroin, morphine) and less than 24 hours after long-acting opioids (such as methadone).(3) DISCUSSION: Concurrent use of buprenorphine with other opioids in opioid dependent patients could result in withdrawal symptoms. Concurrent use in other patients may result in additive or decreased analgesia, decreased opioid side effects, and/or renarcotization.(2) In clinical trials, administration of buprenorphine injection produced withdrawal symptoms in patients maintained on methadone (30 mg daily) when administered 2 hours post-methadone,(4) but not when administered 20 hours post-methadone.(5) In another study, sublingual buprenorphine produced withdrawal symptoms in patients maintained on methadone. Symptoms were more pronounced in patients maintained on 60 mg daily doses than in patients maintained on 30 mg daily doses.(6) In a study of 10 patients maintained on methadone (100 mg daily), only three were able to tolerate escalating sublingual doses of buprenorphine/naloxone up to 32/8 mg. Split doses produced less withdrawal symptoms than full doses.(7) In a case report, a heroin-user maintained in a buprenorphine-maintenance program began stockpiling his buprenorphine instead of ingesting it and began using heroin. He then decided to re-initiate treatment on his own and ingested between 80 and 88 mg of buprenorphine over a two day period and experienced extreme withdrawal symptoms, despite restarting heroin during these symptoms. Methadone relieved his withdrawal symptoms.(8) |
BELBUCA, BRIXADI, BUPRENORPHINE, BUPRENORPHINE HCL, BUPRENORPHINE-NALOXONE, BUTRANS, PENTAZOCINE-NALOXONE HCL, SUBLOCADE, SUBOXONE, ZUBSOLV |
| Acetaminophen/Isoniazid SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Isoniazid may induce the metabolism of acetaminophen to its toxic N-acetyl-p-benzoquinone imine (NAPQI) metabolite by CYP2E1.(1) CLINICAL EFFECTS: Concurrent isoniazid and acetaminophen may result in hepatotoxicity.(1) Symptoms can include nausea, vomiting, jaundice, dark urine, abdominal pain, and unexplained fatigue. PREDISPOSING FACTORS: The interaction may be more severe in fast acetylators. PATIENT MANAGEMENT: Concurrent use of acetaminophen in patients treated with isoniazid should be approached with caution. Consider an alternative analgesic agent. If concurrent therapy is warranted, advise patients not to exceed the maximum recommended daily dose of acetaminophen and to immediately report any symptoms of hepatotoxicity. DISCUSSION: Isoniazid has been shown to induce, after initially inhibiting, the metabolism of acetaminophen to N-acetyl-p-benzoquinone imine (NAPQI), which is hepatotoxicity. Normally, NAPQI is rapidly converted to non-toxic metabolites by glutathione; however, high levels of NAPQI can overwhelm this system.(2-4) In a case report, a patient receiving isoniazid developed severe acetaminophen toxicity following a suicide attempt, despite only having ingested a maximum of 11.5 grams of acetaminophen and having a blood acetaminophen level of 15 mmol/L 13 hours later. Toxicity is usually seen with levels greater than 26 mmol/L.(5) In a retrospective review of 20 deaths in patients taking isoniazid alone or with ethambutol during a 13 year period, two deaths involved patients receiving concurrent isoniazid and acetaminophen.(6,7) |
ISONIAZID |
| Selected Anticoagulants/Acetaminophen SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Acetaminophen may reduce levels of functional Factor VI, thereby increasing the International Normalized Ratio (INR).(1) In one trial factors II and VII levels were also reduced, thereby increasing the INR. (2) CLINICAL EFFECTS: Concurrent use of routine acetaminophen, especially at dosages greater than 2 grams/day, and coumarin anticoagulants may result in elevated anticoagulant effects. PREDISPOSING FACTORS: Routine use of acetaminophen at dosages greater than 2 grams/day may increase the risk of the interaction. PATIENT MANAGEMENT: Patients receiving routine acetaminophen at dosages greater than 2 grams/day with coumarin anticoagulants should be closely monitored for changes in anticoagulant effects. The dosage of the anticoagulant may need to be adjusted. Patients receiving coumarin anticoagulants should be counseled on the use of acetaminophen. DISCUSSION: 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 4 of those studies found a higher rate of clinically significant bleeding in patients on warfarin and non-NSAID analgesics (OR=2.12; 95% CI 1.65-2.73). Increased bleeding risk was also seen in subgroup analyses with acetaminophen (OR=2.32; 95% CI 1.22-4.44).(3) In a study in 11 patients maintained on warfarin, use of acetaminophen (4 grams daily for 14 days) increased INR values by an average of 1.04.(4) In a study in 36 patients maintained on warfarin, the addition of acetaminophen (2 grams/day or 4 grams/day) increased INR values.(5) In a study in 20 patients maintained on warfarin, the addition of acetaminophen (4 grams/day for 14 days) increased average INR values by 1.20 (from 2.6 to 3.45).(6) In a study, 12 patients maintained on various anticoagulants (anisindione, dicoumarol, phenprocoumon, and warfarin) who received 4 weeks of acetaminophen (2.6 grams/day) were compared to 50 subjects maintained on various anticoagulants who did not receive acetaminophen. By the third week of concurrent acetaminophen, prothrombin times increased from 23 seconds to 28.4 seconds. The average warfarin-equivalent dose decreased by 5.8 mg to 4.4 mg. In another phase, 50 subjects maintained on various anticoagulants received acetaminophen (2.6 grams/day for 14 days). The mean prothrombin increase was 3.6 seconds.(7) There have been case reports of increased INRs following concurrent acetaminophen in patients maintained on warfarin(8-11) and acenocoumarol.(12) In contrast to the above reports, other studies have found no effects on acenocoumarol,(14) phenprocoumon,(13-15) or warfarin(16,17) by acetaminophen. In a study in 45 patients maintained on warfarin, the addition of acetaminophen (2 or 3 grams/day for 10 days) increased average INR by 0.7 and 0.67 with 2 grams/day and 3 grams/day, respectively. This increase was apparent by day 3, and a decrease in factor II and VII was observed.(2) 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 acetaminophen resulted in a ratio of rate ratios (95% CI) of 1.28 (1.18-1.38).(18) 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. |
DICUMAROL, JANTOVEN, WARFARIN SODIUM |
| Selected Opioids/Selected Moderate CYP3A4 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the metabolism of alfentanil, benzhydrocodone, fentanyl,(1) hydrocodone, meperidine,(2) oxycodone,(3) and sufentanil.(4) CLINICAL EFFECTS: The concurrent administration of a CYP3A4 inhibitor may result in elevated levels of and toxicity from alfentanil, benzhydrocodone, fentanyl,(1,5) hydrocodone, meperidine,(2) oxycodone(3) and sufentanil(4), including somnolence and potentially fatal respiratory depression. PREDISPOSING FACTORS: Heat. PATIENT MANAGEMENT: Monitor patients receiving moderate CYP3A4 inhibitors for an extended period of time. Dosage adjustments should be made if warranted. The manufacturer of sufentanil sublingual tablets states that if concomitant use with CYP3A4 inhibitors is necessary, consider use of an alternate agent that allows dose adjustment.(4) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. Consider this risk when using concurrently with agents that may increase opioid drug levels.(6) Discuss naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(7) Avoid exposing the fentanyl patch application site and surrounding area to direct external heat sources as there have been reports of overdose and death as a result of exposure to heat.(1) DISCUSSION: Fentanyl(1) and oxycodone(3) are metabolized by the CYP3A4 isoenzyme. Moderate and strong inhibitors of this isoenzyme are expected to increase fentanyl(1) and oxycodone(3) levels. In a single dose study of sufentanil sublingual tablet 15 mcg with a strong CYP3A4 inhibitor, ketoconazole, resulted in 77% and 19% greater AUC and Cmax values of sufentanil, respectively, compared to its administration alone.(4) In a randomized study in 30 patients, continuous diltiazem (1 mcg/kg/min) infusion had no effect on epidural fentanyl consumption when compared to placebo. There were no significant differences in Visual Analogue Scores (VAS), Verbal Rating Scores (VRS), or incidence of side effects, although there was a trend towards increased nausea with concurrent diltiazem.(5) In a randomized study of coronary artery bypass patients, concurrent diltiazem (60 mg orally 2 hours before induction of anesthesia then 0.1 mg/kg/hr infusion) increased the area-under-curve (AUC) and half-life of alfentanil by 40% and 50%, respectively, when compared to placebo. Patients who received diltiazem were extubated an average of 2.5 hours later than in patients who received placebo.(8) In a study in 13 patients, administration of a single dose of verapamil (75mcg/kg to 150mcg/kg) had no significant effects on the pharmacodynamic effects of a single dose of fentanyl; however, individual patients had modest decreases in blood pressure.(9) In a case report, concurrent diltiazem and fentanyl produced delirium.(10) A study in healthy subjects shown that the application of heat over the fentanyl patch system increased mean overall fentanyl exposure by 120% and average maximum fentanyl level by 61%.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, darunavir, diltiazem, dronedarone, duvelisib, fedratinib, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, schisandra, treosulfan and verapamil.(11,12) |
AKYNZEO, APONVIE, APREPITANT, ATAZANAVIR SULFATE, CARDIZEM, CARDIZEM CD, CARDIZEM LA, CARTIA XT, CINVANTI, CLOFAZIMINE, CONIVAPTAN-D5W, COPIKTRA, CRESEMBA, DANZITEN, DARUNAVIR, DILT-XR, DILTIAZEM 12HR ER, DILTIAZEM 24HR ER, DILTIAZEM 24HR ER (CD), DILTIAZEM 24HR ER (LA), DILTIAZEM 24HR ER (XR), DILTIAZEM HCL, DILTIAZEM HCL-0.7% NACL, DILTIAZEM HCL-0.9% NACL, DILTIAZEM HCL-NACL, DILTIAZEM-D5W, EMEND, FOSAMPRENAVIR CALCIUM, GLEEVEC, GRAFAPEX, IMATINIB MESYLATE, IMKELDI, INREBIC, MATZIM LA, MULTAQ, NILOTINIB HCL, ORLADEYO, PREVYMIS, PREZISTA, REYATAZ, SUNLENCA, TASIGNA, TAVNEOS, TIADYLT ER, TIAZAC, TRANDOLAPRIL-VERAPAMIL ER, VAPRISOL-5% DEXTROSE, VERAPAMIL ER, VERAPAMIL ER PM, VERAPAMIL HCL, VERAPAMIL SR |
| Gabapentinoids/Opioids (IR & ER) SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Opioid-induced reduction in GI motility may increase the absorption of gabapentin and pregabalin.(1) Gabapentin and pregabalin may reverse opioid-induced tolerance of respiratory depression.(2) Concurrent use may result in profound sedation, respiratory depression, coma, and/or death.(3) CLINICAL EFFECTS: Concurrent use of opioids may result in elevated levels of and toxicity from gabapentin and pregabalin, including profound sedation, respiratory depression, coma, and/or death.(1-7) PREDISPOSING FACTORS: Patients who are elderly, are taking other CNS depressants, have decreased renal function, and/or have conditions that reduce lung function (e.g. Chronic Obstructive Pulmonary Disease [COPD]) may be at a higher risk of this interaction. PATIENT MANAGEMENT: Limit prescribing opioid analgesics and gabapentinoids to patients for whom alternatives are inadequate.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a gabapentinoid with an opioid analgesic, prescribe a lower initial dose of the gabapentinoid than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a gabapentinoid, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. Consider this risk when using concurrently with other agents that may cause CNS depression.(8) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(9) DISCUSSION: In a study in 12 healthy males, administration of a single dose of morphine (60 mg sustained release) increased the area-under-curve (AUC) of a single dose of gabapentin (600 mg) by 44%.(1,3,4) There were no affects on the pharmacokinetics of morphine.(1,3,4) The combination of gabapentin plus morphine increased pain tolerance over the combination of morphine plus placebo. Side effects were not significantly different between morphine plus placebo and morphine plus gabapentin.(1) A retrospective, case-control study of opioid users in Ontario, Canada between August 1, 1997 and December 31, 2013 who died of an opioid-related cause matched cases to up to 4 controls who also used opioids. Use of gabapentin in the 120 days prior to death resulted in a significant increase in odds of opioid-related death (OR 1.99, CI=1.61-2.47, p<0.001), compared to opioid use alone. Use of moderate dose (900 mg to 1,799 mg daily) or high dose (>= 1,800 mg daily) gabapentin increased the odds of opioid-related death 60% compared to opioid use without gabapentin. Review of gabapentin prescriptions from calendar year 2013 found that 46% of gabapentin users received at least 1 opioid prescription.(3) Among 49 case reports submitted to FDA over a 5 year period (2012-2017), 12 people died from respiratory depression with gabapentinoids. Two randomized, double-blind, placebo-controlled clinical trials in healthy people, three observational studies, and several studies in animals were reviewed. A trial showed that using pregabalin alone and using it with an opioid pain reliever can depress breathing function. Three observational studies showed a relationship between gabapentinoids given before surgery and respiratory depression occurring after surgery. Several animal studies also showed that pregabalin plus opioids can depress respiratory function.(7) A retrospective cohort study evaluated the risk of mortality among Medicare beneficiaries aged 65 and older who were taking gabapentin with or without concurrent use of opioids. All-cause mortality in gabapentin users compared to duloxetine users was 12.16 per 1,000 person years vs. 9.94 per 1,000 person years, respectively. Adjusted for covariates, the risk of all-cause mortality among gabapentin users on high-dose opioids was more than double the control group (hazard ratio (HR) 2.03, CI=1.19-3.46).(10) |
GABAPENTIN, GABAPENTIN ER, GABARONE, GRALISE, HORIZANT, LYRICA, LYRICA CR, NEURONTIN, PREGABALIN, PREGABALIN ER |
| Opioids/Butorphanol SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Butorphanol antagonize mu-opiate receptors. Other opioids agonize mu-opiate receptors.(1) CLINICAL EFFECTS: Concurrent use of butorphanol with other opioids in opioid dependent patients may result in withdrawal symptoms. Concurrent use in other patients may result in additive or decreased analgesia and decreased opioid side effects. PREDISPOSING FACTORS: Patients dependent on opioids may be more likely to experience withdrawal symptoms with concurrent use. Patients using higher doses of opioids may also be at a higher risk. PATIENT MANAGEMENT: Use butorphanol with caution in patients maintained or dependent on other opioids and monitor for signs of withdrawal. In other patients, also monitor for changes in analgesic effects. DISCUSSION: Because butorphanol antagonizes mu-opiate receptors and other opioids agonize mu-opiate receptors, concurrent use of buprenorphine with other opioids in opioid dependent patients may result in withdrawal symptoms. Concurrent use in other patients may result in additive or decreased analgesia and decreased opioid side effects.(1) In a study in patients maintained on methadone, butorphanol produced withdrawal symptoms comparable to naloxone.(2) In a case report, the use of remifentanil for conscious sedation in a patient maintained on butorphanol produced severe withdrawal symptoms.(3) |
BUTORPHANOL TARTRATE |
| Opioids/Nalbuphine SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Nalbuphine(1) antagonizes mu-opiate receptors. Other opioids agonize mu-opiate receptors. CLINICAL EFFECTS: Concurrent use of nalbuphine with other opioids in opioid dependent patients may result in withdrawal symptoms. Concurrent use in other patients may result in additive or decreased analgesia, decreased opioid side effects, and/or renarcotization. PREDISPOSING FACTORS: Patients dependent on opioids may be more likely to experience withdrawal symptoms with concurrent use. In opioid naive patients, higher doses of nalbuphine may result in decreased analgesic effects. PATIENT MANAGEMENT: Use nalbuphine with caution in patients maintained or dependent on other opioids and monitor for signs of withdrawal. In other patients, also monitor for changes in analgesic effects. If nalbuphine is used to reverse opioid anesthesia, monitor patients for renarcotization. DISCUSSION: Nalbuphine has been successfully used as an adjunct to morphine without decreasing analgesic effects.(2,3) However, other studies reported increased morphine requirements in patients who had initially received nalbuphine.(4,5) Nalbuphine has been used to reverse fentanyl anesthesia;(8-13) however, patients often required additional pain medication(5-7) and some studies reported renarcotization after the effects of nalbuphine wore off.(9,10) Nalbuphine has also been used to prevent epidural fentanyl,(13) morphine(14-16), and hydromorphone induced pruritus;(17-18) however, one study reported shortening of the duration of analgesia(16) and another reported increased PCA demands.(17) In methadone-dependent subjects, administration of nalbuphine produced withdrawal symptoms similar to naloxone.(19,20) Administration of nalbuphine to patients maintained on controlled-release morphine resulted in withdrawal symptoms.(20,21) |
NALBUPHINE HCL |
| Selected Opioids/Barbiturates; Phenobarbital; Primidone SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: There are two mechanisms involved in this interaction. Pharmacokinetic: alfentanil, benzhydrocodone, buprenorphine, fentanyl, hydrocodone, meperidine, oxycodone, and sufentanil are primarily metabolized by CYP3A4/5 and glucuronidation pathways.(1-8) Phenobarbital is an inducer of these pathways. Pharmacodynamic: both opioids and barbiturates are associated with respiratory depression; these effects may be additive.(1,3,9) Benzhydrocodone is a prodrug of hydrocodone.(2) Primidone is metabolized to phenobarbital. CLINICAL EFFECTS: Short term or intermittent use of phenobarbital and opioids metabolized by CYP3A4 may be associated with respiratory suppression or other CNS depression. Continuous, longer term use of phenobarbital may result in decreased levels and effectiveness of the opioid. Induction of meperidine metabolism may result in an increase in levels of normeperidine, the toxic metabolite of meperidine, resulting in a higher risk of excitatory effects, including hallucinations, tremors, and seizures.(6,10) PREDISPOSING FACTORS: Patients with a history of alcohol or sedative abuse may be at risk for relapse and overuse or abuse of prescribed phenobarbital.(1,3,5,11) Individuals with significant obstructive pulmonary disease, the elderly, and debilitated patients are at greater risk for respiratory depression from either agent.(1,3) Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Patients on chronic therapy with phenobarbital who are newly starting opioids metabolized by CYP3A4 may need higher than usual doses of the opioid for analgesia or opioid maintenance.(1,3,12) Opioid-treated patients newly started on phenobarbital should be monitored initially for additive CNS sedation or respiratory depression, particularly when predisposing factors (e.g. COPD, sleep apnea, debilitation, elderly) are present. Continued use of phenobarbital leads to induction of the opioids' metabolism. The onset is gradual and may not peak for several weeks. Monitor patient for possible loss of efficacy or opioid withdrawal. If a patient has been maintained on concurrent treatment with an opioid metabolized by CYP3A4 and phenobarbital, and the phenobarbital is discontinued, opioid levels will gradually rise as induction effects diminish. Monitor for increased opioid effects and adjust the dose accordingly.(1,3,12) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. Consider this risk when using concurrently with other agents that may cause CNS depression.(13) For patients receiving opioid maintenance treatment, it would be prudent to assure all controlled substance prescriptions are approved or written by the opioid provider. Discuss naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(14) DISCUSSION: Alfentanil, benzhydrocodone, fentanyl, hydrocodone, meperidine, oxycodone, and sufentanil are metabolized by CYP3A4, and barbiturates, phenobarbital, and primidone would be expected to induce their metabolism.(1,2,4-6) Newer metabolites and minor metabolic pathways for buprenorphine have been recently described. Phenobarbital, an inducer of multiple enzyme pathways (e.g. CYP2B, CYP2C, CYP3A and UGT) could potentially lower systemic buprenorphine levels via major and minor pathways.(12) |
ASA-BUTALB-CAFFEINE-CODEINE, ASCOMP WITH CODEINE, BUTALB-ACETAMINOPH-CAFF-CODEIN, BUTALBITAL, BUTALBITAL-ACETAMINOPHEN, BUTALBITAL-ACETAMINOPHEN-CAFFE, BUTALBITAL-ASPIRIN-CAFFEINE, DONNATAL, FIORICET, FIORICET WITH CODEINE, MYSOLINE, PENTOBARBITAL SODIUM, PHENOBARBITAL, PHENOBARBITAL SODIUM, PHENOBARBITAL-BELLADONNA, PHENOBARBITAL-HYOSC-ATROP-SCOP, PHENOHYTRO, PRIMIDONE, SEZABY, TENCON |
| Busulfan/Acetaminophen SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Busulfan is eliminated from the body via glutathione conjugation. Acetaminophen reduces glutathione levels in the blood and tissues and therefore could decrease the elimination rate of busulfan.(1,2) CLINICAL EFFECTS: Concurrent use of acetaminophen may result in elevated levels of, prolonged exposure to, and toxicity from busulfan, including myelosuppression, granulocytopenia, thrombocytopenia, anemia, seizures, hepatic veno-occlusive disease, cardiac tamponade, bronchopulmonary dysplasia, or cellular dysplasia.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Use acetaminophen concurrent with busulfan with caution.(1) Consider withholding acetaminophen for 72 hours before and during busulfan therapy. If concurrent use cannot be avoided, monitor patients for busulfan toxicity. DISCUSSION: Although a small population study in adult patients found no effect of acetaminophen on busulfan clearance,(3) caution is still warranted.(1) |
BUSULFAN, BUSULFEX, MYLERAN |
| Opioids (Immediate Release)/Benzodiazepines SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Concurrent use of opioids and benzodiazepines may result in additive CNS depression.(1) CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as benzodiazepines, may result in profound sedation, respiratory depression, coma, and/or death.(1) PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as benzodiazepines to patients for whom alternatives are inadequate.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. Consider this risk when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(3) DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(4) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(5) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(6) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(7) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(8) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(9) A study of 315,428 privately insured patients who filled at least one prescription for an opioid from 2001 to 2013 were enrolled in a retrospective study. Concurrent use of a benzodiazepine was recorded as having at least one day of overlap in a given calendar year. Baseline characteristics among opioid users with concurrent use of a benzodiazepine were older (44.5 v. 42.4, p<0.001), less likely to be men (35% v. 43%, p<0.001), and had a higher prevalence rate of every comorbidity examined (p<0.001). The proportion of opioid users with concurrent benzodiazepine use nearly doubled from 9% in 2001 to 17% in 2013. The primary outcome was an emergency room visit or inpatient admission for opioid overdose within a calendar year. Among all opioid users, the annual adjusted incidence for the primary outcome was 1.16% without concurrent benzodiazepine use compared to 2.42% with concurrent benzodiazepine use (OR 2.14; 95% CI 2.05-2.24; p<0.001). Intermittent opioid users (1.45% v. 1.02%; OR 1.42; 95% CI 1.33-1.51; p<0.001) and chronic opioid users (5.36% v. 3.13%; OR 1.81; 95% CI 1.67-1.96; p<0.001) also experienced a higher adjusted incidence of the primary outcome with concurrent benzodiazepine use compared to without concurrent benzodiazepine use, respectively.(10) In a nested case-control study of adults with a new opioid dispensing between 2010-2018, patients with concurrent use of an opioid with a benzodiazepine were significantly more likely to have opioid-related overdose compared to patients receiving opioids, benzodiazepines, or neither (OR 9.28; 95% CI 7.87, 10.93). Longer concurrent use of 1-7, 8-30, and 31-90 days was associated with 4.6, 12.1, and 26.7-fold higher likelihood of opioid-related overdose (p<0.01). Patients with overlapping prescriptions during previous 0-30, 31-60, and 61-90 days were 13.2, 6.0, and 3.2-times more likely to experience an overdose (p<0.01).(11) |
ALPRAZOLAM, ALPRAZOLAM ER, ALPRAZOLAM INTENSOL, ALPRAZOLAM ODT, ALPRAZOLAM XR, ATIVAN, BYFAVO, CHLORDIAZEPOXIDE HCL, CHLORDIAZEPOXIDE-AMITRIPTYLINE, CHLORDIAZEPOXIDE-CLIDINIUM, CLOBAZAM, CLONAZEPAM, CLORAZEPATE DIPOTASSIUM, DIAZEPAM, DORAL, ESTAZOLAM, FLURAZEPAM HCL, HALCION, KLONOPIN, LIBRAX, LORAZEPAM, LORAZEPAM INTENSOL, LOREEV XR, MIDAZOLAM, MIDAZOLAM HCL, MIDAZOLAM HCL-0.8% NACL, MIDAZOLAM HCL-0.9% NACL, MIDAZOLAM HCL-D5W, MIDAZOLAM HCL-NACL, MIDAZOLAM-0.9% NACL, MIDAZOLAM-NACL, MKO (MIDAZOLAM-KETAMINE-ONDAN), NAYZILAM, ONFI, OXAZEPAM, QUAZEPAM, RESTORIL, SYMPAZAN, TEMAZEPAM, TRIAZOLAM, VALIUM, VALTOCO, XANAX, XANAX XR |
| Opioids (Immediate Release)/Sleep Drugs SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Concurrent use of opioids and sleep drugs may result in additive CNS depression and sleep-related disorders.(1) CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as sleep drugs, may result in profound sedation, respiratory depression, coma, and/or death.(1) Concurrent use of opioids with eszopiclone, zaleplon, or zolpidem may increase the risk of sleep-related disorders including central sleep apnea and sleep-related hypoxemia and complex sleep behaviors like sleepwalking, sleep driving, and other activities while not fully awake. Rarely, serious injuries or death have resulted from complex sleep behaviors.(2) PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as sleep drugs to patients for whom alternatives are inadequate.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. Consider this risk when using concurrently with other agents that may cause CNS depression.(3) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Eszopiclone, zaleplon, and zolpidem are contraindicated in patients who have had a previous episode of complex sleep behavior.(2) Discuss naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(4) DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10) As of April 2019, the FDA had identified 66 cases of complex sleep behaviors with eszopiclone, zaleplon, or zolpidem, of which 20 cases resulted in death and the remainder resulted in serious injuries. It was not reported how many of the cases involved concomitant use of other CNS depressants.(2) |
AMBIEN, AMBIEN CR, BELSOMRA, DAYVIGO, EDLUAR, ESZOPICLONE, LUNESTA, QUVIVIQ, RAMELTEON, ROZEREM, ZALEPLON, ZOLPIDEM TARTRATE, ZOLPIDEM TARTRATE ER |
| Opioids (Immediate Release)/Muscle Relaxants SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Concurrent use of opioids and muscle relaxants may result in additive CNS depression.(1) CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as muscle relaxants, may result in profound sedation, respiratory depression, coma, and/or death.(1) PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as muscle relaxants to patients for whom alternatives are inadequate.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. Consider this risk when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(3) DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(4) A retrospective cohort study compared the risk of opioid overdose associated with concomitant use of opioids and skeletal muscle relaxants versus opioid use alone. The study examined two types of opioid users (naive opioid use and prevalent opioid use) with and without exposure to skeletal muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the naive and prevalent opioid user cohorts, respectively, generating a combined estimate of 1.21. The risk increased with treatment duration (less than or equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80) and for the use of baclofen and carisoprodol (HR 1.83 and 1.84, respectively). Elevated risk was associated with concomitant users with daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and 1.39, respectively).(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10) |
BACLOFEN, CARISOPRODOL, CARISOPRODOL-ASPIRIN, CARISOPRODOL-ASPIRIN-CODEINE, CHLORZOXAZONE, DANTRIUM, DANTROLENE SODIUM, FLEQSUVY, LORZONE, LYVISPAH, MEPROBAMATE, METHOCARBAMOL, NORGESIC, NORGESIC FORTE, ORPHENADRINE CITRATE, ORPHENADRINE CITRATE ER, ORPHENADRINE-ASPIRIN-CAFFEINE, ORPHENGESIC FORTE, OZOBAX, OZOBAX DS, REVONTO, ROBAXIN, RYANODEX, SOMA, TANLOR, TIZANIDINE HCL, VANADOM, ZANAFLEX |
| Slt Opioids (Immediate Release)/Antipsychotics;Phenothiazine SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Concurrent use of opioids and antipsychotics, including phenothiazine derivatives, may result in additive CNS depression.(1) CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as antipsychotics, including phenothiazine derivatives, may result in profound sedation, respiratory depression, coma, and/or death.(1) PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as antipsychotics, including phenothiazine derivatives, to patients for whom alternatives are inadequate.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. Consider this risk when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(3) DISCUSSION: A nested case-control study looked at the relationship between antipsychotic use and risk of acute respiratory failure. Current use of antipsychotics was associated with a 2.33-fold increase in risk of respiratory failure compared to no use of antipsychotics. The risk was also significantly increased in patients with recent use of antipsychotics (within the past 15-30 days, OR = 1.79) and recent past use (within 31-90 days OR = 1.41). The risk increased with higher doses and longer duration of use.(4) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10) |
ABILIFY, ABILIFY ASIMTUFII, ABILIFY MAINTENA, ADASUVE, ARIPIPRAZOLE, ARIPIPRAZOLE ODT, ARISTADA, ARISTADA INITIO, ASENAPINE MALEATE, BARHEMSYS, CAPLYTA, CHLORPROMAZINE HCL, CLOZAPINE, CLOZAPINE ODT, CLOZARIL, COMPAZINE, COMPRO, DROPERIDOL, ERZOFRI, FANAPT, FLUPHENAZINE DECANOATE, FLUPHENAZINE HCL, HALDOL DECANOATE 100, HALDOL DECANOATE 50, HALOPERIDOL, HALOPERIDOL DECANOATE, HALOPERIDOL DECANOATE 100, HALOPERIDOL LACTATE, INVEGA, INVEGA HAFYERA, INVEGA SUSTENNA, INVEGA TRINZA, LATUDA, LOXAPINE, LURASIDONE HCL, MOLINDONE HCL, NUPLAZID, OLANZAPINE, OLANZAPINE ODT, OLANZAPINE-FLUOXETINE HCL, OPIPZA, PALIPERIDONE ER, PERPHENAZINE, PERPHENAZINE-AMITRIPTYLINE, PERSERIS, PHENERGAN, PIMOZIDE, PROCHLORPERAZINE, PROCHLORPERAZINE EDISYLATE, PROCHLORPERAZINE MALEATE, PROMETHAZINE HCL, PROMETHAZINE HCL-0.9% NACL, PROMETHAZINE VC, PROMETHAZINE-CODEINE, PROMETHAZINE-DM, PROMETHAZINE-PHENYLEPHRINE HCL, PROMETHEGAN, QUETIAPINE FUMARATE, QUETIAPINE FUMARATE ER, REXULTI, RISPERDAL, RISPERDAL CONSTA, RISPERIDONE, RISPERIDONE ER, RISPERIDONE ODT, RYKINDO, SAPHRIS, SECUADO, SEROQUEL, SEROQUEL XR, THIORIDAZINE HCL, THIORIDAZINE HYDROCHLORIDE, THIOTHIXENE, TRIFLUOPERAZINE HCL, UZEDY, VERSACLOZ, VRAYLAR, ZYPREXA |
| Desmopressin/Agents with Hyponatremia Risk SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Carbamazepine, chlorpromazine, lamotrigine, NSAIDs, opioids, SSRIs, thiazide diuretics, and/or tricyclic antidepressants increase the risk of hyponatremia.(1-3) CLINICAL EFFECTS: Concurrent use may increase the risk of hyponatremia with desmopressin.(1-3) PREDISPOSING FACTORS: Predisposing factors for hyponatremia include: polydipsia, renal impairment (eGFR < 50 ml/min/1.73m2), illnesses that can cause fluid/electrolyte imbalances, age >=65, medications that cause water retention and/or increase the risk of hyponatremia (glucocorticoids, loop diuretics). PATIENT MANAGEMENT: The concurrent use of agents with a risk of hyponatremia with desmopressin may increase the risk of hyponatremia. If concurrent use is deemed medically necessary, make sure serum sodium levels are normal before beginning therapy and consider using the desmopressin nasal 0.83 mcg dose. Consider measuring serum sodium levels more frequently than the recommended intervals of: within 7 days of concurrent therapy initiation, one month after concurrent therapy initiation and periodically during treatment. Counsel patients to report symptoms of hyponatremia, which may include: headache, nausea/vomiting, feeling restless, fatigue, drowsiness, dizziness, muscle cramps, changes in mental state (confusion, decreased awareness/alertness), seizures, coma, and trouble breathing. Counsel patients to limit the amount of fluids they drink in the evening and night-time and to stop taking desmopressin if they develop a stomach/intestinal virus with nausea/vomiting or any nose problems (blockage, stuffy/runny nose, drainage).(1) DISCUSSION: In clinical trials of desmopressin for the treatment of nocturia, 4 of 5 patients who developed severe hyponatremia (serum sodium <= 125 mmol/L) were taking systemic or inhaled glucocorticoids. Three of these patients were also taking NSAIDs and one was receiving a thiazide diuretic.(2) Drugs associated with hyponatremia may increase the risk, including loop diuretics, carbamazepine, chlorpromazine, glucocorticoids, lamotrigine, NSAIDs, opioids, SSRIs, thiazide diuretics, and/or tricyclic antidepressants.(1,3-4) |
DDAVP, DESMOPRESSIN ACETATE, NOCDURNA |
| Opioids (Immediate Release)/Selected Stimulants SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Opioids and stimulants exhibit opposing effects on the CNS. CLINICAL EFFECTS: Concurrent use of opioids and stimulants may have unpredictable effects and may mask overdose symptoms of the opioid, such as drowsiness and inability to focus. PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS stimulants such as amphetamines to patients for whom alternatives are inadequate. If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. Consider this risk when using concurrently with stimulants.(1) Monitor patients receiving concurrent therapy for signs of substance abuse. DISCUSSION: A total of 70,237 persons died from drug overdoses in the United States in 2017; approximately two thirds of these deaths involved an opioid.(2). The CDC analyzed 2016-2017 changes in age-adjusted death rates involving cocaine and psychostimulants by demographic characteristics, urbanization levels, U.S. Census region, 34 states, and the District of Columbia (DC). The CDC also examined trends in age-adjusted cocaine-involved and psychostimulant-involved death rates from 2003 to 2017 overall, as well as with and without co-involvement of opioids. Among all 2017 drug overdose deaths, 13,942 (19.8%) involved cocaine, and 10,333 (14.7%) involved psychostimulants. Death rates increased from 2016 to 2017 for both drug categories across demographic characteristics, urbanization levels, Census regions, and states. In 2017, opioids were involved in 72.7% and 50.4% of cocaine-involved and psychostimulant-involved overdoses, respectively, and the data suggest that increases in cocaine-involved overdose deaths from 2012 to 2017 were driven primarily by synthetic opioids.(3) There was opioid co-involvement in 72.7 percent of cocaine and 50.4 percent of stimulant-involved overdose deaths. This was largely driven by synthetic opioids such as fentanyl. However, stimulant-involved overdose without opioid co-involvement is also increasing.(2) |
ADDERALL, ADDERALL XR, ADZENYS XR-ODT, AMPHETAMINE SULFATE, APTENSIO XR, AZSTARYS, CONCERTA, COTEMPLA XR-ODT, DAYTRANA, DESOXYN, DEXEDRINE, DEXMETHYLPHENIDATE HCL, DEXMETHYLPHENIDATE HCL ER, DEXTROAMPHETAMINE SULFATE, DEXTROAMPHETAMINE SULFATE ER, DEXTROAMPHETAMINE-AMPHET ER, DEXTROAMPHETAMINE-AMPHETAMINE, DYANAVEL XR, EVEKEO, FOCALIN, FOCALIN XR, JORNAY PM, LISDEXAMFETAMINE DIMESYLATE, METADATE CD, METADATE ER, METHAMPHETAMINE HCL, METHYLIN, METHYLPHENIDATE, METHYLPHENIDATE ER, METHYLPHENIDATE ER (LA), METHYLPHENIDATE HCL, METHYLPHENIDATE HCL CD, METHYLPHENIDATE HCL ER (CD), MYDAYIS, PROCENTRA, QUILLICHEW ER, QUILLIVANT XR, RELEXXII, RITALIN, RITALIN LA, VYVANSE, XELSTRYM, ZENZEDI |
| METAXALONE | |
| AMRIX, CYCLOBENZAPRINE HCL, CYCLOBENZAPRINE HCL ER, CYCLOPAK, CYCLOTENS, FEXMID, NOPIOID-LMC KIT | |
| GEODON, ZIPRASIDONE HCL, ZIPRASIDONE MESYLATE |
The following contraindication information is available for HYDROCODONE-ACETAMINOPHEN (hydrocodone bitartrate/acetaminophen):
Drug contraindication overview.
No enhanced Contraindications information available for this drug.
No enhanced Contraindications information available for this drug.
There are 5 contraindications.
Absolute contraindication.
| Contraindication List |
|---|
| Acetaminophen overdose |
| Acute asthma attack |
| Acute hepatic failure |
| Acute hepatitis C |
| Paralytic ileus |
There are 30 severe contraindications.
Adequate patient monitoring is recommended for safer drug use.
| Severe List |
|---|
| Adrenocortical insufficiency |
| Alcohol intoxication |
| Benign prostatic hyperplasia |
| Coma |
| Cor pulmonale |
| Debilitation |
| Dehydration |
| Disease of liver |
| Drug abuse |
| Exacerbation of chronic obstructive pulmonary disease |
| Familial dysautonomia |
| Gastrointestinal obstruction |
| History of opioid overdose |
| Hypercapnia |
| Hypotension |
| Inflammatory bowel disease |
| Intracranial hypertension |
| Kidney disease with reduction in glomerular filtration rate (GFr) |
| Morbid obesity |
| Neoplasm of brain |
| Primary adrenocortical insufficiency |
| Protein-calorie malnutrition |
| Respiratory depression |
| Severe hepatic disease |
| Shock |
| Sleep apnea |
| Systemic mastocytosis |
| Toxic psychosis |
| Urethral stricture |
| Urinary retention |
There are 9 moderate contraindications.
Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.
| Moderate List |
|---|
| Acute abdominal pain |
| Acute pancreatitis |
| Alcohol withdrawal delirium |
| Biliary spasm |
| Constipation |
| Gallbladder disease |
| Gastrointestinal tract surgery |
| Seizure disorder |
| Untreated hypothyroidism |
The following adverse reaction information is available for HYDROCODONE-ACETAMINOPHEN (hydrocodone bitartrate/acetaminophen):
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 50 severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
| None. |
Abnormal hepatic function tests Angioedema Atelectasis Bradycardia Bronchospastic pulmonary disease CNS depression Dyspnea Laryngeal edema Laryngismus Respiratory depression Tachycardia |
| Rare/Very Rare |
|---|
|
Accidental fall Acute generalized exanthematous pustulosis Acute hepatic failure Adrenocortical insufficiency Agranulocytosis Allergic dermatitis Anaphylaxis Angioedema Biliary spasm Dehydration Depression Disorder of adrenal gland Drug dependence Drug-induced hepatitis Female hypogonadism Hallucinations Hearing loss Hypertension Hypokalemia Ileus Increased cerebrospinal fluid pressure Involuntary muscle movement Ischemic colitis Laryngeal edema Leukopenia Maculopapular rash Male hypogonadism Muscle rigidity Neutropenic disorder Pancreatitis Paralytic ileus Seizure disorder Skin rash Sleep apnea Stevens-johnson syndrome Thrombocytopenic disorder Tinnitus Toxic epidermal necrolysis Urticaria |
There are 63 less severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Constipation Dizziness Drowsy General weakness Hypotension Malaise Nausea Sedation Syncope |
Acute abdominal pain Acute cognitive impairment Anorexia Arthralgia Back pain Blurred vision Diplopia Dysphoric mood False sense of well-being Fatigue Flushing Gastroesophageal reflux disease Headache disorder Hyperhidrosis Lethargy Mood changes Muscle spasm Myalgia Nervousness Night sweats Opioid dependence Orthostatic hypotension Peripheral edema Symptoms of anxiety Tremor Upper respiratory infection Ureteral spasm Urinary tract infection Visual changes Vomiting Xerostomia |
| Rare/Very Rare |
|---|
|
Androgen deficiency Ataxia Dysgeusia Dysphagia Elevated serum amylase Erectile dysfunction Erythema Gastrointestinal irritation Infertility Insomnia Libido changes Medication overuse headache Migraine Musculoskeletal pain Neck pain Nightmares Opioid induced allodynia Opioid induced hyperalgesia Palpitations Paresthesia Pruritus of skin Skin rash Urticaria |
The following precautions are available for HYDROCODONE-ACETAMINOPHEN (hydrocodone bitartrate/acetaminophen):
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 |
Safe use of hydrocodone during pregnancy has not been established; therefore, the drug should not be administered to pregnant women unless the possible benefits outweigh the potential risks. Epidemiologic data regarding oral acetaminophen use in pregnant women have shown no increased risk of major congenital malformations in infants exposed in utero to the drug. In a large population-based prospective cohort study involving more than 26,000 women with live-born singleton infants who were exposed to oral acetaminophen during the first trimester of pregnancy, no increase in the risk of congenital malformations was observed in exposed children compared with a control group of unexposed children; the rate of congenital malformations (4.3%) was similar to the rate in the general population.
A population-based, case-control study from the National Birth Defects Prevention Study also found no increase in the risk of major birth defects in a group of 11,610 children who had been exposed to acetaminophen during the first trimester of pregnancy compared with a control group of 4500 children. Animal reproduction studies in pregnant rats given oral acetaminophen during organogenesis at dosages up to 0.85 times the maximum recommended human daily dosage (4 g daily, based on body surface area comparison) showed evidence of fetotoxicity (reduced fetal weight and length) and a dose-related increase in bone variations (reduced ossification and rudimentary rib changes); the offspring showed no evidence of external, visceral, or skeletal malformations.
When pregnant rats received oral acetaminophen throughout gestation at a dosage of 1.2 times the maximum recommended human daily dosage, areas of necrosis occurred in both the liver and kidney of pregnant rats and fetuses; these effects did not occur in animals given acetaminophen at dosages of 0.3 times the maximum recommended human dosage.
In a continuous breeding study in which pregnant mice were given acetaminophen at dosages approximately equivalent to 0.43, 0.87, or 1.7
times the maximum recommended human daily dosage (based on body surface area comparison), a dose-related reduction in body weight of the fourth and fifth litter offspring of the treated mating pair occurred during lactation and following weaning at all dosages studied. Animals receiving the highest dosage had a reduced number of litters per mating pair, male offspring with an increased percentage of abnormal sperm, and reduced birth weights in the next-generation pups. Acetaminophen is commonly used during all stages of pregnancy for its analgesic and antipyretic effects.
Although acetaminophen has been thought not to be associated with risk in offspring, some recent reports have questioned this assessment, especially with frequent maternal use or in cases involving genetic variability. FDA reviewed data on a possible association between acetaminophen use during pregnancy and risk of attention deficit hyperactivity disorder (ADHD) in children and announced in January 2015 that the data were inconclusive. Some experts state that as with all drug use during pregnancy, routine use of acetaminophen should be avoided.
The manufacturer states that there are no studies of IV acetaminophen in pregnant women and animal reproduction studies have not been conducted with this preparation. Therefore, the manufacturer states that IV acetaminophen should be used during pregnancy only when clearly needed. Because there are no adequate and well-controlled studies of IV acetaminophen during labor and delivery, the manufacturer states that IV acetaminophen should be used in this setting only after careful assessment of potential benefits and risks.
A population-based, case-control study from the National Birth Defects Prevention Study also found no increase in the risk of major birth defects in a group of 11,610 children who had been exposed to acetaminophen during the first trimester of pregnancy compared with a control group of 4500 children. Animal reproduction studies in pregnant rats given oral acetaminophen during organogenesis at dosages up to 0.85 times the maximum recommended human daily dosage (4 g daily, based on body surface area comparison) showed evidence of fetotoxicity (reduced fetal weight and length) and a dose-related increase in bone variations (reduced ossification and rudimentary rib changes); the offspring showed no evidence of external, visceral, or skeletal malformations.
When pregnant rats received oral acetaminophen throughout gestation at a dosage of 1.2 times the maximum recommended human daily dosage, areas of necrosis occurred in both the liver and kidney of pregnant rats and fetuses; these effects did not occur in animals given acetaminophen at dosages of 0.3 times the maximum recommended human dosage.
In a continuous breeding study in which pregnant mice were given acetaminophen at dosages approximately equivalent to 0.43, 0.87, or 1.7
times the maximum recommended human daily dosage (based on body surface area comparison), a dose-related reduction in body weight of the fourth and fifth litter offspring of the treated mating pair occurred during lactation and following weaning at all dosages studied. Animals receiving the highest dosage had a reduced number of litters per mating pair, male offspring with an increased percentage of abnormal sperm, and reduced birth weights in the next-generation pups. Acetaminophen is commonly used during all stages of pregnancy for its analgesic and antipyretic effects.
Although acetaminophen has been thought not to be associated with risk in offspring, some recent reports have questioned this assessment, especially with frequent maternal use or in cases involving genetic variability. FDA reviewed data on a possible association between acetaminophen use during pregnancy and risk of attention deficit hyperactivity disorder (ADHD) in children and announced in January 2015 that the data were inconclusive. Some experts state that as with all drug use during pregnancy, routine use of acetaminophen should be avoided.
The manufacturer states that there are no studies of IV acetaminophen in pregnant women and animal reproduction studies have not been conducted with this preparation. Therefore, the manufacturer states that IV acetaminophen should be used during pregnancy only when clearly needed. Because there are no adequate and well-controlled studies of IV acetaminophen during labor and delivery, the manufacturer states that IV acetaminophen should be used in this setting only after careful assessment of potential benefits and risks.
It is not known whether hydrocodone is distributed into human milk. A decision should be made to discontinue nursing or the drug, taking into account the importance of the drug to the woman. Acetaminophen is distributed into human milk in small quantities after oral administration.
Data from more than 15 nursing women suggest that approximately 1-2% of the maternal daily dosage would be ingested by a nursing infant. A case of maculopapular rash in a breast-fed infant has been reported; the rash resolved when the mother discontinued acetaminophen use and recurred when she resumed acetaminophen therapy. The American Academy of Pediatrics and other experts state that acetaminophen is an acceptable choice for use in nursing women. The manufacturer states that IV acetaminophen should be used with caution in nursing women.
Data from more than 15 nursing women suggest that approximately 1-2% of the maternal daily dosage would be ingested by a nursing infant. A case of maculopapular rash in a breast-fed infant has been reported; the rash resolved when the mother discontinued acetaminophen use and recurred when she resumed acetaminophen therapy. The American Academy of Pediatrics and other experts state that acetaminophen is an acceptable choice for use in nursing women. The manufacturer states that IV acetaminophen should be used with caution in nursing women.
No enhanced Geriatric Use information available for this drug.
The following prioritized warning is available for HYDROCODONE-ACETAMINOPHEN (hydrocodone bitartrate/acetaminophen):
WARNING: Hydrocodone/acetaminophen has a risk for abuse and addiction, which can lead to overdose and death. Hydrocodone/acetaminophen may also cause severe, possibly fatal, breathing problems. To lower your risk, your doctor should have you take the smallest dose of hydrocodone/acetaminophen that works, and take it for the shortest possible time.
See also How to Use section for more information about addiction. Ask your doctor or pharmacist if you should have naloxone available to treat opioid overdose. Teach your family or household members about the signs of an opioid overdose and how to treat it.
The risk for severe breathing problems is higher when you start this medication and after a dose increase, or if you take the wrong dose/strength. Taking this medication with alcohol or other drugs that can cause drowsiness or breathing problems may cause very serious side effects, including death. Also, other medications can affect the removal of hydrocodone/acetaminophen from your body, which may affect how it works.
Be sure you know how to take hydrocodone/acetaminophen and what other drugs you should avoid taking with it. See also Drug Interactions section. Get medical help right away if any of these very serious side effects occur: slow/shallow breathing, unusual lightheadedness, severe drowsiness/dizziness, difficulty waking up.
Keep this medicine in a safe place to prevent theft, misuse, or abuse. If someone accidentally swallows this drug, get medical help right away. One ingredient in this product is acetaminophen.
Taking too much acetaminophen may cause serious (possibly fatal) liver disease. Adults should not take more than 4000 milligrams (4 grams) of acetaminophen a day. People with liver problems and children should take less acetaminophen.
Ask your doctor or pharmacist how much acetaminophen is safe to take. Do not use with any other drug containing acetaminophen without asking your doctor or pharmacist first. Acetaminophen is in many nonprescription and prescription medications (such as pain/fever drugs or cough-and-cold products).
Check the labels on all your medicines to see if they contain acetaminophen, and ask your pharmacist if you are unsure. Get medical help right away if you take too much acetaminophen (overdose), even if you feel well. Overdose symptoms may include nausea, vomiting, loss of appetite, sweating, stomach/abdominal pain, extreme tiredness, yellowing eyes/skin, and dark urine.
Daily alcohol use, especially when combined with acetaminophen, may damage your liver. Avoid alcohol. Before using this medication, women of childbearing age should talk with their doctor(s) about the risks and benefits.
Tell your doctor if you are pregnant or if you plan to become pregnant. During pregnancy, this medication should be used only when clearly needed. It may slightly increase the risk of birth defects if used during the first two months of pregnancy.
Also, using it for a long time or in high doses near the expected delivery date may harm the unborn baby. To lessen the risk, take the smallest effective dose for the shortest possible time. Babies born to mothers who use this drug for a long time may develop severe (possibly fatal) withdrawal symptoms. Tell the doctor right away if you notice any symptoms in your newborn baby such as crying that doesn't stop, slow/shallow breathing, irritability, shaking, vomiting, diarrhea, poor feeding, or difficulty gaining weight.
WARNING: Hydrocodone/acetaminophen has a risk for abuse and addiction, which can lead to overdose and death. Hydrocodone/acetaminophen may also cause severe, possibly fatal, breathing problems. To lower your risk, your doctor should have you take the smallest dose of hydrocodone/acetaminophen that works, and take it for the shortest possible time.
See also How to Use section for more information about addiction. Ask your doctor or pharmacist if you should have naloxone available to treat opioid overdose. Teach your family or household members about the signs of an opioid overdose and how to treat it.
The risk for severe breathing problems is higher when you start this medication and after a dose increase, or if you take the wrong dose/strength. Taking this medication with alcohol or other drugs that can cause drowsiness or breathing problems may cause very serious side effects, including death. Also, other medications can affect the removal of hydrocodone/acetaminophen from your body, which may affect how it works.
Be sure you know how to take hydrocodone/acetaminophen and what other drugs you should avoid taking with it. See also Drug Interactions section. Get medical help right away if any of these very serious side effects occur: slow/shallow breathing, unusual lightheadedness, severe drowsiness/dizziness, difficulty waking up.
Keep this medicine in a safe place to prevent theft, misuse, or abuse. If someone accidentally swallows this drug, get medical help right away. One ingredient in this product is acetaminophen.
Taking too much acetaminophen may cause serious (possibly fatal) liver disease. Adults should not take more than 4000 milligrams (4 grams) of acetaminophen a day. People with liver problems and children should take less acetaminophen.
Ask your doctor or pharmacist how much acetaminophen is safe to take. Do not use with any other drug containing acetaminophen without asking your doctor or pharmacist first. Acetaminophen is in many nonprescription and prescription medications (such as pain/fever drugs or cough-and-cold products).
Check the labels on all your medicines to see if they contain acetaminophen, and ask your pharmacist if you are unsure. Get medical help right away if you take too much acetaminophen (overdose), even if you feel well. Overdose symptoms may include nausea, vomiting, loss of appetite, sweating, stomach/abdominal pain, extreme tiredness, yellowing eyes/skin, and dark urine.
Daily alcohol use, especially when combined with acetaminophen, may damage your liver. Avoid alcohol. Before using this medication, women of childbearing age should talk with their doctor(s) about the risks and benefits.
Tell your doctor if you are pregnant or if you plan to become pregnant. During pregnancy, this medication should be used only when clearly needed. It may slightly increase the risk of birth defects if used during the first two months of pregnancy.
Also, using it for a long time or in high doses near the expected delivery date may harm the unborn baby. To lessen the risk, take the smallest effective dose for the shortest possible time. Babies born to mothers who use this drug for a long time may develop severe (possibly fatal) withdrawal symptoms. Tell the doctor right away if you notice any symptoms in your newborn baby such as crying that doesn't stop, slow/shallow breathing, irritability, shaking, vomiting, diarrhea, poor feeding, or difficulty gaining weight.
The following icd codes are available for HYDROCODONE-ACETAMINOPHEN (hydrocodone bitartrate/acetaminophen)'s list of indications:
| Pain | |
| G43 | Migraine |
| G43.0 | Migraine without aura |
| G43.00 | Migraine without aura, not intractable |
| G43.001 | Migraine without aura, not intractable, with status migrainosus |
| G43.009 | Migraine without aura, not intractable, without status migrainosus |
| G43.01 | Migraine without aura, intractable |
| G43.011 | Migraine without aura, intractable, with status migrainosus |
| G43.019 | Migraine without aura, intractable, without status migrainosus |
| G43.1 | Migraine with aura |
| G43.10 | Migraine with aura, not intractable |
| G43.101 | Migraine with aura, not intractable, with status migrainosus |
| G43.109 | Migraine with aura, not intractable, without status migrainosus |
| G43.11 | Migraine with aura, intractable |
| G43.111 | Migraine with aura, intractable, with status migrainosus |
| G43.119 | Migraine with aura, intractable, without status migrainosus |
| G43.4 | Hemiplegic migraine |
| G43.40 | Hemiplegic migraine, not intractable |
| G43.401 | Hemiplegic migraine, not intractable, with status migrainosus |
| G43.409 | Hemiplegic migraine, not intractable, without status migrainosus |
| G43.41 | Hemiplegic migraine, intractable |
| G43.411 | Hemiplegic migraine, intractable, with status migrainosus |
| 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 |
| G43.501 | Persistent migraine aura without cerebral infarction, not intractable, with status migrainosus |
| G43.509 | Persistent migraine aura without cerebral infarction, not intractable, without status migrainosus |
| G43.51 | Persistent migraine aura without cerebral infarction, intractable |
| G43.511 | Persistent migraine aura without cerebral infarction, intractable, with status migrainosus |
| 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 |
| G43.601 | Persistent migraine aura with cerebral infarction, not intractable, with status migrainosus |
| G43.609 | Persistent migraine aura with cerebral infarction, not intractable, without status migrainosus |
| G43.61 | Persistent migraine aura with cerebral infarction, intractable |
| G43.611 | Persistent migraine aura with cerebral infarction, intractable, with status migrainosus |
| 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 |
| G43.701 | Chronic migraine without aura, not intractable, with status migrainosus |
| G43.709 | Chronic migraine without aura, not intractable, without status migrainosus |
| G43.71 | Chronic migraine without aura, intractable |
| G43.711 | Chronic migraine without aura, intractable, with status migrainosus |
| G43.719 | Chronic migraine without aura, intractable, without status migrainosus |
| G43.8 | Other migraine |
| G43.80 | Other migraine, not intractable |
| G43.801 | Other migraine, not intractable, with status migrainosus |
| G43.809 | Other migraine, not intractable, without status migrainosus |
| G43.81 | Other migraine, intractable |
| G43.811 | Other migraine, intractable, with status migrainosus |
| G43.819 | Other migraine, intractable, without status migrainosus |
| G43.82 | Menstrual migraine, not intractable |
| G43.821 | Menstrual migraine, not intractable, with status migrainosus |
| G43.829 | Menstrual migraine, not intractable, without status migrainosus |
| G43.83 | Menstrual migraine, intractable |
| G43.831 | Menstrual migraine, intractable, with status migrainosus |
| G43.839 | Menstrual migraine, intractable, without status migrainosus |
| G43.9 | Migraine, unspecified |
| G43.90 | Migraine, unspecified, not intractable |
| G43.901 | Migraine, unspecified, not intractable, with status migrainosus |
| G43.909 | Migraine, unspecified, not intractable, without status migrainosus |
| G43.91 | Migraine, unspecified, intractable |
| G43.911 | Migraine, unspecified, intractable, with status migrainosus |
| 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.E01 | Chronic migraine with aura, not intractable, with status migrainosus |
| G43.E09 | Chronic migraine with aura, not intractable, without status migrainosus |
| G43.E1 | Chronic migraine with aura, intractable |
| G43.E11 | Chronic migraine with aura, intractable, with status migrainosus |
| G43.E19 | Chronic migraine with aura, intractable, without status migrainosus |
| G44 | Other headache syndromes |
| 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 |
| G44.1 | 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 |
| G44.86 | Cervicogenic headache |
| G44.89 | Other headache syndrome |
| G50.1 | Atypical facial pain |
| G89 | Pain, not elsewhere classified |
| G89.0 | Central pain syndrome |
| G89.1 | Acute pain, not elsewhere classified |
| G89.11 | Acute pain due to trauma |
| G89.12 | Acute post-thoracotomy pain |
| G89.18 | Other acute postprocedural pain |
| G89.2 | Chronic pain, not elsewhere classified |
| G89.21 | Chronic pain due to trauma |
| G89.22 | Chronic post-thoracotomy pain |
| G89.28 | Other chronic postprocedural pain |
| G89.29 | Other chronic pain |
| G89.3 | Neoplasm related pain (acute) (chronic) |
| G89.4 | Chronic pain syndrome |
| G90.5 | Complex regional pain syndrome I (CRPS i) |
| G90.50 | Complex regional pain syndrome i, unspecified |
| G90.51 | Complex regional pain syndrome I of upper limb |
| G90.511 | Complex regional pain syndrome I of right upper limb |
| G90.512 | Complex regional pain syndrome I of left upper limb |
| G90.513 | Complex regional pain syndrome I of upper limb, bilateral |
| G90.519 | Complex regional pain syndrome I of unspecified upper limb |
| G90.52 | Complex regional pain syndrome I of lower limb |
| G90.521 | Complex regional pain syndrome I of right lower limb |
| G90.522 | Complex regional pain syndrome I of left lower limb |
| G90.523 | Complex regional pain syndrome I of lower limb, bilateral |
| G90.529 | Complex regional pain syndrome I of unspecified lower limb |
| G90.59 | Complex regional pain syndrome I of other specified site |
| H57.1 | Ocular pain |
| H57.10 | Ocular pain, unspecified eye |
| H57.11 | Ocular pain, right eye |
| H57.12 | Ocular pain, left eye |
| H57.13 | Ocular pain, bilateral |
| H92 | Otalgia and effusion of ear |
| H92.0 | Otalgia |
| H92.01 | Otalgia, right ear |
| H92.02 | Otalgia, left ear |
| H92.03 | Otalgia, bilateral |
| H92.09 | Otalgia, unspecified ear |
| K14.6 | Glossodynia |
| M25.5 | Pain in joint |
| M25.50 | Pain in unspecified joint |
| M25.51 | Pain in shoulder |
| M25.511 | Pain in right shoulder |
| M25.512 | Pain in left shoulder |
| M25.519 | Pain in unspecified shoulder |
| M25.52 | Pain in elbow |
| M25.521 | Pain in right elbow |
| M25.522 | Pain in left elbow |
| M25.529 | Pain in unspecified elbow |
| M25.53 | Pain in wrist |
| M25.531 | Pain in right wrist |
| M25.532 | Pain in left wrist |
| M25.539 | Pain in unspecified wrist |
| M25.54 | Pain in joints of hand |
| M25.541 | Pain in joints of right hand |
| M25.542 | Pain in joints of left hand |
| M25.549 | Pain in joints of unspecified hand |
| M25.55 | Pain in hip |
| M25.551 | Pain in right hip |
| M25.552 | Pain in left hip |
| M25.559 | Pain in unspecified hip |
| M25.56 | Pain in knee |
| M25.561 | Pain in right knee |
| M25.562 | Pain in left knee |
| M25.569 | Pain in unspecified knee |
| M25.57 | Pain in ankle and joints of foot |
| M25.571 | Pain in right ankle and joints of right foot |
| M25.572 | Pain in left ankle and joints of left foot |
| M25.579 | Pain in unspecified ankle and joints of unspecified foot |
| M25.59 | Pain in other specified joint |
| M26.62 | Arthralgia of temporomandibular joint |
| M26.621 | Arthralgia of right temporomandibular joint |
| M26.622 | Arthralgia of left temporomandibular joint |
| M26.623 | Arthralgia of bilateral temporomandibular joint |
| M26.629 | Arthralgia of temporomandibular joint, unspecified side |
| M54 | Dorsalgia |
| M54.2 | Cervicalgia |
| M54.4 | Lumbago with sciatica |
| M54.40 | Lumbago with sciatica, unspecified side |
| M54.41 | Lumbago with sciatica, right side |
| M54.42 | Lumbago with sciatica, left side |
| M54.5 | Low back pain |
| M54.50 | Low back pain, unspecified |
| M54.51 | Vertebrogenic low back pain |
| M54.59 | Other low back pain |
| M54.6 | Pain in thoracic spine |
| M54.8 | Other dorsalgia |
| M54.89 | Other dorsalgia |
| M54.9 | Dorsalgia, unspecified |
| M77.4 | Metatarsalgia |
| M77.40 | Metatarsalgia, unspecified foot |
| M77.41 | Metatarsalgia, right foot |
| M77.42 | Metatarsalgia, left foot |
| M79.1 | Myalgia |
| M79.10 | Myalgia, unspecified site |
| M79.11 | Myalgia of mastication muscle |
| M79.12 | Myalgia of auxiliary muscles, head and neck |
| M79.18 | Myalgia, other site |
| M79.6 | Pain in limb, hand, foot, fingers and toes |
| M79.60 | Pain in limb, unspecified |
| M79.601 | Pain in right arm |
| M79.602 | Pain in left arm |
| M79.603 | Pain in arm, unspecified |
| M79.604 | Pain in right leg |
| M79.605 | Pain in left leg |
| M79.606 | Pain in leg, unspecified |
| M79.609 | Pain in unspecified limb |
| M79.62 | Pain in upper arm |
| M79.621 | Pain in right upper arm |
| M79.622 | Pain in left upper arm |
| M79.629 | Pain in unspecified upper arm |
| M79.63 | Pain in forearm |
| M79.631 | Pain in right forearm |
| M79.632 | Pain in left forearm |
| M79.639 | Pain in unspecified forearm |
| M79.64 | Pain in hand and fingers |
| M79.641 | Pain in right hand |
| M79.642 | Pain in left hand |
| M79.643 | Pain in unspecified hand |
| M79.644 | Pain in right finger(s) |
| M79.645 | Pain in left finger(s) |
| M79.646 | Pain in unspecified finger(s) |
| M79.65 | Pain in thigh |
| M79.651 | Pain in right thigh |
| M79.652 | Pain in left thigh |
| M79.659 | Pain in unspecified thigh |
| M79.66 | Pain in lower leg |
| M79.661 | Pain in right lower leg |
| M79.662 | Pain in left lower leg |
| M79.669 | Pain in unspecified lower leg |
| M79.67 | Pain in foot and toes |
| M79.671 | Pain in right foot |
| M79.672 | Pain in left foot |
| M79.673 | Pain in unspecified foot |
| M79.674 | Pain in right toe(s) |
| M79.675 | Pain in left toe(s) |
| M79.676 | Pain in unspecified toe(s) |
| N23 | Unspecified renal colic |
| N64.4 | Mastodynia |
| N94 | Pain and other conditions associated with female genital organs and menstrual cycle |
| N94.0 | Mittelschmerz |
| N94.3 | Premenstrual tension syndrome |
| N94.4 | Primary dysmenorrhea |
| N94.5 | Secondary dysmenorrhea |
| N94.6 | Dysmenorrhea, unspecified |
| R07 | Pain in throat and chest |
| R07.0 | Pain in throat |
| R07.1 | Chest pain on breathing |
| R07.2 | Precordial pain |
| R07.81 | Pleurodynia |
| R07.82 | Intercostal pain |
| R07.89 | Other chest pain |
| R07.9 | Chest pain, unspecified |
| R10 | Abdominal and pelvic pain |
| R10.0 | Acute abdomen |
| R10.1 | Pain localized to upper abdomen |
| R10.10 | Upper abdominal pain, unspecified |
| R10.11 | Right upper quadrant pain |
| R10.12 | Left upper quadrant pain |
| R10.2 | Pelvic and perineal pain |
| R10.3 | Pain localized to other parts of lower abdomen |
| R10.30 | Lower abdominal pain, unspecified |
| R10.31 | Right lower quadrant pain |
| R10.32 | Left lower quadrant pain |
| R10.33 | Periumbilical pain |
| R10.8 | Other abdominal pain |
| R10.83 | Colic |
| R10.84 | Generalized abdominal pain |
| R10.9 | Unspecified abdominal pain |
| R51 | Headache |
| R51.0 | Headache with orthostatic component, not elsewhere classified |
| R51.9 | Headache, unspecified |
| R52 | Pain, unspecified |
| R68.84 | Jaw pain |
| T82.84 | Pain due to cardiac and vascular prosthetic devices, implants and grafts |
| T82.847 | Pain due to cardiac prosthetic devices, implants and grafts |
| T82.847A | Pain due to cardiac prosthetic devices, implants and grafts, initial encounter |
| T82.847D | Pain due to cardiac prosthetic devices, implants and grafts, subsequent encounter |
| T82.848 | Pain due to vascular prosthetic devices, implants and grafts |
| T82.848A | Pain due to vascular prosthetic devices, implants and grafts, initial encounter |
| T82.848D | Pain due to vascular prosthetic devices, implants and grafts, subsequent encounter |
| T83.84 | Pain due to genitourinary prosthetic devices, implants and grafts |
| T83.84xA | Pain due to genitourinary prosthetic devices, implants and grafts, initial encounter |
| T83.84xD | Pain due to genitourinary prosthetic devices, implants and grafts, subsequent encounter |
| T84.84 | Pain due to internal orthopedic prosthetic devices, implants and grafts |
| T84.84xA | Pain due to internal orthopedic prosthetic devices, implants and grafts, initial encounter |
| T84.84xD | Pain due to internal orthopedic prosthetic devices, implants and grafts, subsequent encounter |
| T85.84 | Pain due to internal prosthetic devices, implants and grafts, not elsewhere classified |
| T85.840 | Pain due to nervous system prosthetic devices, implants and grafts |
| T85.840A | Pain due to nervous system prosthetic devices, implants and grafts, initial encounter |
| T85.840D | Pain due to nervous system prosthetic devices, implants and grafts, subsequent encounter |
| T85.848 | Pain due to other internal prosthetic devices, implants and grafts |
| T85.848A | Pain due to other internal prosthetic devices, implants and grafts, initial encounter |
| T85.848D | Pain due to other internal prosthetic devices, implants and grafts, subsequent encounter |
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