codeine/acetaminophen/butalbital/caffeine (Rx)

Brand and Other Names:Fioricet with Codeine
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

codeine/acetaminophen/butalbital/caffeine

capsule: Schedule III

  • 30mg/325mg/50mg/40mg
  • 30mg/300mg/50mg/40mg

Tension Headache

1-2 tab/cap PO q4hr; not to exceed 6 tab/cap per day

To discontinue therapy, decrease dose by 25% to 50% every 2-4 days; monitor for symptoms/signs of withdrawal; if withdrawal symptoms occur, raise dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both; do not abruptly discontinue therapy in a physically dependent patient

Dosing Considerations

Use lowest effective dosage for shortest duration consistent with individual patient treatment goals

Initiate dosing regimen for each patient individually, taking into account patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse

Evidence supporting efficacy and safety of drug in treatment of multiple recurrent headaches is unavailable

Limitation of Use

  • Because of the risks of addiction, abuse, and misuse with opioids and butalbital, even at recommended doses, reserve therapy for use in patients for whom alternative treatment options [e.g., non-opioid, non-barbiturate analgesics] have not been tolerated, or are not expected to be tolerated, have not provided adequate analgesia, or are not expected to provide adequate analgesia

Access to naloxone for opioid overdose

  • Assess need for naloxone upon initiating and renewing treatment
  • Consider prescribing naloxone
    • Based on patient’s risk factors for overdose (eg, concomitant use of CNS depressants, a history of opioid use disorder, prior opioid overdose); presence of risk factors should not prevent proper pain management
    • Household members (including children) or other close contacts at risk for accidental ingestion or overdose
  • Consult patients and caregivers on the following:
    • Availability of naloxone for emergency treatment of opioid overdose
    • Ways differ on how to obtain naloxone as permitted by individual state dispensing and prescribing requirements or guidelines (eg, by prescription, directly from a pharmacist, as part of a community-based program)

Dosage Forms & Strengths

codeine/acetaminophen/butalbital/caffeine

capsule: Schedule III

  • 30mg/325mg/50mg/40mg
  • 30mg/300/mg/50mg/40mg

The FDA has recommended that codeine not be used in children <12 years and all pediatric patients undergoing tonsillectomy and/or adenoidectomy

Tension Headache (Off-label)

<12 years: Safety and efficacy not established

≥12 years: 1-2 tab/cap PO q4hr; not to exceed 6 tab/cap per day (not to exceed acetaminophen 4 g/day); to discontinue therapy, decrease dose by 25% to 50% every 2-4 days; monitor for symptoms/signs of withdrawal; if withdrawal symptoms occur, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both; do not abruptly discontinue therapy in a physically dependent patient

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Interactions

Interaction Checker

and codeine/acetaminophen/butalbital/caffeine

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            Contraindicated (3)

            • alvimopan

              alvimopan, codeine. receptor binding competition. Contraindicated. Alvimopan is contraindicated in opioid tolerant patients (ie, those who have taken therapeutic doses of opioids for >7 consecutive days immediately prior to taking alvimopan). Patients recently exposed to opioids are expected to be more sensitive to the effects of alvimopan and therefore may experience abdominal pain, nausea and vomiting, and diarrhea. No significant interaction is expected with concurrent use of opioid analgesics and alvimopan in patients who received opioid analgesics for 7 or fewer consecutive days prior to alvimopan.

            • doravirine

              butalbital will decrease the level or effect of doravirine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Coadministration of doravirine with a strong CYP3A inducer may decrease doravirine plasma concentrations and/or effects. Potential for loss of virologic response and possible resistance to doravirine.

            • isocarboxazid

              isocarboxazid increases effects of caffeine by pharmacodynamic synergism. Contraindicated. Risk of acute hypertensive episode.

            Serious - Use Alternative (82)

            • abametapir

              abametapir will increase the level or effect of caffeine by affecting hepatic enzyme CYP1A2 metabolism. Avoid or Use Alternate Drug. For 2 weeks after abametapir application, avoid taking drugs that are CYP1A2 substrates. If not feasible, avoid use of abametapir.

            • abemaciclib

              butalbital will decrease the level or effect of abemaciclib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration of abemaciclib with strong CYP3A4 inducers reduces plasma concentration of abemaciclib and its metabolites.

            • acalabrutinib

              butalbital will decrease the level or effect of acalabrutinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of acalabrutinib with strong CYP3A inducers. If a strong CYP3A inducer must be used, increase acalabrutinib dose to 200 mg twice daily.

            • alosetron

              butalbital will decrease the level or effect of alosetron by affecting hepatic enzyme CYP1A2 metabolism. Avoid or Use Alternate Drug.

            • alpelisib

              butalbital will decrease the level or effect of alpelisib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of alpelisib (CYP3A4 substrate) with strong CYP3A4 inducers.

            • antithrombin alfa

              butalbital decreases effects of antithrombin alfa by increasing metabolism. Avoid or Use Alternate Drug.

            • antithrombin III

              butalbital decreases effects of antithrombin III by increasing metabolism. Avoid or Use Alternate Drug.

            • argatroban

              butalbital decreases effects of argatroban by increasing metabolism. Avoid or Use Alternate Drug.

            • avapritinib

              butalbital will decrease the level or effect of avapritinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • bemiparin

              butalbital decreases effects of bemiparin by increasing metabolism. Avoid or Use Alternate Drug.

            • benzhydrocodone/acetaminophen

              benzhydrocodone/acetaminophen, butalbital. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.

              benzhydrocodone/acetaminophen, codeine. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.

            • bivalirudin

              butalbital decreases effects of bivalirudin by increasing metabolism. Avoid or Use Alternate Drug.

            • bremelanotide

              bremelanotide will decrease the level or effect of codeine by Other (see comment). Avoid or Use Alternate Drug. Bremelanotide may slow gastric emptying and potentially reduces the rate and extent of absorption of concomitantly administered oral medications. Avoid use when taking any oral drug that is dependent on threshold concentrations for efficacy. Interactions listed are representative examples and do not include all possible clinical examples.

            • brigatinib

              butalbital will decrease the level or effect of brigatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration with strong CYP3A4 inducers may decrease brigatinib efficacy.

            • buprenorphine

              buprenorphine, codeine. Other (see comment). Avoid or Use Alternate Drug. Comment: Mixed opiate agonist/antagonists usually produce additive sedation with narcotics; however, in narcotic addicted pts., the antagonist activity may provoke withdrawal Sx.

            • buprenorphine buccal

              buprenorphine buccal, codeine. Other (see comment). Avoid or Use Alternate Drug. Comment: Mixed opiate agonist/antagonists usually produce additive sedation with narcotics; however, in narcotic addicted pts., the antagonist activity may provoke withdrawal Sx.

            • bupropion

              caffeine increases toxicity of bupropion by unspecified interaction mechanism. Avoid or Use Alternate Drug. May lower seizure threshold; keep bupropion dose as low as possible.

            • butorphanol

              butorphanol, codeine. Other (see comment). Avoid or Use Alternate Drug. Comment: Mixed opiate agonist/antagonists usually produce additive sedation with narcotics; however, in narcotic addicted pts., the antagonist activity may provoke withdrawal Sx.

            • calcium/magnesium/potassium/sodium oxybates

              codeine, calcium/magnesium/potassium/sodium oxybates. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.

              butalbital, calcium/magnesium/potassium/sodium oxybates. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.

            • clonidine

              clonidine, codeine. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Coadministration enhances CNS depressant effects.

            • copanlisib

              butalbital will decrease the level or effect of copanlisib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of copanlisib with strong CYP3A4 inducers.

            • dacomitinib

              dacomitinib will increase the level or effect of codeine by affecting hepatic enzyme CYP2D6 metabolism. Avoid or Use Alternate Drug. Avoid use with CYP2D6 substrates where minimal increases in concentration of the CYP2D6 substrate may lead to serious or life-threatening toxicities.

            • dalteparin

              butalbital decreases effects of dalteparin by increasing metabolism. Avoid or Use Alternate Drug.

            • deflazacort

              butalbital will decrease the level or effect of deflazacort by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of deflazacort with moderate or strong CYP3A4 inducers.

            • diazepam intranasal

              diazepam intranasal, codeine. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.

            • dihydroergotamine

              butalbital will decrease the level or effect of dihydroergotamine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • dihydroergotamine intranasal

              butalbital will decrease the level or effect of dihydroergotamine intranasal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • dipyridamole

              caffeine decreases effects of dipyridamole by pharmacodynamic antagonism. Contraindicated.

              butalbital decreases levels of dipyridamole by increasing metabolism. Contraindicated.

            • dronedarone

              butalbital will decrease the level or effect of dronedarone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • givosiran

              givosiran will increase the level or effect of caffeine by affecting hepatic enzyme CYP1A2 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of sensitive CYP1A2 substrates with givosiran. If unavoidable, decrease the CYP1A2 substrate dosage in accordance with approved product labeling.

            • duloxetine

              butalbital will decrease the level or effect of duloxetine by affecting hepatic enzyme CYP1A2 metabolism. Avoid or Use Alternate Drug.

            • duvelisib

              butalbital will increase the level or effect of duvelisib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration with a strong CYP3A inducer decreases duvelisib area under the curve (AUC), which may reduce duvelisib efficacy.

            • eluxadoline

              codeine, eluxadoline. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Avoid coadministration with other drugs that cause constipation. Increases risk for constipation related serious adverse reactions. .

            • enoxaparin

              butalbital decreases effects of enoxaparin by increasing metabolism. Avoid or Use Alternate Drug.

            • erdafitinib

              butalbital will decrease the level or effect of erdafitinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • ergotamine

              butalbital will decrease the level or effect of ergotamine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • erythromycin base

              butalbital will decrease the level or effect of erythromycin base by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • erythromycin ethylsuccinate

              butalbital will decrease the level or effect of erythromycin ethylsuccinate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • erythromycin lactobionate

              butalbital will decrease the level or effect of erythromycin lactobionate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • erythromycin stearate

              butalbital will decrease the level or effect of erythromycin stearate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • everolimus

              butalbital will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • fedratinib

              butalbital will decrease the level or effect of fedratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Effect of coadministering a strong CYP3A4 inducer with fedratinib has not been studied.

            • fentanyl

              fentanyl, butalbital. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Coadministration with other CNS depressants, such as skeletal muscle relaxants, may cause respiratory depression, hypotension, profound sedation, coma, and/or death. Consider dose reduction of either or both agents to avoid serious adverse effects. Monitor for hypotension, respiratory depression, and profound sedation.

              fentanyl, codeine. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Coadministration with other CNS depressants, such as skeletal muscle relaxants, may cause respiratory depression, hypotension, profound sedation, coma, and/or death. Consider dose reduction of either or both agents to avoid serious adverse effects. Monitor for hypotension, respiratory depression, and profound sedation.

            • fentanyl intranasal

              fentanyl intranasal, codeine. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Coadministration with other CNS depressants, such as skeletal muscle relaxants, may cause respiratory depression, hypotension, profound sedation, coma, and/or death. Consider dose reduction of either or both agents to avoid serious adverse effects. Monitor for hypotension, respiratory depression, and profound sedation.

              fentanyl intranasal, butalbital. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Coadministration with other CNS depressants, such as skeletal muscle relaxants, may cause respiratory depression, hypotension, profound sedation, coma, and/or death. Consider dose reduction of either or both agents to avoid serious adverse effects. Monitor for hypotension, respiratory depression, and profound sedation.

            • fentanyl transdermal

              fentanyl transdermal, butalbital. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Coadministration with other CNS depressants, such as skeletal muscle relaxants, may cause respiratory depression, hypotension, profound sedation, coma, and/or death. Consider dose reduction of either or both agents to avoid serious adverse effects. Monitor for hypotension, respiratory depression, and profound sedation.

              fentanyl transdermal, codeine. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Coadministration with other CNS depressants, such as skeletal muscle relaxants, may cause respiratory depression, hypotension, profound sedation, coma, and/or death. Consider dose reduction of either or both agents to avoid serious adverse effects. Monitor for hypotension, respiratory depression, and profound sedation.

            • fentanyl transmucosal

              fentanyl transmucosal, codeine. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Coadministration with other CNS depressants, such as skeletal muscle relaxants, may cause respiratory depression, hypotension, profound sedation, coma, and/or death. Consider dose reduction of either or both agents to avoid serious adverse effects. Monitor for hypotension, respiratory depression, and profound sedation.

              fentanyl transmucosal, butalbital. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Coadministration with other CNS depressants, such as skeletal muscle relaxants, may cause respiratory depression, hypotension, profound sedation, coma, and/or death. Consider dose reduction of either or both agents to avoid serious adverse effects. Monitor for hypotension, respiratory depression, and profound sedation.

            • fexinidazole

              butalbital will increase the level or effect of fexinidazole by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. CYP450 inducers may significantly increase plasma concentrations of fexinidazole?s active metabolites: fexinidazole sulfoxide (M1) and fexinidazole sulfone (M2). M2 plasma concentrations associated with increased QT prolongation risks.

            • givosiran

              givosiran will increase the level or effect of codeine by affecting hepatic enzyme CYP2D6 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of sensitive CYP2D6 substrates with givosiran. If unavoidable, decrease the CYP2D6 substrate dosage in accordance with approved product labeling.

            • finerenone

              butalbital will decrease the level or effect of finerenone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • fondaparinux

              butalbital decreases effects of fondaparinux by increasing metabolism. Avoid or Use Alternate Drug.

            • fostamatinib

              butalbital will decrease the level or effect of fostamatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • glasdegib

              butalbital will decrease the level or effect of glasdegib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of glasdegib with strong CYP3A inducers.

            • heparin

              butalbital decreases effects of heparin by increasing metabolism. Avoid or Use Alternate Drug.

            • hydrocodone

              hydrocodone, butalbital. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.

              hydrocodone, codeine. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.

            • infigratinib

              butalbital will decrease the level or effect of infigratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • iobenguane I 131

              caffeine will decrease the level or effect of iobenguane I 131 by Other (see comment). Avoid or Use Alternate Drug. Based on the mechanism of action of iobenguane, drugs that reduce catecholamine uptake or that deplete catecholamine stores may interfere with iobenguane uptake into cells, and thus, reduce iobenguane efficacy. Discontinue interfering drugs for at least 5 half-lives before administration of either the dosimetry or an iobenguane dose. Do not administer these drugs until at least 7 days after each iobenguane dose.

            • isocarboxazid

              isocarboxazid increases toxicity of codeine by unknown mechanism. Avoid or Use Alternate Drug. Risk of hypotension, hyperpyrexia, somnolence, or death; separate by 14 d.

            • isocarboxazid

              isocarboxazid, butalbital. Other (see comment). Contraindicated. Comment: CNS depressants such as barbiturates should not be used in combination with isocarboxazid.

            • istradefylline

              butalbital will decrease the level or effect of istradefylline by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of istradefylline with strong CYP3A4 inducers.

            • ivosidenib

              butalbital will decrease the level or effect of ivosidenib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration of ivosidenib with strong CYP3A4 inducers decreased ivosidenib plasma concentrations.

            • larotrectinib

              butalbital will decrease the level or effect of larotrectinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration of larotrectinib with strong CYP3A4 inducers is unavoidable, double larotrectinib dose. Resume prior larotrectinib dose once CYP3A4 inducer discontinued for 3-5 half-lives.

            • lefamulin

              butalbital will decrease the level or effect of lefamulin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of lefamulin with strong or moderate CYP3A inducers unless the benefit outweighs risks. Monitor for reduced efficacy.

            • lemborexant

              butalbital will decrease the level or effect of lemborexant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              lemborexant, butalbital. Either increases effects of the other by sedation. Avoid or Use Alternate Drug. Use of lemborexant with other drugs to treat insomnia is not recommended.

            • linezolid

              linezolid increases toxicity of codeine by unknown mechanism. Avoid or Use Alternate Drug. Risk of hypotension, hyperpyrexia, somnolence, or death; separate by 14 d.

            • lonafarnib

              acetaminophen will increase the level or effect of lonafarnib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration of lonafarnib (a sensitive CYP3A substrate) with weak CYP3A inhibitors is unavoidable, reduce to, or continue lonafarnib at starting dose. Closely monitor for arrhythmias and events (eg, syncope, heart palpitations) since lonafarnib effect on QT interval is unknown.

            • lovastatin

              butalbital will decrease the level or effect of lovastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • lurbinectedin

              butalbital will decrease the level or effect of lurbinectedin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • macimorelin

              butalbital will decrease the level or effect of macimorelin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Potential for false positive test results if macimorelin and strong CYP3A4 inducers are coadministered. Discontinue strong CYP3A4 inducer, allowing for sufficient washout time, before testing.

            • mestranol

              butalbital decreases levels of mestranol by increasing metabolism. Avoid or Use Alternate Drug. May result in contraceptive failure.

            • methoxyflurane

              butalbital increases toxicity of methoxyflurane by increasing metabolism. Contraindicated. Increased metabolism of methoxyflurane to nephrotoxic compounds.

            • methylene blue

              methylene blue and codeine both increase serotonin levels. Avoid or Use Alternate Drug. If drug combination must be administered, monitor for evidence of serotonergic or opioid-related toxicities

              methylene blue and butalbital both increase serotonin levels. Avoid or Use Alternate Drug. If drug combination must be administered, monitor for evidence of serotonergic or opioid-related toxicities

            • metoclopramide intranasal

              codeine, metoclopramide intranasal. Either increases effects of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Avoid use of metoclopramide intranasal or interacting drug, depending on importance of drug to patient.

              butalbital, metoclopramide intranasal. Either increases effects of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Avoid use of metoclopramide intranasal or interacting drug, depending on importance of drug to patient.

            • midostaurin

              butalbital will decrease the level or effect of midostaurin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Strong CYP3A4 inducers may decrease midostaurin concentrations resulting in reduced efficacy.

            • nalbuphine

              nalbuphine, codeine. Other (see comment). Avoid or Use Alternate Drug. Comment: Mixed opiate agonist/antagonists usually produce additive sedation with narcotics; however, in narcotic addicted pts., the antagonist activity may provoke withdrawal Sx.

            • mobocertinib

              butalbital will decrease the level or effect of mobocertinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • naldemedine

              butalbital will decrease the level or effect of naldemedine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration with strong CYP3A4 inducers.

            • neratinib

              butalbital will decrease the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inducers.

            • ozanimod

              ozanimod and codeine both increase sympathetic (adrenergic) effects, including increased blood pressure and heart rate. Avoid or Use Alternate Drug. Because the active metabolite of ozanimod inhibits MAO-B in vitro, there is a potential for serious adverse reactions, including hypertensive crisis. Therefore, coadministration of ozanimod with drugs that can increase norepinephrine or serotonin is not recommended. Monitor for hypertension with concomitant use.

              ozanimod increases toxicity of caffeine by sympathetic (adrenergic) effects, including increased blood pressure and heart rate. Avoid or Use Alternate Drug. Because the active metabolite of ozanimod inhibits MAO-B in vitro, there is a potential for serious adverse reactions, including hypertensive crisis. Therefore, coadministration of ozanimod with drugs that can increase norepinephrine or serotonin is not recommended. Monitor for hypertension with concomitant use.

            • pemigatinib

              butalbital will decrease the level or effect of pemigatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • pexidartinib

              acetaminophen and pexidartinib both increase Other (see comment). Avoid or Use Alternate Drug. Pexidartinib can cause hepatotoxicity. Avoid coadministration of pexidartinib with other products know to cause hepatoxicity.

            • pretomanid

              acetaminophen, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.

            • regadenoson

              caffeine decreases effects of regadenoson by pharmacodynamic antagonism. Avoid or Use Alternate Drug. Avoid methylxanthines for 12 hours before regadenoson administration.

            Monitor Closely (445)

            • abiraterone

              abiraterone increases levels of codeine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Avoid coadministration of abiraterone with substrates of CYP2D6. If alternative therapy cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate.

            • acebutolol

              butalbital decreases levels of acebutolol by increasing metabolism. Use Caution/Monitor. Consider a higher beta-blocker dose during coadministration of butalbital. Atenolol, sotalol, nadolol less likely to be affected than other beta blockers.

            • albuterol

              codeine increases and albuterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              butalbital increases and albuterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              albuterol and caffeine both decrease sedation. Use Caution/Monitor.

            • alfentanil

              alfentanil increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              alfentanil and codeine both increase sedation. Use Caution/Monitor.

              butalbital and alfentanil both increase sedation. Use Caution/Monitor.

            • alitretinoin

              butalbital will decrease the level or effect of alitretinoin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • alprazolam

              alprazolam increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • alprazolam

              alprazolam and codeine both increase sedation. Use Caution/Monitor.

            • almotriptan

              butalbital will decrease the level or effect of almotriptan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • alprazolam

              butalbital will decrease the level or effect of alprazolam by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              butalbital and alprazolam both increase sedation. Use Caution/Monitor.

            • amiodarone

              butalbital will decrease the level or effect of amiodarone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              amiodarone will increase the level or effect of codeine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Prevents conversion of codeine to its active metabolite morphine.

            • amitriptyline

              amitriptyline increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              butalbital will decrease the level or effect of amitriptyline by affecting hepatic enzyme CYP2C19 metabolism. Use Caution/Monitor.

              butalbital will decrease the level or effect of amitriptyline by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely.

              butalbital and amitriptyline both increase sedation. Use Caution/Monitor.

              codeine and amitriptyline both increase sedation. Use Caution/Monitor.

            • amlodipine

              butalbital will decrease the level or effect of amlodipine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • amobarbital

              amobarbital increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • amobarbital

              amobarbital and codeine both increase sedation. Use Caution/Monitor.

            • amobarbital

              amobarbital and butalbital both increase sedation. Use Caution/Monitor.

            • amoxapine

              amoxapine increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              codeine and amoxapine both increase sedation. Use Caution/Monitor.

              butalbital and amoxapine both increase sedation. Use Caution/Monitor.

            • apalutamide

              apalutamide will decrease the level or effect of acetaminophen by increasing elimination. Use Caution/Monitor. Apalutamide induces UGT and may decrease systemic exposure of drugs that are UGT substrates.

            • apomorphine

              butalbital and apomorphine both increase sedation. Use Caution/Monitor.

              codeine and apomorphine both increase sedation. Use Caution/Monitor.

            • arformoterol

              arformoterol and caffeine both decrease sedation. Use Caution/Monitor.

            • aprepitant

              butalbital will decrease the level or effect of aprepitant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • arformoterol

              codeine increases and arformoterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • arformoterol

              butalbital increases and arformoterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • aripiprazole

              aripiprazole increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              codeine and aripiprazole both increase sedation. Use Caution/Monitor.

              butalbital and aripiprazole both increase sedation. Use Caution/Monitor.

              butalbital will decrease the level or effect of aripiprazole by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • armodafinil

              butalbital increases and armodafinil decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              codeine increases and armodafinil decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              armodafinil and caffeine both decrease sedation. Use Caution/Monitor.

            • artemether/lumefantrine

              artemether/lumefantrine will increase the level or effect of codeine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.

              butalbital will decrease the level or effect of artemether/lumefantrine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • avapritinib

              acetaminophen will increase the level or effect of avapritinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • axitinib

              acetaminophen increases levels of axitinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • azelastine

              azelastine increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • atenolol

              butalbital decreases levels of atenolol by increasing metabolism. Use Caution/Monitor. Consider a higher beta-blocker dose during coadministration of butalbital. Atenolol, sotalol, nadolol less likely to be affected than other beta blockers.

            • azelastine

              azelastine and codeine both increase sedation. Use Caution/Monitor.

            • atorvastatin

              butalbital will decrease the level or effect of atorvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • avanafil

              butalbital will decrease the level or effect of avanafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. For patients with ED, monitor response carefully because of potential for decreased effectiveness

            • azelastine

              azelastine and butalbital both increase sedation. Use Caution/Monitor.

            • baclofen

              baclofen and codeine both increase sedation. Use Caution/Monitor.

              butalbital and baclofen both increase sedation. Use Caution/Monitor.

            • bazedoxifene/conjugated estrogens

              butalbital will decrease the level or effect of bazedoxifene/conjugated estrogens by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • belladonna and opium

              codeine and belladonna and opium both increase sedation. Use Caution/Monitor.

              belladonna and opium increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • belladonna and opium

              butalbital and belladonna and opium both increase sedation. Use Caution/Monitor.

            • benperidol

              benperidol increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • benazepril

              butalbital increases toxicity of benazepril by unspecified interaction mechanism. Use Caution/Monitor.

            • benperidol

              codeine and benperidol both increase sedation. Use Caution/Monitor.

              butalbital and benperidol both increase sedation. Use Caution/Monitor.

            • benzphetamine

              caffeine and benzphetamine both decrease sedation. Use Caution/Monitor.

              butalbital increases and benzphetamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              codeine increases and benzphetamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • betaxolol

              butalbital decreases levels of betaxolol by increasing metabolism. Use Caution/Monitor. Consider a higher beta-blocker dose during coadministration of butalbital. Atenolol, sotalol, nadolol less likely to be affected than other beta blockers.

            • brompheniramine

              brompheniramine increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • brexanolone

              brexanolone, codeine. Either increases toxicity of the other by sedation. Use Caution/Monitor.

            • bisoprolol

              butalbital decreases levels of bisoprolol by increasing metabolism. Use Caution/Monitor. Consider a higher beta-blocker dose during coadministration of butalbital. Atenolol, sotalol, nadolol less likely to be affected than other beta blockers.

            • bortezomib

              butalbital will decrease the level or effect of bortezomib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • brexanolone

              brexanolone, butalbital. Either increases toxicity of the other by sedation. Use Caution/Monitor.

            • brompheniramine

              brompheniramine and codeine both increase sedation. Use Caution/Monitor.

              brompheniramine and butalbital both increase sedation. Use Caution/Monitor.

            • budesonide

              butalbital will decrease the level or effect of budesonide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • bupivacaine implant

              acetaminophen, bupivacaine implant. Either increases toxicity of the other by Other (see comment). Use Caution/Monitor. Comment: Local anesthetics may increase the risk of developing methemoglobinemia when concurrently exposed to drugs that also cause methemoglobinemia.

            • buprenorphine

              buprenorphine and codeine both increase sedation. Use Caution/Monitor.

            • buprenorphine

              butalbital and buprenorphine both increase sedation. Use Caution/Monitor.

            • buprenorphine buccal

              buprenorphine buccal and codeine both increase sedation. Use Caution/Monitor.

              butalbital and buprenorphine buccal both increase sedation. Use Caution/Monitor.

              buprenorphine buccal increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • buprenorphine, long-acting injection

              butalbital increases toxicity of buprenorphine, long-acting injection by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Coadministration of buprenorphine and benzodiazepines or other CNS depressants increases risk of adverse reactions including overdose, respiratory depression, and death. Cessation of benzodiazepines or other CNS depressants is preferred in most cases. In some cases, monitoring at a higher level of care for tapering CNS depressants may be appropriate. In others, gradually tapering a patient off of a prescribed benzodiazepine or other CNS depressant or decreasing to the lowest effective dose may be appropriate.

              codeine increases toxicity of buprenorphine, long-acting injection by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Coadministration of buprenorphine and benzodiazepines or other CNS depressants increases risk of adverse reactions including overdose, respiratory depression, and death. Cessation of benzodiazepines or other CNS depressants is preferred in most cases. In some cases, monitoring at a higher level of care for tapering CNS depressants may be appropriate. In others, gradually tapering a patient off of a prescribed benzodiazepine or other CNS depressant or decreasing to the lowest effective dose may be appropriate.

              butalbital will decrease the level or effect of buprenorphine, long-acting injection by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Patients who transfer to buprenorphine long-acting injection from transmucosal buprenorphine coadministered with CYP3A4 inducers should be monitored to ensure buprenorphine plasma levels are adequate. If the buprenorphine dose is inadequate and the CYP3A4 inducer cannot be reduced or discontinued, transition the patient back to a buprenorphine formulation that permits dose adjustments.

            • busulfan

              acetaminophen increases levels of busulfan by decreasing metabolism. Use Caution/Monitor. Use of acetaminophen prior to (< 72 hours) or concurrently with busulfan may result in decreased clearance of busulfan due to acetaminophen-induced decreases in glutathione levels.

            • butabarbital

              butabarbital increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • bupropion

              butalbital, bupropion. increasing metabolism. Use Caution/Monitor. Decr levels of bupropion, but incr levels of active metabolites. .

              bupropion will decrease the level or effect of codeine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Prevents the conversion of codeine to its active metabolite morphine.

            • buspirone

              butalbital will decrease the level or effect of buspirone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • butabarbital

              butabarbital and codeine both increase sedation. Use Caution/Monitor.

            • butabarbital

              butabarbital and butalbital both increase sedation. Use Caution/Monitor.

            • butalbital

              butalbital and codeine both increase sedation. Use Caution/Monitor.

              butalbital increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • butorphanol

              butorphanol and codeine both increase sedation. Use Caution/Monitor.

              butalbital and butorphanol both increase sedation. Use Caution/Monitor.

              butorphanol increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • caffeine

              butalbital increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              codeine increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • carbinoxamine

              carbinoxamine increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • cannabidiol

              butalbital will decrease the level or effect of cannabidiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Consider an increase in cannabidiol dosage (based on clinical response and tolerability) when coadministered with a strong CYP3A4 inducer.

            • carbinoxamine

              carbinoxamine and codeine both increase sedation. Use Caution/Monitor.

            • captopril

              butalbital, captopril. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Enhanced hypotensive effects.

            • carbamazepine

              butalbital will decrease the level or effect of carbamazepine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • carbinoxamine

              carbinoxamine and butalbital both increase sedation. Use Caution/Monitor.

            • carisoprodol

              carisoprodol and codeine both increase sedation. Use Caution/Monitor.

              butalbital and carisoprodol both increase sedation. Use Caution/Monitor.

            • carvedilol

              butalbital will decrease the level or effect of carvedilol by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

              butalbital decreases levels of carvedilol by increasing metabolism. Use Caution/Monitor. Consider a higher beta-blocker dose during coadministration of butalbital. Atenolol, sotalol, nadolol less likely to be affected than other beta blockers.

            • celecoxib

              celecoxib decreases effects of codeine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Prevents conversion of codeine to its active metabolite morphine.

            • celiprolol

              butalbital decreases levels of celiprolol by increasing metabolism. Use Caution/Monitor. Atenolol, sotalol, nadolol less likely to be affected than other beta blockers.

            • cenobamate

              cenobamate, butalbital. Either increases effects of the other by sedation. Use Caution/Monitor.

              cenobamate, codeine. Either increases effects of the other by sedation. Use Caution/Monitor.

            • chloral hydrate

              chloral hydrate and codeine both increase sedation. Use Caution/Monitor.

              chloral hydrate increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              butalbital and chloral hydrate both increase sedation. Use Caution/Monitor.

            • chlordiazepoxide

              chlordiazepoxide and codeine both increase sedation. Use Caution/Monitor.

              butalbital and chlordiazepoxide both increase sedation. Use Caution/Monitor.

              chlordiazepoxide increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • chloroquine

              chloroquine will increase the level or effect of codeine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Prevents conversion of codeine to its active metabolite morphine.

            • chlorpheniramine

              chlorpheniramine increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • chlorpheniramine

              chlorpheniramine and butalbital both increase sedation. Use Caution/Monitor.

            • chlorpheniramine

              chlorpheniramine and codeine both increase sedation. Use Caution/Monitor.

            • chlorpromazine

              chlorpromazine will decrease the level or effect of codeine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Prevents conversion of codeine to its active metabolite morphine

              codeine and chlorpromazine both increase sedation. Use Caution/Monitor.

              butalbital and chlorpromazine both increase sedation. Use Caution/Monitor.

              chlorpromazine increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • chlorzoxazone

              chlorzoxazone and codeine both increase sedation. Use Caution/Monitor.

              butalbital and chlorzoxazone both increase sedation. Use Caution/Monitor.

            • cinnarizine

              cinnarizine increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • cilostazol

              butalbital will decrease the level or effect of cilostazol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • cimetidine

              cimetidine will increase the level or effect of codeine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Prevents conversion of codeine to its active metabolite morphine.

            • cinacalcet

              cinacalcet decreases effects of codeine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Prevents conversion of codeine to its active metabolite morphine.

              butalbital will decrease the level or effect of cinacalcet by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • cinnarizine

              cinnarizine and butalbital both increase sedation. Use Caution/Monitor.

              cinnarizine and codeine both increase sedation. Use Caution/Monitor.

            • ciprofloxacin

              ciprofloxacin will increase the level or effect of caffeine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor. The hepatic metabolism of caffeine may be decreased by ciprofloxacin; pharmacologic effects of caffeine may be increased.

            • clemastine

              clemastine increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              clemastine and butalbital both increase sedation. Use Caution/Monitor.

              clemastine and codeine both increase sedation. Use Caution/Monitor.

            • clobazam

              codeine, clobazam. Other (see comment). Use Caution/Monitor. Comment: Concomitant administration can increase the potential for CNS effects (e.g., increased sedation or respiratory depression).

              clobazam decreases effects of codeine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Prevents conversion of codeine to its active metabolite morphine.

            • clomipramine

              clomipramine increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • clobetasone

              butalbital will decrease the level or effect of clobetasone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • clomipramine

              butalbital will decrease the level or effect of clomipramine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely.

              codeine and clomipramine both increase sedation. Use Caution/Monitor.

              butalbital will decrease the level or effect of clomipramine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

              butalbital and clomipramine both increase sedation. Use Caution/Monitor.

              clomipramine decreases effects of codeine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Prevents conversion of codeine to its active metabolite morphine.

            • clonazepam

              butalbital and clonazepam both increase sedation. Use Caution/Monitor.

              clonazepam increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              clonazepam and codeine both increase sedation. Use Caution/Monitor.

            • clopidogrel

              butalbital will increase the level or effect of clopidogrel by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. CYP3A4 inducers may increase the metabolism of clopidogrel to its active metabolite. Monitor patients for potential increase in antiplatelet effects when CYP3A4 inducers are used in combination with clopidogrel

            • clorazepate

              clorazepate increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • clorazepate

              clorazepate and codeine both increase sedation. Use Caution/Monitor.

            • clorazepate

              butalbital and clorazepate both increase sedation. Use Caution/Monitor.

            • clozapine

              clozapine increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              codeine and clozapine both increase sedation. Use Caution/Monitor.

              butalbital will decrease the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              butalbital and clozapine both increase sedation. Use Caution/Monitor.

              butalbital will decrease the level or effect of clozapine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

              clozapine decreases effects of codeine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Prevents conversion of codeine to its active metabolite morphine.

            • cocaine

              cocaine decreases effects of codeine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Prevents conversion of codeine to its active metabolite morphine.

            • codeine

              codeine increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • codeine

              butalbital and codeine both increase sedation. Use Caution/Monitor.

            • colchicine

              butalbital will decrease the level or effect of colchicine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • conivaptan

              butalbital will decrease the level or effect of conivaptan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • conjugated estrogens

              butalbital will decrease the level or effect of conjugated estrogens by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • conjugated estrogens, vaginal

              butalbital will decrease the level or effect of conjugated estrogens, vaginal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • cortisone

              butalbital will decrease the level or effect of cortisone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • cyclizine

              cyclizine increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              cyclizine and codeine both increase sedation. Use Caution/Monitor.

              cyclizine and butalbital both increase sedation. Use Caution/Monitor.

            • cyclobenzaprine

              butalbital and cyclobenzaprine both increase sedation. Use Caution/Monitor.

              cyclobenzaprine and codeine both increase sedation. Use Caution/Monitor.

            • cyproheptadine

              cyproheptadine increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • cyclosporine

              butalbital will decrease the level or effect of cyclosporine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • cyproheptadine

              cyproheptadine and codeine both increase sedation. Use Caution/Monitor.

            • cyproheptadine

              cyproheptadine and butalbital both increase sedation. Use Caution/Monitor.

            • dantrolene

              dantrolene and codeine both increase sedation. Use Caution/Monitor.

              butalbital and dantrolene both increase sedation. Use Caution/Monitor.

            • dapsone topical

              acetaminophen increases toxicity of dapsone topical by altering metabolism. Modify Therapy/Monitor Closely. May induce methemoglobinemia .

            • darifenacin

              darifenacin decreases effects of codeine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Prevents conversion of codeine to its active metabolite morphine.

              butalbital will decrease the level or effect of darifenacin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • darunavir

              butalbital will decrease the level or effect of darunavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • deferasirox

              deferasirox increases levels of caffeine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

            • desflurane

              desflurane and codeine both increase sedation. Use Caution/Monitor. Opioids may decrease MAC requirements, less inhalation anesthetic may be required.

            • dasatinib

              butalbital will decrease the level or effect of dasatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • desipramine

              codeine and desipramine both increase sedation. Use Caution/Monitor.

              butalbital and desipramine both increase sedation. Use Caution/Monitor.

              desipramine increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              desipramine decreases effects of codeine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Prevents conversion of codeine to its active metabolite morphine.

              butalbital will decrease the level or effect of desipramine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely.

            • desvenlafaxine

              desvenlafaxine will increase the level or effect of codeine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Desvenlafaxine inhibits CYP2D6; with higher desvenlafaxine doses (ie, 400 mg) decrease the CYP2D6 substrate dose by up to 50%; no dosage adjustment needed with desvenlafaxine doses <100 mg

            • dexchlorpheniramine

              dexchlorpheniramine increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • deutetrabenazine

              butalbital and deutetrabenazine both increase sedation. Use Caution/Monitor.

            • deutetrabenazine

              codeine and deutetrabenazine both increase sedation. Use Caution/Monitor.

            • dexamethasone

              butalbital will decrease the level or effect of dexamethasone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • dexchlorpheniramine

              dexchlorpheniramine and codeine both increase sedation. Use Caution/Monitor.

              dexchlorpheniramine and butalbital both increase sedation. Use Caution/Monitor.

            • dexfenfluramine

              caffeine and dexfenfluramine both decrease sedation. Use Caution/Monitor.

              butalbital increases and dexfenfluramine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              codeine increases and dexfenfluramine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • dexmedetomidine

              dexmedetomidine increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              dexmedetomidine and codeine both increase sedation. Use Caution/Monitor.

              butalbital and dexmedetomidine both increase sedation. Use Caution/Monitor.

            • dexmethylphenidate

              butalbital increases and dexmethylphenidate decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              codeine increases and dexmethylphenidate decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              caffeine and dexmethylphenidate both decrease sedation. Use Caution/Monitor.

            • dextroamphetamine

              butalbital increases and dextroamphetamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              codeine increases and dextroamphetamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              caffeine and dextroamphetamine both decrease sedation. Use Caution/Monitor.

            • dextromoramide

              butalbital and dextromoramide both increase sedation. Use Caution/Monitor.

              codeine and dextromoramide both increase sedation. Use Caution/Monitor.

              dextromoramide increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • diamorphine

              butalbital and diamorphine both increase sedation. Use Caution/Monitor.

              codeine and diamorphine both increase sedation. Use Caution/Monitor.

              diamorphine increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • diazepam

              diazepam and codeine both increase sedation. Use Caution/Monitor.

              butalbital will decrease the level or effect of diazepam by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              butalbital and diazepam both increase sedation. Use Caution/Monitor.

            • diethylpropion

              caffeine and diethylpropion both decrease sedation. Use Caution/Monitor.

            • diazepam intranasal

              butalbital will decrease the level or effect of diazepam intranasal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Strong or moderate CYP3A4 inducers may increase rate of diazepam elimination; therefore, efficacy of diazepam may be decreased.

              diazepam intranasal, butalbital. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Coadministration may potentiate the CNS-depressant effects of each drug.

            • diethylpropion

              codeine increases and diethylpropion decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • diethylpropion

              butalbital increases and diethylpropion decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • difenoxin hcl

              difenoxin hcl increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              codeine and difenoxin hcl both increase sedation. Use Caution/Monitor.

              butalbital and difenoxin hcl both increase sedation. Use Caution/Monitor.

            • diltiazem

              butalbital will decrease the level or effect of diltiazem by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • dimenhydrinate

              dimenhydrinate increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • dimenhydrinate

              dimenhydrinate and codeine both increase sedation. Use Caution/Monitor.

            • dimenhydrinate

              dimenhydrinate and butalbital both increase sedation. Use Caution/Monitor.

            • diphenhydramine

              diphenhydramine decreases effects of codeine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Prevents conversion of codeine to its active metabolite morphine.

              diphenhydramine and codeine both increase sedation. Use Caution/Monitor.

              diphenhydramine and butalbital both increase sedation. Use Caution/Monitor.

              diphenhydramine increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • diphenoxylate hcl

              butalbital and diphenoxylate hcl both increase sedation. Use Caution/Monitor.

              codeine and diphenoxylate hcl both increase sedation. Use Caution/Monitor.

              diphenoxylate hcl increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • dipipanone

              butalbital and dipipanone both increase sedation. Use Caution/Monitor.

              codeine and dipipanone both increase sedation. Use Caution/Monitor.

              dipipanone increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • dobutamine

              butalbital increases and dobutamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              codeine increases and dobutamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              dobutamine and caffeine both decrease sedation. Use Caution/Monitor.

            • dopamine

              butalbital increases and dopamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              codeine increases and dopamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              caffeine and dopamine both decrease sedation. Use Caution/Monitor.

            • dopexamine

              butalbital increases and dopexamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              codeine increases and dopexamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              dopexamine and caffeine both decrease sedation. Use Caution/Monitor.

            • dosulepin

              butalbital and dosulepin both increase sedation. Use Caution/Monitor.

              codeine and dosulepin both increase sedation. Use Caution/Monitor.

            • doxepin

              doxepin increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • doxepin

              butalbital and doxepin both increase sedation. Use Caution/Monitor.

              codeine and doxepin both increase sedation. Use Caution/Monitor.

            • doxycycline

              butalbital decreases levels of doxycycline by increasing metabolism. Use Caution/Monitor.

            • doxylamine

              doxylamine and codeine both increase sedation. Use Caution/Monitor.

            • doxylamine

              butalbital and doxylamine both increase sedation. Use Caution/Monitor.

            • dronabinol

              butalbital will increase the level or effect of dronabinol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Dronabinol is a CYP3A4 substrate.

            • dronedarone

              dronedarone decreases effects of codeine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Prevents conversion of codeine to its active metabolite morphine.

            • droperidol

              codeine and droperidol both increase sedation. Use Caution/Monitor.

              butalbital and droperidol both increase sedation. Use Caution/Monitor.

              droperidol increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • droxidopa

              caffeine and droxidopa both increase sympathetic (adrenergic) effects, including increased blood pressure and heart rate. Use Caution/Monitor. May increase risk for supine hypertension

            • duloxetine

              duloxetine decreases effects of codeine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Prevents conversion of codeine to its active metabolite morphine.

            • elagolix

              butalbital will decrease the level or effect of elagolix by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • eletriptan

              butalbital will decrease the level or effect of eletriptan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • eltrombopag

              eltrombopag increases levels of acetaminophen by decreasing metabolism. Use Caution/Monitor. UGT inhibition; significance of interaction unclear.

              butalbital will decrease the level or effect of eltrombopag by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

              butalbital will decrease the level or effect of eltrombopag by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

            • elvitegravir/cobicistat/emtricitabine/tenofovir DF

              elvitegravir/cobicistat/emtricitabine/tenofovir DF increases levels of codeine by affecting hepatic enzyme CYP2D6 metabolism. Modify Therapy/Monitor Closely. Cobicistat is a CYP2D6 inhibitor; caution with CYP2D6 substrates for which elevated plasma concentrations are associated with serious and/or life-threatening events.

            • exenatide injectable solution

              exenatide injectable solution will decrease the level or effect of acetaminophen by unspecified interaction mechanism. Use Caution/Monitor. To avoid potential interaction, give acetaminophen at least 1 hour before or 4 hours after exenatide injection.

            • ephedrine

              ephedrine and caffeine both decrease sedation. Use Caution/Monitor.

              codeine increases and ephedrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              butalbital increases and ephedrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • epinephrine

              epinephrine and caffeine both decrease sedation. Use Caution/Monitor.

              butalbital increases and epinephrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              codeine increases and epinephrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • epinephrine inhaled

              caffeine, epinephrine inhaled. Either increases effects of the other by sympathetic (adrenergic) effects, including increased blood pressure and heart rate. Use Caution/Monitor.

            • epinephrine racemic

              butalbital increases and epinephrine racemic decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              codeine increases and epinephrine racemic decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • epinephrine racemic

              epinephrine racemic and caffeine both decrease sedation. Use Caution/Monitor.

            • erlotinib

              butalbital will decrease the level or effect of erlotinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • esketamine intranasal

              esketamine intranasal, codeine. Either increases toxicity of the other by sedation. Modify Therapy/Monitor Closely.

              esketamine intranasal, caffeine. Either increases toxicity of the other by sympathetic (adrenergic) effects, including increased blood pressure and heart rate. Use Caution/Monitor. Closely monitor blood pressure with concomitant use of esketamine nasal with stimulants. .

            • escitalopram

              butalbital will decrease the level or effect of escitalopram by affecting hepatic enzyme CYP2C19 metabolism. Use Caution/Monitor.

            • estazolam

              estazolam increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • esketamine intranasal

              esketamine intranasal, butalbital. Either increases toxicity of the other by sedation. Modify Therapy/Monitor Closely.

            • esmolol

              butalbital decreases levels of esmolol by increasing metabolism. Use Caution/Monitor. Consider a higher beta-blocker dose during coadministration of butalbital. Atenolol, sotalol, nadolol less likely to be affected than other beta blockers.

            • estazolam

              estazolam and codeine both increase sedation. Use Caution/Monitor.

              butalbital and estazolam both increase sedation. Use Caution/Monitor.

            • estradiol

              butalbital will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • ethanol

              ethanol increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              codeine and ethanol both increase sedation. Use Caution/Monitor.

            • estradiol vaginal

              butalbital will decrease the level or effect of estradiol vaginal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • ethinylestradiol

              ethinylestradiol will increase the level or effect of caffeine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

            • estrogens conjugated synthetic

              butalbital will decrease the level or effect of estrogens conjugated synthetic by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • estropipate

              butalbital will decrease the level or effect of estropipate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • ethanol

              butalbital and ethanol both increase sedation. Use Caution/Monitor.

            • ethotoin

              butalbital will decrease the level or effect of ethotoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

            • etomidate

              etomidate and codeine both increase sedation. Use Caution/Monitor.

              etomidate and butalbital both increase sedation. Use Caution/Monitor.

            • etonogestrel

              butalbital will decrease the level or effect of etonogestrel by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • exenatide injectable suspension

              exenatide injectable suspension will decrease the level or effect of acetaminophen by unspecified interaction mechanism. Use Caution/Monitor. To avoid potential interaction, give acetaminophen at least 1 hour before or 4 hours after exenatide injection.

            • fedratinib

              fedratinib will increase the level or effect of codeine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Adjust dose of drugs that are CYP2D6 substrates as necessary.

            • etravirine

              butalbital will decrease the level or effect of etravirine by affecting hepatic enzyme CYP2C19 metabolism. Use Caution/Monitor.

              butalbital will decrease the level or effect of etravirine by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

              butalbital will decrease the level or effect of etravirine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • felodipine

              butalbital will decrease the level or effect of felodipine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • fenfluramine

              caffeine and fenfluramine both decrease sedation. Use Caution/Monitor.

              codeine increases and fenfluramine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              butalbital increases and fenfluramine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • fesoterodine

              butalbital will decrease the level or effect of fesoterodine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • fexinidazole

              fexinidazole will increase the level or effect of caffeine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

            • finerenone

              acetaminophen will increase the level or effect of finerenone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Monitor serum potassium during initiation and dosage adjustment of either finererone or moderate CYP3A4 inhibitors. Adjust finererone dosage as needed.

            • flibanserin

              codeine and flibanserin both increase sedation. Modify Therapy/Monitor Closely. Risk for sedation increased if flibanserin is coadministration with other CNS depressants.

              acetaminophen will increase the level or effect of flibanserin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Increased flibanserin adverse effects may occur if coadministered with multiple weak CYP3A4 inhibitors.

            • flibanserin

              butalbital and flibanserin both increase sedation. Modify Therapy/Monitor Closely. Risk for sedation increased if flibanserin is coadministration with other CNS depressants.

            • imatinib

              imatinib decreases levels of acetaminophen by decreasing hepatic clearance. Modify Therapy/Monitor Closely. In vitro, imatinib was found to inhibit acetaminophen O-glucuronidation (Ki value of 58.5 micro-M) at therapeutic levels; avoid chronic acetaminophen therapy with imatinib; if occasional acetaminophen administered, do not exceed 1300 mg/day.

            • fludrocortisone

              butalbital will decrease the level or effect of fludrocortisone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • fluoxetine

              fluoxetine will decrease the level or effect of codeine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Prevents conversion of codeine to its active metabolite morphine

            • fluphenazine

              fluphenazine increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              codeine and fluphenazine both increase sedation. Use Caution/Monitor.

              butalbital and fluphenazine both increase sedation. Use Caution/Monitor.

            • flurazepam

              butalbital and flurazepam both increase sedation. Use Caution/Monitor.

              flurazepam and codeine both increase sedation. Use Caution/Monitor.

              flurazepam increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • fluvoxamine

              fluvoxamine will increase the level or effect of caffeine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

            • formoterol

              butalbital increases and formoterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              codeine increases and formoterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • formoterol

              formoterol and caffeine both decrease sedation. Use Caution/Monitor.

            • fosamprenavir

              butalbital will decrease the level or effect of fosamprenavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • gabapentin

              gabapentin, codeine. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Coadministration of CNS depressants can result in serious, life-threatening, and fatal respiratory depression. Use lowest dose possible and monitor for respiratory depression and sedation.

            • fosphenytoin

              butalbital will decrease the level or effect of fosphenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

            • gabapentin

              gabapentin, butalbital. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Coadministration of CNS depressants can result in serious, life-threatening, and fatal respiratory depression. Use lowest dose possible and monitor for respiratory depression and sedation.

            • gabapentin enacarbil

              gabapentin enacarbil, codeine. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Coadministration of CNS depressants can result in serious, life-threatening, and fatal respiratory depression. Use lowest dose possible and monitor for respiratory depression and sedation.

              gabapentin enacarbil, butalbital. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Coadministration of CNS depressants can result in serious, life-threatening, and fatal respiratory depression. Use lowest dose possible and monitor for respiratory depression and sedation.

            • glecaprevir/pibrentasvir

              butalbital will decrease the level or effect of glecaprevir/pibrentasvir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration of drugs that induce CYP3A4 with glecaprevir/pibrentasvir may decrease glecaprevir/pibrentasvir plasma concentrations. Potential for loss of therapeutic effect.

            • green tea

              green tea increases effects of caffeine by Other (see comment). Use Caution/Monitor. Comment: Potential for increased risk of CNS stimulation due to caffeine component of green tea. Caution advised.

            • guselkumab

              guselkumab, caffeine. Other (see comment). Use Caution/Monitor. Comment: Formation of CYP450 enzymes can be altered by increased levels of certain cytokines during chronic inflammation; thus, normalizing the formation of CYP450 enzymes. Upon initiation or discontinuation of guselkumab in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for therapeutic effect.

            • haloperidol

              haloperidol increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              codeine and haloperidol both increase sedation. Use Caution/Monitor.

              haloperidol decreases effects of codeine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Prevents conversion of codeine to its active metabolite morphine.

            • gotu kola

              gotu kola increases effects of butalbital by pharmacodynamic synergism. Use Caution/Monitor. May enhance CNS depression.

            • hydromorphone

              hydromorphone increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • guanfacine

              butalbital will decrease the level or effect of guanfacine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Strong or moderate CYP3A4 inducers significantly reduce guanfacine plasma concentrations and elimination half-life. If coadministered, more frequent dosing of the IR product may be required to achieve or maintain the desired hypotensive response. For patients with ADHD, FDA-approved labeling for ER guanfacine recommends that, if coadministered, doubling the recommended dose of guanfacine should be considered.

            • haloperidol

              butalbital and haloperidol both increase sedation. Use Caution/Monitor.

            • hawthorn

              hawthorn increases effects of butalbital by pharmacodynamic synergism. Use Caution/Monitor. May enhance CNS depression.

            • hemin

              butalbital decreases effects of hemin by pharmacodynamic antagonism. Use Caution/Monitor. Drugs that increase delta-aminolevulinic acid synthetase may decrease hemin effect.

            • hops

              hops increases effects of butalbital by pharmacodynamic synergism. Use Caution/Monitor. May enhance CNS depression.

            • hydrocortisone

              butalbital will decrease the level or effect of hydrocortisone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • hydromorphone

              codeine and hydromorphone both increase sedation. Use Caution/Monitor.

              butalbital and hydromorphone both increase sedation. Use Caution/Monitor.

            • hydroxyprogesterone caproate

              butalbital will decrease the level or effect of hydroxyprogesterone caproate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • hydroxyzine

              hydroxyzine and codeine both increase sedation. Use Caution/Monitor.

              hydroxyzine increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • hydroxyzine

              hydroxyzine and butalbital both increase sedation. Use Caution/Monitor.

            • iloperidone

              iloperidone increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • ifosfamide

              butalbital increases effects of ifosfamide by affecting hepatic enzyme CYP2B6 metabolism. Use Caution/Monitor. Coadministration of ifosfamide with CYP2B6 inducers may increase metabolism of ifosfamide to its metabolite. Monitor for increased effects/toxicities if combined with CYP2B6 inducers.

              butalbital increases effects of ifosfamide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. CYP3A4 inducers may increase the metabolism of ifosfamide to its active alkylating metabolites. CYP3A4 inducers may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde. Closely monitor patients taking ifosfamide with CYP3A4 inducers for toxicities and consider dose adjustment.

            • iloperidone

              butalbital will decrease the level or effect of iloperidone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              codeine and iloperidone both increase sedation. Use Caution/Monitor.

              butalbital and iloperidone both increase sedation. Use Caution/Monitor.

            • imipramine

              butalbital will decrease the level or effect of imipramine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely.

              butalbital and imipramine both increase sedation. Use Caution/Monitor.

              codeine and imipramine both increase sedation. Use Caution/Monitor.

              imipramine increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              imipramine decreases effects of codeine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Prevents conversion of codeine to its active metabolite morphine.

              butalbital will decrease the level or effect of imipramine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

              butalbital will decrease the level or effect of imipramine by affecting hepatic enzyme CYP2C19 metabolism. Use Caution/Monitor.

            • indinavir

              butalbital will decrease the level or effect of indinavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • isoniazid

              isoniazid will increase the level or effect of acetaminophen by affecting hepatic enzyme CYP2E1 metabolism. Use Caution/Monitor.

            • isoproterenol

              isoproterenol and caffeine both decrease sedation. Use Caution/Monitor.

            • isoniazid

              isoniazid decreases effects of codeine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Prevents conversion of codeine to its active metabolite morphine.

            • isoproterenol

              codeine increases and isoproterenol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              butalbital increases and isoproterenol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • ivacaftor

              acetaminophen increases levels of ivacaftor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Monitor when coadministered with weak CYP3A4 inhibitors .

            • ixabepilone

              butalbital will decrease the level or effect of ixabepilone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • ketamine

              ketamine and codeine both increase sedation. Use Caution/Monitor.

            • kava

              kava increases effects of butalbital by pharmacodynamic synergism. Use Caution/Monitor. May enhance CNS depression.

            • ketamine

              ketamine and butalbital both increase sedation. Use Caution/Monitor.

            • ketoconazole

              ketoconazole decreases effects of codeine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Prevents conversion of codeine to its active metabolite morphine.

            • ketotifen, ophthalmic

              codeine and ketotifen, ophthalmic both increase sedation. Use Caution/Monitor.

              butalbital and ketotifen, ophthalmic both increase sedation. Use Caution/Monitor.

              ketotifen, ophthalmic increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • labetalol

              butalbital decreases levels of labetalol by increasing metabolism. Use Caution/Monitor. Consider a higher beta-blocker dose during coadministration of butalbital. Atenolol, sotalol, nadolol less likely to be affected than other beta blockers.

            • lemborexant

              acetaminophen will increase the level or effect of lemborexant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Lower nightly dose of lemborexant recommended if coadministered with weak CYP3A4 inhibitors. See drug monograph for specific dosage modification.

            • letermovir

              letermovir increases levels of caffeine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • lasmiditan

              lasmiditan, codeine. Either increases effects of the other by sedation. Use Caution/Monitor. Coadministration of lasmiditan and other CNS depressant drugs, including alcohol have not been evaluated in clinical studies. Lasmiditan may cause sedation, as well as other cognitive and/or neuropsychiatric adverse reactions.

            • lapatinib

              butalbital will decrease the level or effect of lapatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • lasmiditan

              lasmiditan, butalbital. Either increases effects of the other by sedation. Use Caution/Monitor. Coadministration of lasmiditan and other CNS depressant drugs, including alcohol have not been evaluated in clinical studies. Lasmiditan may cause sedation, as well as other cognitive and/or neuropsychiatric adverse reactions.

            • lemborexant

              lemborexant, codeine. Either increases effects of the other by sedation. Modify Therapy/Monitor Closely. Dosage adjustment may be necessary if lemborexant is coadministered with other CNS depressants because of potentially additive effects.

            • letermovir

              letermovir increases levels of codeine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • levalbuterol

              levalbuterol and caffeine both decrease sedation. Use Caution/Monitor.

              codeine increases and levalbuterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              butalbital increases and levalbuterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • levamlodipine

              butalbital will decrease the level or effect of levamlodipine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. No information is available on the quantitative effects of CYP3A4 inducers on amlodipine. Closely monitor blood pressure when amlodipine is coadministered with CYP3A4 inducers.

            • levonorgestrel oral/ethinylestradiol/ferrous bisglycinate

              levonorgestrel oral/ethinylestradiol/ferrous bisglycinate will decrease the level or effect of acetaminophen by unknown mechanism. Use Caution/Monitor.

              acetaminophen increases levels of levonorgestrel oral/ethinylestradiol/ferrous bisglycinate by decreasing hepatic clearance. Use Caution/Monitor. Coadministration of ascorbic acid and certain combined hormonal contraceptives (CHCs) containing EE may increase plasma EE concentrations, possibly by inhibition of conjugation.

            • levorphanol

              levorphanol increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • levorphanol

              codeine and levorphanol both increase sedation. Use Caution/Monitor.

            • levonorgestrel oral/ethinylestradiol/ferrous bisglycinate

              butalbital will decrease the level or effect of levonorgestrel oral/ethinylestradiol/ferrous bisglycinate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. The efficacy of hormonal contraceptives may be reduced. Use an alternative method of contraception or a backup method when enzyme inducers are used with combined hormonal contraceptives (CHCs), and continue backup contraception for 28 days after discontinuing enzyme inducer to ensure contraceptive reliability.

            • levorphanol

              butalbital and levorphanol both increase sedation. Use Caution/Monitor.

            • levothyroxine

              caffeine decreases levels of levothyroxine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor. COFFEE binds levothyroxine in the GI tract. Separate by 2 hours.

            • lidocaine

              butalbital will decrease the level or effect of lidocaine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

            • lisdexamfetamine

              caffeine and lisdexamfetamine both decrease sedation. Use Caution/Monitor.

              codeine increases and lisdexamfetamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              butalbital increases and lisdexamfetamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • lixisenatide

              lixisenatide will decrease the level or effect of acetaminophen by inhibition of GI absorption. Applies only to oral form of both agents. Modify Therapy/Monitor Closely. GLP1 agonists delay gastric emptying, which may affect absorption of concomitantly administered oral medications. No effects on acetaminophen Cmax and Tmax were observed when acetaminophen was administered 1 hr before lixisenatide. When administered 1 or 4 hr after lixisenatide, acetaminophen Cmax was decreased by 29% and 31% respectively and median Tmax was delayed by 2 and 1.75 hr, respectively.

            • lofepramine

              butalbital and lofepramine both increase sedation. Use Caution/Monitor.

              codeine and lofepramine both increase sedation. Use Caution/Monitor.

              lofepramine increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • lofexidine

              butalbital and lofexidine both increase sedation. Use Caution/Monitor.

              codeine and lofexidine both increase sedation. Use Caution/Monitor.

              lofexidine increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • lomitapide

              acetaminophen increases levels of lomitapide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Lomitapide dose should not exceed 30 mg/day.

            • lopinavir

              lopinavir decreases effects of codeine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Prevents conversion of codeine to its active metabolite morphine.

              butalbital will decrease the level or effect of lopinavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • loprazolam

              loprazolam increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • loprazolam

              butalbital and loprazolam both increase sedation. Use Caution/Monitor.

              loprazolam and codeine both increase sedation. Use Caution/Monitor.

            • loratadine

              butalbital will decrease the level or effect of loratadine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • lorazepam

              lorazepam increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              lorazepam and codeine both increase sedation. Use Caution/Monitor.

            • lorazepam

              butalbital and lorazepam both increase sedation. Use Caution/Monitor.

            • lormetazepam

              lormetazepam increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • lorcaserin

              lorcaserin will increase the level or effect of codeine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Prevents conversion of codeine to its active metabolite morphine.

            • lormetazepam

              lormetazepam and codeine both increase sedation. Use Caution/Monitor.

              butalbital and lormetazepam both increase sedation. Use Caution/Monitor.

            • loxapine

              butalbital and loxapine both increase sedation. Use Caution/Monitor.

              codeine and loxapine both increase sedation. Use Caution/Monitor.

              loxapine increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • loxapine inhaled

              loxapine inhaled increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              codeine and loxapine inhaled both increase sedation. Use Caution/Monitor.

              butalbital and loxapine inhaled both increase sedation. Use Caution/Monitor.

            • lumefantrine

              butalbital will decrease the level or effect of lumefantrine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              lumefantrine will increase the level or effect of codeine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.

            • maprotiline

              maprotiline increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • lurasidone

              lurasidone, butalbital. Either increases toxicity of the other by Other (see comment). Use Caution/Monitor. Comment: Potential for increased CNS depressant effects when used concurrently; monitor for increased adverse effects and toxicity.

              lurasidone, codeine. Either increases toxicity of the other by Other (see comment). Use Caution/Monitor. Comment: Potential for increased CNS depressant effects when used concurrently; monitor for increased adverse effects and toxicity.

            • maprotiline

              butalbital and maprotiline both increase sedation. Use Caution/Monitor.

              codeine and maprotiline both increase sedation. Use Caution/Monitor.

            • maraviroc

              butalbital will decrease the level or effect of maraviroc by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • marijuana

              marijuana increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              codeine and marijuana both increase sedation. Use Caution/Monitor.

            • marijuana

              butalbital and marijuana both increase sedation. Use Caution/Monitor.

            • melatonin

              melatonin increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • melatonin

              codeine and melatonin both increase sedation. Use Caution/Monitor.

              butalbital and melatonin both increase sedation. Use Caution/Monitor.

            • meperidine

              butalbital and meperidine both increase sedation. Use Caution/Monitor.

              codeine and meperidine both increase sedation. Use Caution/Monitor.

              meperidine increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • meprobamate

              meprobamate increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              butalbital and meprobamate both increase sedation. Use Caution/Monitor.

              codeine and meprobamate both increase sedation. Use Caution/Monitor.

            • mestranol

              butalbital will decrease the level or effect of mestranol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • metaproterenol

              metaproterenol and caffeine both decrease sedation. Use Caution/Monitor.

            • metaproterenol

              codeine increases and metaproterenol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • metaproterenol

              butalbital increases and metaproterenol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • metaxalone

              butalbital and metaxalone both increase sedation. Use Caution/Monitor.

              metaxalone and codeine both increase sedation. Use Caution/Monitor.

            • methadone

              butalbital will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              butalbital and methadone both increase sedation. Use Caution/Monitor.

              codeine and methadone both increase sedation. Use Caution/Monitor.

              methadone increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • methamphetamine

              butalbital increases and methamphetamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              codeine increases and methamphetamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              caffeine and methamphetamine both decrease sedation. Use Caution/Monitor.

            • methocarbamol

              butalbital and methocarbamol both increase sedation. Use Caution/Monitor.

              methocarbamol and codeine both increase sedation. Use Caution/Monitor.

            • methotrexate

              caffeine decreases effects of methotrexate by pharmacodynamic antagonism. Use Caution/Monitor.

            • methylenedioxymethamphetamine

              caffeine and methylenedioxymethamphetamine both decrease sedation. Use Caution/Monitor.

              butalbital increases and methylenedioxymethamphetamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              codeine increases and methylenedioxymethamphetamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • methylphenidate

              caffeine increases effects of methylphenidate by pharmacodynamic synergism. Use Caution/Monitor. Risk of acute hypertensive episode.

            • methylprednisolone

              butalbital will decrease the level or effect of methylprednisolone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • midazolam

              midazolam increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              midazolam and codeine both increase sedation. Use Caution/Monitor.

            • metoprolol

              butalbital decreases levels of metoprolol by increasing metabolism. Use Caution/Monitor. Consider a higher beta-blocker dose during coadministration of butalbital. Atenolol, sotalol, nadolol less likely to be affected than other beta blockers.

            • midazolam intranasal

              acetaminophen will increase the level or effect of midazolam intranasal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration of mild CYP3A4 inhibitors with midazolam intranasal may cause higher midazolam systemic exposure, which may prolong sedation.

            • midodrine

              caffeine and midodrine both decrease sedation. Use Caution/Monitor.

            • mexiletine

              butalbital will decrease the level or effect of mexiletine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

            • midazolam

              butalbital will decrease the level or effect of midazolam by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              butalbital and midazolam both increase sedation. Use Caution/Monitor.

            • midazolam intranasal

              midazolam intranasal, codeine. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Concomitant use of barbiturates, alcohol, or other CNS depressants may increase the risk of hypoventilation, airway obstruction, desaturation, or apnea and may contribute to profound and/or prolonged drug effect.

              midazolam intranasal, butalbital. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Concomitant use of barbiturates, alcohol, or other CNS depressants may increase the risk of hypoventilation, airway obstruction, desaturation, or apnea and may contribute to profound and/or prolonged drug effect.

            • midodrine

              butalbital increases and midodrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              codeine increases and midodrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • mipomersen

              mipomersen, acetaminophen. Either increases toxicity of the other by Other (see comment). Use Caution/Monitor. Comment: Both drugs have potential to increase hepatic enzymes; monitor LFTs.

            • mirabegron

              mirabegron will increase the level or effect of codeine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.

            • mirtazapine

              butalbital and mirtazapine both increase sedation. Use Caution/Monitor.

              mirtazapine increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • mirtazapine

              codeine and mirtazapine both increase sedation. Use Caution/Monitor.

            • modafinil

              caffeine and modafinil both decrease sedation. Use Caution/Monitor.

            • modafinil

              codeine increases and modafinil decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              butalbital increases and modafinil decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • morphine

              butalbital and morphine both increase sedation. Use Caution/Monitor.

              codeine and morphine both increase sedation. Use Caution/Monitor.

              morphine increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • motherwort

              butalbital and motherwort both increase sedation. Use Caution/Monitor.

              codeine and motherwort both increase sedation. Use Caution/Monitor.

              motherwort increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • moxonidine

              butalbital and moxonidine both increase sedation. Use Caution/Monitor.

              codeine and moxonidine both increase sedation. Use Caution/Monitor.

              moxonidine increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • nabilone

              butalbital and nabilone both increase sedation. Use Caution/Monitor.

              codeine and nabilone both increase sedation. Use Caution/Monitor.

              nabilone increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • nadolol

              butalbital decreases levels of nadolol by increasing metabolism. Use Caution/Monitor. Consider a higher beta-blocker dose during coadministration of butalbital. Atenolol, sotalol, nadolol less likely to be affected than other beta blockers.

            • nalbuphine

              nalbuphine increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • nalbuphine

              codeine and nalbuphine both increase sedation. Use Caution/Monitor.

            • nalbuphine

              butalbital and nalbuphine both increase sedation. Use Caution/Monitor.

            • nateglinide

              butalbital will decrease the level or effect of nateglinide by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

            • nebivolol

              butalbital decreases levels of nebivolol by increasing metabolism. Use Caution/Monitor. Consider a higher beta-blocker dose during coadministration of butalbital. Atenolol, sotalol, nadolol less likely to be affected than other beta blockers.

            • nelfinavir

              butalbital will decrease the level or effect of nelfinavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • nicardipine

              butalbital will decrease the level or effect of nicardipine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • nilotinib

              butalbital will decrease the level or effect of nilotinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • nisoldipine

              butalbital will decrease the level or effect of nisoldipine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • norepinephrine

              norepinephrine and caffeine both decrease sedation. Use Caution/Monitor.

              codeine increases and norepinephrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              butalbital increases and norepinephrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • nortriptyline

              butalbital and nortriptyline both increase sedation. Use Caution/Monitor.

              codeine and nortriptyline both increase sedation. Use Caution/Monitor.

              nortriptyline increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • olanzapine

              butalbital will decrease the level or effect of olanzapine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

              butalbital and olanzapine both increase sedation. Use Caution/Monitor.

              codeine and olanzapine both increase sedation. Use Caution/Monitor.

              olanzapine increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • oliceridine

              oliceridine, butalbital. Either increases toxicity of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.

              butalbital will decrease the level or effect of oliceridine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. If coadministration with a CYP3A4 inducer is necessary, consider increasing oliceridine dose until stable drug effects are achieved; monitor for signs of opioid withdrawal. If inducer is discontinued, consider oliceridine dosage reduction and monitor for signs of respiratory depression.

              oliceridine, codeine. Either increases toxicity of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.

            • opium tincture

              opium tincture increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • omeprazole

              butalbital will decrease the level or effect of omeprazole by affecting hepatic enzyme CYP2C19 metabolism. Use Caution/Monitor.

            • opium tincture

              codeine and opium tincture both increase sedation. Use Caution/Monitor.

            • opium tincture

              butalbital and opium tincture both increase sedation. Use Caution/Monitor.

            • orphenadrine

              orphenadrine and codeine both increase sedation. Use Caution/Monitor.

              butalbital and orphenadrine both increase sedation. Use Caution/Monitor.

            • osilodrostat

              butalbital will decrease the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Monitor cortisol concentration and patient?s signs and symptoms during coadministration or discontinuation with strong CYP3A4 inducers. Adjust dose of osilodrostat if necessary.

            • oxazepam

              oxazepam and codeine both increase sedation. Use Caution/Monitor.

              oxazepam increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • oxazepam

              butalbital and oxazepam both increase sedation. Use Caution/Monitor.

            • oxycodone

              oxycodone increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • oxycodone

              codeine and oxycodone both increase sedation. Use Caution/Monitor.

              butalbital and oxycodone both increase sedation. Use Caution/Monitor.

            • oxymorphone

              oxymorphone increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              butalbital and oxymorphone both increase sedation. Use Caution/Monitor.

              codeine and oxymorphone both increase sedation. Use Caution/Monitor.

            • paliperidone

              butalbital and paliperidone both increase sedation. Use Caution/Monitor.

              codeine and paliperidone both increase sedation. Use Caution/Monitor.

              paliperidone increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • papaveretum

              butalbital and papaveretum both increase sedation. Use Caution/Monitor.

              codeine and papaveretum both increase sedation. Use Caution/Monitor.

              papaveretum increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • papaverine

              butalbital and papaverine both increase sedation. Use Caution/Monitor.

              codeine and papaverine both increase sedation. Use Caution/Monitor.

            • pefloxacin

              pefloxacin will increase the level or effect of caffeine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

            • parecoxib

              butalbital will decrease the level or effect of parecoxib by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

            • paroxetine

              paroxetine will decrease the level or effect of codeine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Prevents conversion of codeine to its active metabolite morphine.

            • passion flower

              passion flower increases effects of butalbital by pharmacodynamic synergism. Use Caution/Monitor. May enhance CNS depression.

            • pazopanib

              butalbital will decrease the level or effect of pazopanib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • peginterferon alfa 2b

              peginterferon alfa 2b, codeine. Other (see comment). Use Caution/Monitor. Comment: When patients are administered peginterferon alpha-2b with CYP2D6 substrates, the therapeutic effect of these drugs may be altered. Peginterferon alpha-2b may increase or decrease levels of CYP2D6 substrate.

            • pegvisomant

              codeine decreases effects of pegvisomant by unknown mechanism. Use Caution/Monitor.

            • penbutolol

              butalbital decreases levels of penbutolol by increasing metabolism. Use Caution/Monitor. Consider a higher beta-blocker dose during coadministration of butalbital. Atenolol, sotalol, nadolol less likely to be affected than other beta blockers.

            • pentazocine

              codeine and pentazocine both increase sedation. Use Caution/Monitor.

              butalbital and pentazocine both increase sedation. Use Caution/Monitor.

              pentazocine increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • pentobarbital

              butalbital and pentobarbital both increase sedation. Use Caution/Monitor.

              pentobarbital increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              pentobarbital and codeine both increase sedation. Use Caution/Monitor.

            • perampanel

              perampanel and codeine both increase sedation. Use Caution/Monitor.

            • perphenazine

              perphenazine increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • perphenazine

              butalbital and perphenazine both increase sedation. Use Caution/Monitor.

            • perphenazine

              codeine and perphenazine both increase sedation. Use Caution/Monitor.

            • phendimetrazine

              caffeine and phendimetrazine both decrease sedation. Use Caution/Monitor.

              codeine increases and phendimetrazine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              butalbital increases and phendimetrazine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • phenobarbital

              phenobarbital and codeine both increase sedation. Use Caution/Monitor.

              butalbital and phenobarbital both increase sedation. Use Caution/Monitor.

              phenobarbital increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • phentermine

              butalbital increases and phentermine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              codeine increases and phentermine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              caffeine and phentermine both decrease sedation. Use Caution/Monitor.

            • phenylephrine

              butalbital increases and phenylephrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              codeine increases and phenylephrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              caffeine and phenylephrine both decrease sedation. Use Caution/Monitor.

            • phenylephrine PO

              codeine increases and phenylephrine PO decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor. .

              caffeine and phenylephrine PO both decrease sedation. Use Caution/Monitor.

              butalbital increases and phenylephrine PO decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor. .

            • phenytoin

              butalbital will decrease the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

            • pholcodine

              pholcodine increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • pholcodine

              codeine and pholcodine both increase sedation. Use Caution/Monitor.

            • pholcodine

              butalbital and pholcodine both increase sedation. Use Caution/Monitor.

            • pimozide

              codeine and pimozide both increase sedation. Use Caution/Monitor.

              butalbital and pimozide both increase sedation. Use Caution/Monitor.

              pimozide increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • pindolol

              butalbital decreases levels of pindolol by increasing metabolism. Use Caution/Monitor. Consider a higher beta-blocker dose during coadministration of butalbital. Atenolol, sotalol, nadolol less likely to be affected than other beta blockers.

            • pirbuterol

              pirbuterol and caffeine both decrease sedation. Use Caution/Monitor.

            • pirbuterol

              codeine increases and pirbuterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • pirbuterol

              butalbital increases and pirbuterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • pitolisant

              butalbital will decrease the level or effect of pitolisant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Pitolisant exposure is decreased by 50% if coadministered with strong CYP3A4 inducers. For patients stable on pitolisant 8.9 mg/day or 17.8 mg/day, double the pitolisant dose (ie, 17.8 mg or 35.6 mg, respectively) over 7 days. If the strong CYP3A4 inducer is discontinued, reduce pitolisant dosage by half.

            • polatuzumab vedotin

              butalbital will decrease the level or effect of polatuzumab vedotin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Polatuzumab undergoes catabolism to small peptides, amino acids, monomethyl auristatin E (MMAE), and unconjugated MMAE-related catabolites. MMAE is a CYP3A4 substrate. Coadministration of polatuzumab vedotin with a strong CYP3A4 inducer may decrease unconjugated MMAE AUC.

            • prednisolone

              butalbital will decrease the level or effect of prednisolone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • prednisone

              butalbital will decrease the level or effect of prednisone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • pregabalin

              pregabalin, codeine. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Coadministration of CNS depressants can result in serious, life-threatening, and fatal respiratory depression. Use lowest dose possible and monitor for respiratory depression and sedation.

              pregabalin, butalbital. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Coadministration of CNS depressants can result in serious, life-threatening, and fatal respiratory depression. Use lowest dose possible and monitor for respiratory depression and sedation.

            • primidone

              primidone increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              primidone and codeine both increase sedation. Use Caution/Monitor.

              butalbital and primidone both increase sedation. Use Caution/Monitor.

            • prochlorperazine

              butalbital and prochlorperazine both increase sedation. Use Caution/Monitor.

              codeine and prochlorperazine both increase sedation. Use Caution/Monitor.

              prochlorperazine increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • promethazine

              promethazine increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              promethazine and butalbital both increase sedation. Use Caution/Monitor.

              promethazine and codeine both increase sedation. Use Caution/Monitor.

            • propafenone

              butalbital decreases levels of propafenone by increasing metabolism. Use Caution/Monitor.

            • propylhexedrine

              caffeine and propylhexedrine both decrease sedation. Use Caution/Monitor.

            • propofol

              propofol and codeine both increase sedation. Use Caution/Monitor.

            • propofol

              propofol and butalbital both increase sedation. Use Caution/Monitor.

            • propranolol

              butalbital decreases levels of propranolol by increasing metabolism. Use Caution/Monitor. Consider a higher beta-blocker dose during coadministration of butalbital. Atenolol, sotalol, nadolol less likely to be affected than other beta blockers.

            • propylhexedrine

              codeine increases and propylhexedrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              butalbital increases and propylhexedrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • protriptyline

              butalbital and protriptyline both increase sedation. Use Caution/Monitor.

              codeine and protriptyline both increase sedation. Use Caution/Monitor.

              protriptyline increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • quazepam

              quazepam and codeine both increase sedation. Use Caution/Monitor.

              butalbital and quazepam both increase sedation. Use Caution/Monitor.

              quazepam increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • quetiapine

              butalbital and quetiapine both increase sedation. Use Caution/Monitor.

              codeine and quetiapine both increase sedation. Use Caution/Monitor.

              quetiapine increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              butalbital will decrease the level or effect of quetiapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • quinidine

              quinidine will decrease the level or effect of codeine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Prevents conversion of codeine to its active metabolite morphine.

              butalbital will decrease the level or effect of quinidine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • rasagiline

              rasagiline increases effects of caffeine by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Risk of acute hypertensive episode.

            • ramelteon

              butalbital and ramelteon both increase sedation. Use Caution/Monitor.

              codeine and ramelteon both increase sedation. Use Caution/Monitor.

              butalbital will decrease the level or effect of ramelteon by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

            • remimazolam

              remimazolam, codeine. Either increases toxicity of the other by sedation. Modify Therapy/Monitor Closely. Coadministration may result in profound sedation, respiratory depression, coma, and/or death. Continuously monitor vital signs during sedation and recovery period if coadministered. Carefully titrate remimazolam dose if administered with opioid analgesics and/or sedative/hypnotics.

              remimazolam, butalbital. Either increases toxicity of the other by sedation. Modify Therapy/Monitor Closely. Coadministration may result in profound sedation, respiratory depression, coma, and/or death. Continuously monitor vital signs during sedation and recovery period if coadministered. Carefully titrate remimazolam dose if administered with opioid analgesics and/or sedative/hypnotics.

            • repaglinide

              butalbital will decrease the level or effect of repaglinide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • ribociclib

              ribociclib will increase the level or effect of codeine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • rifampin

              rifampin decreases levels of butalbital by increasing metabolism. Use Caution/Monitor.

            • risperidone

              codeine and risperidone both increase sedation. Use Caution/Monitor.

              butalbital and risperidone both increase sedation. Use Caution/Monitor.

              risperidone increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • ritonavir

              ritonavir will decrease the level or effect of codeine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Prevents conversion of codeine to its active metabolite morphine.

              butalbital will decrease the level or effect of ritonavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • rucaparib

              rucaparib will increase the level or effect of caffeine by affecting hepatic enzyme CYP1A2 metabolism. Modify Therapy/Monitor Closely. Adjust dosage of CYP1A2 substrates, if clinically indicated.

            • rolapitant

              rolapitant will increase the level or effect of codeine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Rolapitant may increase plasma concentrations of CYP2D6 substrates for at least 28 days following rolapitant administration.

            • salmeterol

              butalbital increases and salmeterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              salmeterol and caffeine both decrease sedation. Use Caution/Monitor.

            • salmeterol

              codeine increases and salmeterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • scullcap

              scullcap increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • saquinavir

              butalbital will decrease the level or effect of saquinavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • scullcap

              codeine and scullcap both increase sedation. Use Caution/Monitor.

              butalbital and scullcap both increase sedation. Use Caution/Monitor.

            • secobarbital

              secobarbital increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              butalbital and secobarbital both increase sedation. Use Caution/Monitor.

              secobarbital and codeine both increase sedation. Use Caution/Monitor.

            • selegiline

              selegiline increases effects of caffeine by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Risk of acute hypertensive episode.

              selegiline increases toxicity of codeine by unknown mechanism. Modify Therapy/Monitor Closely. Potential for increased CNS depression, drowsiness, dizziness or hypotension, so use with any MAOI should be cautious.

            • shepherd's purse

              butalbital and shepherd's purse both increase sedation. Use Caution/Monitor.

              shepherd's purse increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • sertraline

              sertraline decreases effects of codeine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Prevents conversion of codeine to its active metabolite morphine.

            • solriamfetol

              caffeine and solriamfetol both increase sympathetic (adrenergic) effects, including increased blood pressure and heart rate. Use Caution/Monitor.

            • sevoflurane

              sevoflurane and codeine both increase sedation. Use Caution/Monitor.

            • shepherd's purse

              codeine and shepherd's purse both increase sedation. Use Caution/Monitor.

            • sildenafil

              butalbital will decrease the level or effect of sildenafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • solifenacin

              butalbital will decrease the level or effect of solifenacin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • sorafenib

              butalbital decreases levels of sorafenib by increasing metabolism. Use Caution/Monitor.

            • sotalol

              butalbital decreases levels of sotalol by increasing metabolism. Use Caution/Monitor. Consider a higher beta-blocker dose during coadministration of butalbital. Atenolol, sotalol, nadolol less likely to be affected than other beta blockers.

            • stiripentol

              stiripentol, codeine. Either increases effects of the other by sedation. Use Caution/Monitor. Concomitant use stiripentol with other CNS depressants, including alcohol, may increase the risk of sedation and somnolence.

              stiripentol, caffeine. affecting hepatic enzyme CYP1A2 metabolism. Modify Therapy/Monitor Closely. Stiripentol is a CYP1A2 inhibitor and inducer. Monitor CYP1A2 substrates coadministered with stiripentol for increased or decreased effects. CYP1A2 substrates may require dosage adjustment.

            • sufentanil

              codeine and sufentanil both increase sedation. Use Caution/Monitor.

              butalbital and sufentanil both increase sedation. Use Caution/Monitor.

              sufentanil increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • sufentanil SL

              butalbital decreases effects of sufentanil SL by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Coadministration of CYP3A4 inducers may decrease sufentanil levels and efficacy, possibly precipitating withdrawal syndrome in patients who have developed physical dependence to sufentanil. Discontinuation of concomitantly used CYP3A4 inducers may increase sufentanil plasma concentration.

            • tapentadol

              tapentadol increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • suvorexant

              suvorexant and codeine both increase sedation. Modify Therapy/Monitor Closely. Dosage adjustments of suvorexant and concomitant CNS depressants may be necessary

            • sunitinib

              butalbital will decrease the level or effect of sunitinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • tacrolimus

              butalbital will decrease the level or effect of tacrolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • tadalafil

              butalbital will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • tapentadol

              codeine and tapentadol both increase sedation. Use Caution/Monitor.

              butalbital and tapentadol both increase sedation. Use Caution/Monitor.

            • tazemetostat

              acetaminophen will increase the level or effect of tazemetostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • temazepam

              temazepam increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              butalbital and temazepam both increase sedation. Use Caution/Monitor.

              temazepam and codeine both increase sedation. Use Caution/Monitor.

            • temsirolimus

              butalbital will decrease the level or effect of temsirolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • terbutaline

              terbutaline and caffeine both decrease sedation. Use Caution/Monitor.

            • terbinafine

              terbinafine will increase the level or effect of codeine by affecting hepatic enzyme CYP2D6 metabolism. Modify Therapy/Monitor Closely. Assess need to reduce dose of CYP2D6-metabolized drug.

            • terbinafine

              butalbital will decrease the level or effect of terbinafine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • terbutaline

              codeine increases and terbutaline decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              butalbital increases and terbutaline decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • teriflunomide

              teriflunomide decreases levels of caffeine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

            • tetracaine

              tetracaine, acetaminophen. Other (see comment). Use Caution/Monitor. Comment: Monitor for signs of methemoglobinemia when methemoglobin-inducing drugs are coadministered.

            • thalidomide

              thalidomide increases effects of butalbital by unspecified interaction mechanism. Use Caution/Monitor. Increased sedative effects.

            • thioridazine

              thioridazine decreases effects of codeine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Prevents conversion of codeine to its active metabolite morphine.

              codeine and thioridazine both increase sedation. Use Caution/Monitor.

              thioridazine increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • theophylline

              butalbital will decrease the level or effect of theophylline by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

              butalbital will decrease the level or effect of theophylline by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • thiothixene

              thiothixene increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • thioridazine

              butalbital and thioridazine both increase sedation. Use Caution/Monitor.

            • thiothixene

              codeine and thiothixene both increase sedation. Use Caution/Monitor.

              butalbital and thiothixene both increase sedation. Use Caution/Monitor.

            • ticlopidine

              ticlopidine decreases effects of codeine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Prevents conversion of codeine to its active metabolite morphine.

            • timolol

              butalbital decreases levels of timolol by increasing metabolism. Use Caution/Monitor. Consider a higher beta-blocker dose during coadministration of butalbital. Atenolol, sotalol, nadolol less likely to be affected than other beta blockers.

            • tinidazole

              butalbital will decrease the level or effect of tinidazole by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              acetaminophen will increase the level or effect of tinidazole by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • tipranavir

              butalbital will decrease the level or effect of tipranavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • warfarin

              acetaminophen increases effects of warfarin by unknown mechanism. Use Caution/Monitor.

            Minor (204)

            • acetazolamide

              acetazolamide decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

              acetazolamide, butalbital. Mechanism: pharmacodynamic synergism. Minor/Significance Unknown. Increased risk of anticonvulsant induced osteomalacia.

            • adenosine

              caffeine decreases effects of adenosine by pharmacodynamic antagonism. Minor/Significance Unknown.

            • albiglutide

              albiglutide decreases levels of acetaminophen by unspecified interaction mechanism. Minor/Significance Unknown.

            • alfentanil

              butalbital will decrease the level or effect of alfentanil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • alfuzosin

              butalbital will decrease the level or effect of alfuzosin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • alosetron

              butalbital will decrease the level or effect of alosetron by affecting hepatic enzyme CYP2C9/10 metabolism. Minor/Significance Unknown.

              butalbital will decrease the level or effect of alosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • amantadine

              amantadine, caffeine. Either increases effects of the other by pharmacodynamic synergism. Minor/Significance Unknown. Potential for additive CNS stimulation.

            • American ginseng

              American ginseng increases effects of caffeine by pharmacodynamic synergism. Minor/Significance Unknown.

            • amitriptyline

              butalbital, amitriptyline. Other (see comment). Minor/Significance Unknown. Comment: Barbiturates may increase adverse effects, including respiratory depression, produced by toxic doses of TCAs. With therapeutic doses of TCAs, barbiturates increase metabolism and decrease blood concentrations of TCAs.

            • amobarbital

              amobarbital will decrease the level or effect of caffeine by affecting hepatic enzyme CYP1A2 metabolism. Minor/Significance Unknown.

            • amoxapine

              butalbital, amoxapine. Other (see comment). Minor/Significance Unknown. Comment: Barbiturates may increase adverse effects, including respiratory depression, produced by toxic doses of TCAs. With therapeutic doses of TCAs, barbiturates increase metabolism and decrease blood concentrations of TCAs.

            • amphotericin B deoxycholate

              butalbital decreases levels of amphotericin B deoxycholate by inhibition of GI absorption. Applies only to oral form of both agents. Minor/Significance Unknown.

            • antipyrine

              butalbital will decrease the level or effect of antipyrine by affecting hepatic enzyme CYP1A2 metabolism. Minor/Significance Unknown.

            • antithrombin alfa

              acetaminophen increases effects of antithrombin alfa by unknown mechanism. Minor/Significance Unknown.

            • antithrombin III

              acetaminophen increases effects of antithrombin III by unknown mechanism. Minor/Significance Unknown.

            • argatroban

              acetaminophen increases effects of argatroban by unknown mechanism. Minor/Significance Unknown.

            • armodafinil

              butalbital will decrease the level or effect of armodafinil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              armodafinil will decrease the level or effect of caffeine by affecting hepatic enzyme CYP1A2 metabolism. Minor/Significance Unknown.

            • ascorbic acid

              butalbital decreases levels of ascorbic acid by increasing elimination. Minor/Significance Unknown.

            • bemiparin

              acetaminophen increases effects of bemiparin by unknown mechanism. Minor/Significance Unknown.

            • bivalirudin

              acetaminophen increases effects of bivalirudin by unknown mechanism. Minor/Significance Unknown.

            • butabarbital

              butabarbital will decrease the level or effect of caffeine by affecting hepatic enzyme CYP1A2 metabolism. Minor/Significance Unknown.

            • asenapine

              butalbital will decrease the level or effect of asenapine by affecting hepatic enzyme CYP1A2 metabolism. Minor/Significance Unknown.

              asenapine will increase the level or effect of codeine by affecting hepatic enzyme CYP2D6 metabolism. Minor/Significance Unknown.

            • ashwagandha

              ashwagandha increases effects of butalbital by pharmacodynamic synergism. Minor/Significance Unknown. May enhance CNS depression.

            • brimonidine

              brimonidine increases effects of codeine by pharmacodynamic synergism. Minor/Significance Unknown. Increased CNS depression.

            • atazanavir

              butalbital will decrease the level or effect of atazanavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • bosentan

              butalbital will decrease the level or effect of bosentan by affecting hepatic enzyme CYP2C9/10 metabolism. Minor/Significance Unknown.

              butalbital will decrease the level or effect of bosentan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • brimonidine

              brimonidine increases effects of butalbital by pharmacodynamic synergism. Minor/Significance Unknown. Increased CNS depression.

            • brinzolamide

              brinzolamide, butalbital. Mechanism: pharmacodynamic synergism. Minor/Significance Unknown. Increased risk of anticonvulsant induced osteomalacia.

            • buprenorphine subdermal implant

              butalbital will decrease the level or effect of buprenorphine subdermal implant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown. Monitor patients already on buprenorphine subdermal implant who require newly-initiated treatment with CYP3A4 inducer for signs and symptoms of withdrawal. If the dose of the concomitant CYP3A4 inhibitor cannot be reduced or discontinued, implant removal may be necessary and the patient should then be treated with a buprenorphine dosage form that permits dose adjustments. If a CYP3A4 inducer is discontinued in a patient who has been stabilized on buprenorphine, monitor the patient for overmedication.

            • butalbital

              butalbital will decrease the level or effect of caffeine by affecting hepatic enzyme CYP1A2 metabolism. Minor/Significance Unknown.

            • caffeine

              butalbital will decrease the level or effect of caffeine by affecting hepatic enzyme CYP1A2 metabolism. Minor/Significance Unknown.

            • calcium acetate

              caffeine decreases levels of calcium acetate by increasing renal clearance. Minor/Significance Unknown.

            • calcium carbonate

              caffeine decreases levels of calcium carbonate by increasing renal clearance. Minor/Significance Unknown.

            • calcium chloride

              caffeine decreases levels of calcium chloride by increasing renal clearance. Minor/Significance Unknown.

            • calcium citrate

              caffeine decreases levels of calcium citrate by increasing renal clearance. Minor/Significance Unknown.

            • calcium gluconate

              caffeine decreases levels of calcium gluconate by increasing renal clearance. Minor/Significance Unknown.

            • carbamazepine

              carbamazepine will decrease the level or effect of caffeine by affecting hepatic enzyme CYP1A2 metabolism. Minor/Significance Unknown.

              carbamazepine decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

            • celecoxib

              butalbital will decrease the level or effect of celecoxib by affecting hepatic enzyme CYP2C9/10 metabolism. Minor/Significance Unknown.

            • cholestyramine

              cholestyramine decreases levels of acetaminophen by inhibition of GI absorption. Applies only to oral form of both agents. Minor/Significance Unknown.

            • cevimeline

              butalbital will decrease the level or effect of cevimeline by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • chloramphenicol

              chloramphenicol increases levels of butalbital by decreasing metabolism. Minor/Significance Unknown.

              butalbital decreases levels of chloramphenicol by increasing metabolism. Minor/Significance Unknown.

            • chlorpromazine

              butalbital decreases levels of chlorpromazine by increasing metabolism. Minor/Significance Unknown.

            • cigarette smoking

              cigarette smoking will decrease the level or effect of caffeine by affecting hepatic enzyme CYP1A2 metabolism. Minor/Significance Unknown.

            • cimetidine

              cimetidine will increase the level or effect of caffeine by affecting hepatic enzyme CYP1A2 metabolism. Minor/Significance Unknown.

              butalbital will decrease the level or effect of cimetidine by affecting hepatic enzyme CYP2C19 metabolism. Minor/Significance Unknown.

            • clarithromycin

              butalbital will decrease the level or effect of clarithromycin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              butalbital decreases levels of clarithromycin by increasing elimination. Minor/Significance Unknown.

            • clonazepam

              clonazepam decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

            • clotrimazole

              clotrimazole increases levels of caffeine by decreasing metabolism. Minor/Significance Unknown.

            • clomipramine

              butalbital, clomipramine. Other (see comment). Minor/Significance Unknown. Comment: Barbiturates may increase adverse effects, including respiratory depression, produced by toxic doses of TCAs. With therapeutic doses of TCAs, barbiturates increase metabolism and decrease blood concentrations of TCAs.

            • clotrimazole

              butalbital decreases levels of clotrimazole by inhibition of GI absorption. Applies only to oral form of both agents. Minor/Significance Unknown.

            • cocaine

              butalbital will decrease the level or effect of cocaine by affecting hepatic enzyme CYP2B6 metabolism. Minor/Significance Unknown.

            • colestipol

              colestipol decreases levels of acetaminophen by inhibition of GI absorption. Applies only to oral form of both agents. Minor/Significance Unknown.

            • dalteparin

              acetaminophen increases effects of dalteparin by unknown mechanism. Minor/Significance Unknown.

            • dapsone

              butalbital will decrease the level or effect of dapsone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • desipramine

              butalbital, desipramine. Other (see comment). Minor/Significance Unknown. Comment: Barbiturates may increase adverse effects, including respiratory depression, produced by toxic doses of TCAs. With therapeutic doses of TCAs, barbiturates increase metabolism and decrease blood concentrations of TCAs.

            • dextroamphetamine

              dextroamphetamine increases effects of codeine by unspecified interaction mechanism. Minor/Significance Unknown.

            • diazepam

              diazepam decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

            • diclofenac

              butalbital will decrease the level or effect of diclofenac by affecting hepatic enzyme CYP2C9/10 metabolism. Minor/Significance Unknown.

            • disopyramide

              butalbital will decrease the level or effect of disopyramide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • disulfiram

              disulfiram will increase the level or effect of acetaminophen by affecting hepatic enzyme CYP2E1 metabolism. Minor/Significance Unknown.

            • docetaxel

              butalbital will decrease the level or effect of docetaxel by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • donepezil

              butalbital will decrease the level or effect of donepezil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • dosulepin

              butalbital, dosulepin. Other (see comment). Minor/Significance Unknown. Comment: Barbiturates may increase adverse effects, including respiratory depression, produced by toxic doses of TCAs. With therapeutic doses of TCAs, barbiturates increase metabolism and decrease blood concentrations of TCAs.

            • doxepin

              butalbital, doxepin. Other (see comment). Minor/Significance Unknown. Comment: Barbiturates may increase adverse effects, including respiratory depression, produced by toxic doses of TCAs. With therapeutic doses of TCAs, barbiturates increase metabolism and decrease blood concentrations of TCAs.

            • dutasteride

              butalbital will decrease the level or effect of dutasteride by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • efavirenz

              butalbital will decrease the level or effect of efavirenz by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • enoxaparin

              acetaminophen increases effects of enoxaparin by unknown mechanism. Minor/Significance Unknown.

            • eplerenone

              butalbital will decrease the level or effect of eplerenone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • erythromycin base

              erythromycin base will increase the level or effect of caffeine by affecting hepatic enzyme CYP1A2 metabolism. Minor/Significance Unknown.

              butalbital decreases levels of erythromycin base by increasing elimination. Minor/Significance Unknown.

            • erythromycin ethylsuccinate

              butalbital decreases levels of erythromycin ethylsuccinate by increasing elimination. Minor/Significance Unknown.

              erythromycin ethylsuccinate will increase the level or effect of caffeine by affecting hepatic enzyme CYP1A2 metabolism. Minor/Significance Unknown.

            • erythromycin lactobionate

              butalbital decreases levels of erythromycin lactobionate by increasing elimination. Minor/Significance Unknown.

              erythromycin lactobionate will increase the level or effect of caffeine by affecting hepatic enzyme CYP1A2 metabolism. Minor/Significance Unknown.

            • erythromycin stearate

              butalbital decreases levels of erythromycin stearate by increasing elimination. Minor/Significance Unknown.

              erythromycin stearate will increase the level or effect of caffeine by affecting hepatic enzyme CYP1A2 metabolism. Minor/Significance Unknown.

            • ethanol

              ethanol will decrease the level or effect of acetaminophen by affecting hepatic enzyme CYP2E1 metabolism. Minor/Significance Unknown.

              ethanol increases toxicity of acetaminophen by decreasing metabolism. Minor/Significance Unknown.

            • ethosuximide

              ethosuximide decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

              ethosuximide decreases effects of butalbital by pharmacodynamic antagonism. Minor/Significance Unknown.

            • eucalyptus

              eucalyptus increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Minor/Significance Unknown.

            • felbamate

              felbamate decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

            • eucalyptus

              butalbital will decrease the level or effect of eucalyptus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              codeine and eucalyptus both increase sedation. Minor/Significance Unknown.

              butalbital and eucalyptus both increase sedation. Minor/Significance Unknown.

            • finasteride

              butalbital will decrease the level or effect of finasteride by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • fluconazole

              fluconazole increases levels of caffeine by decreasing metabolism. Minor/Significance Unknown.

            • fluoxetine

              fluoxetine decreases effects of codeine by decreasing metabolism. Minor/Significance Unknown. Decreased conversion of codeine to active metabolite morphine.

            • fluconazole

              butalbital decreases levels of fluconazole by inhibition of GI absorption. Applies only to oral form of both agents. Minor/Significance Unknown.

            • flurbiprofen

              butalbital will decrease the level or effect of flurbiprofen by affecting hepatic enzyme CYP2C9/10 metabolism. Minor/Significance Unknown.

            • fondaparinux

              acetaminophen increases effects of fondaparinux by unknown mechanism. Minor/Significance Unknown.

            • fosphenytoin

              fosphenytoin decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

            • frovatriptan

              butalbital will decrease the level or effect of frovatriptan by affecting hepatic enzyme CYP1A2 metabolism. Minor/Significance Unknown.

            • gabapentin

              gabapentin decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

            • gabapentin enacarbil

              gabapentin enacarbil decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

            • galantamine

              butalbital will decrease the level or effect of galantamine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • grapefruit

              grapefruit increases levels of caffeine by decreasing metabolism. Minor/Significance Unknown.

            • green tea

              green tea increases effects of acetaminophen by pharmacodynamic synergism. Minor/Significance Unknown. (Theoretical, due to caffeine content).

            • griseofulvin

              butalbital decreases levels of griseofulvin by inhibition of GI absorption. Applies only to oral form of both agents. Minor/Significance Unknown.

            • guarana

              guarana increases effects of caffeine by pharmacodynamic synergism. Minor/Significance Unknown.

            • haloperidol

              haloperidol, butalbital. Mechanism: pharmacodynamic synergism. Minor/Significance Unknown. Risk of hyperthermia if haloperidol admin. during barbiturate withdrawal.

            • heparin

              acetaminophen increases effects of heparin by unknown mechanism. Minor/Significance Unknown.

            • ibuprofen

              butalbital will decrease the level or effect of ibuprofen by affecting hepatic enzyme CYP2C9/10 metabolism. Minor/Significance Unknown.

            • ibuprofen IV

              butalbital will decrease the level or effect of ibuprofen IV by affecting hepatic enzyme CYP2C9/10 metabolism. Minor/Significance Unknown.

            • imatinib

              imatinib decreases effects of codeine by decreasing metabolism. Minor/Significance Unknown. Decreased conversion of codeine to active metabolite morphine.

              butalbital will decrease the level or effect of imatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              imatinib will increase the level or effect of codeine by affecting hepatic enzyme CYP2D6 metabolism. Minor/Significance Unknown.

            • imipramine

              butalbital, imipramine. Other (see comment). Minor/Significance Unknown. Comment: Barbiturates may increase adverse effects, including respiratory depression, produced by toxic doses of TCAs. With therapeutic doses of TCAs, barbiturates increase metabolism and decrease blood concentrations of TCAs.

            • isoniazid

              isoniazid will increase the level or effect of caffeine by affecting hepatic enzyme CYP1A2 metabolism. Minor/Significance Unknown.

              isoniazid increases toxicity of acetaminophen by unknown mechanism. Minor/Significance Unknown.

            • itraconazole

              itraconazole increases levels of caffeine by decreasing metabolism. Minor/Significance Unknown.

            • lacosamide

              lacosamide decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

            • ketoconazole

              ketoconazole increases levels of caffeine by decreasing metabolism. Minor/Significance Unknown.

            • lamotrigine

              lamotrigine decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

            • levetiracetam

              levetiracetam decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

            • lidocaine

              lidocaine increases toxicity of codeine by pharmacodynamic synergism. Minor/Significance Unknown. Risk of increased CNS depression.

            • isocarboxazid

              isocarboxazid increases levels of butalbital by decreasing metabolism. Minor/Significance Unknown. Theoretical interaction.

            • isradipine

              butalbital will decrease the level or effect of isradipine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • ketoconazole

              butalbital will decrease the level or effect of ketoconazole by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              butalbital decreases levels of ketoconazole by inhibition of GI absorption. Applies only to oral form of both agents. Minor/Significance Unknown.

            • lansoprazole

              butalbital will decrease the level or effect of lansoprazole by affecting hepatic enzyme CYP2C19 metabolism. Minor/Significance Unknown.

            • levothyroxine

              butalbital decreases levels of levothyroxine by increasing metabolism. Minor/Significance Unknown.

            • linezolid

              linezolid increases levels of butalbital by decreasing metabolism. Minor/Significance Unknown. Theoretical interaction.

            • liothyronine

              butalbital decreases levels of liothyronine by increasing metabolism. Minor/Significance Unknown.

            • liraglutide

              liraglutide decreases levels of acetaminophen by unspecified interaction mechanism. Minor/Significance Unknown.

            • lofepramine

              butalbital, lofepramine. Other (see comment). Minor/Significance Unknown. Comment: Barbiturates may increase adverse effects, including respiratory depression, produced by toxic doses of TCAs. With therapeutic doses of TCAs, barbiturates increase metabolism and decrease blood concentrations of TCAs.

            • lorazepam

              lorazepam decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

            • losartan

              butalbital will decrease the level or effect of losartan by affecting hepatic enzyme CYP2C9/10 metabolism. Minor/Significance Unknown.

            • maprotiline

              butalbital, maprotiline. Other (see comment). Minor/Significance Unknown. Comment: Barbiturates may increase adverse effects, including respiratory depression, produced by toxic doses of TCAs. With therapeutic doses of TCAs, barbiturates increase metabolism and decrease blood concentrations of TCAs.

            • maraviroc

              maraviroc will increase the level or effect of codeine by affecting hepatic enzyme CYP2D6 metabolism. Minor/Significance Unknown.

            • marijuana

              marijuana will increase the level or effect of codeine by affecting hepatic enzyme CYP2D6 metabolism. Minor/Significance Unknown.

            • meloxicam

              butalbital will decrease the level or effect of meloxicam by affecting hepatic enzyme CYP2C9/10 metabolism. Minor/Significance Unknown.

            • methazolamide

              methazolamide, butalbital. Mechanism: pharmacodynamic synergism. Minor/Significance Unknown. Increased risk of anticonvulsant induced osteomalacia.

            • methsuximide

              methsuximide decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

              methsuximide decreases effects of butalbital by pharmacodynamic antagonism. Minor/Significance Unknown.

            • metoclopramide

              metoclopramide increases levels of acetaminophen by enhancing GI absorption. Applies only to oral form of both agents. Minor/Significance Unknown.

            • mexiletine

              mexiletine will increase the level or effect of caffeine by affecting hepatic enzyme CYP1A2 metabolism. Minor/Significance Unknown.

            • metronidazole

              metronidazole will increase the level or effect of acetaminophen by affecting hepatic enzyme CYP2E1 metabolism. Minor/Significance Unknown.

            • miconazole vaginal

              butalbital decreases levels of miconazole vaginal by inhibition of GI absorption. Applies only to oral form of both agents. Minor/Significance Unknown.

              miconazole vaginal increases levels of caffeine by decreasing metabolism. Minor/Significance Unknown.

            • modafinil

              modafinil will decrease the level or effect of caffeine by affecting hepatic enzyme CYP1A2 metabolism. Minor/Significance Unknown.

            • montelukast

              butalbital will decrease the level or effect of montelukast by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • nettle

              nettle increases effects of butalbital by pharmacodynamic synergism. Minor/Significance Unknown. (High dose nettle; theoretical interaction) May enhance CNS depression.

            • nifedipine

              butalbital will decrease the level or effect of nifedipine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • nilotinib

              nilotinib will increase the level or effect of codeine by affecting hepatic enzyme CYP2D6 metabolism. Minor/Significance Unknown.

            • nimodipine

              butalbital will decrease the level or effect of nimodipine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • nitrendipine

              butalbital will decrease the level or effect of nitrendipine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • nortriptyline

              butalbital, nortriptyline. Other (see comment). Minor/Significance Unknown. Comment: Barbiturates may increase adverse effects, including respiratory depression, produced by toxic doses of TCAs. With therapeutic doses of TCAs, barbiturates increase metabolism and decrease blood concentrations of TCAs.

            • oxcarbazepine

              oxcarbazepine decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

            • oxybutynin

              oxybutynin decreases levels of acetaminophen by unspecified interaction mechanism. Minor/Significance Unknown.

              butalbital will decrease the level or effect of oxybutynin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • oxybutynin topical

              oxybutynin topical decreases levels of acetaminophen by unspecified interaction mechanism. Minor/Significance Unknown.

            • paclitaxel

              butalbital will decrease the level or effect of paclitaxel by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • oxybutynin transdermal

              oxybutynin transdermal decreases levels of acetaminophen by unspecified interaction mechanism. Minor/Significance Unknown.

            • paclitaxel protein bound

              butalbital will decrease the level or effect of paclitaxel protein bound by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • parecoxib

              parecoxib will increase the level or effect of codeine by affecting hepatic enzyme CYP2D6 metabolism. Minor/Significance Unknown.

              butalbital will decrease the level or effect of parecoxib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • peginterferon alfa 2a

              peginterferon alfa 2a will increase the level or effect of caffeine by affecting hepatic enzyme CYP1A2 metabolism. Minor/Significance Unknown.

            • pentobarbital

              pentobarbital will decrease the level or effect of caffeine by affecting hepatic enzyme CYP1A2 metabolism. Minor/Significance Unknown.

            • perphenazine

              perphenazine will increase the level or effect of codeine by affecting hepatic enzyme CYP2D6 metabolism. Minor/Significance Unknown.

              perphenazine decreases effects of codeine by decreasing metabolism. Minor/Significance Unknown. Decreased conversion of codeine to active metabolite morphine.

            • phenelzine

              phenelzine increases levels of butalbital by decreasing metabolism. Minor/Significance Unknown. Theoretical interaction.

            • phenindione

              acetaminophen increases effects of phenindione by unknown mechanism. Minor/Significance Unknown.

            • phenobarbital

              phenobarbital decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

              phenobarbital will decrease the level or effect of caffeine by affecting hepatic enzyme CYP1A2 metabolism. Minor/Significance Unknown.

            • phenytoin

              phenytoin decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

            • pimozide

              butalbital will decrease the level or effect of pimozide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • pioglitazone

              butalbital will decrease the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • pipemidic acid

              pipemidic acid will increase the level or effect of caffeine by affecting hepatic enzyme CYP1A2 metabolism. Minor/Significance Unknown.

            • piroxicam

              butalbital will decrease the level or effect of piroxicam by affecting hepatic enzyme CYP2C9/10 metabolism. Minor/Significance Unknown.

            • posaconazole

              butalbital decreases levels of posaconazole by inhibition of GI absorption. Applies only to oral form of both agents. Minor/Significance Unknown.

              posaconazole increases levels of caffeine by decreasing metabolism. Minor/Significance Unknown.

            • primidone

              primidone decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

              primidone will decrease the level or effect of caffeine by affecting hepatic enzyme CYP1A2 metabolism. Minor/Significance Unknown.

            • propafenone

              propafenone will increase the level or effect of codeine by affecting hepatic enzyme CYP2D6 metabolism. Minor/Significance Unknown.

              butalbital will decrease the level or effect of propafenone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              propafenone decreases effects of codeine by decreasing metabolism. Minor/Significance Unknown. Decreased conversion of codeine to active metabolite morphine.

            • protamine

              acetaminophen increases effects of protamine by unknown mechanism. Minor/Significance Unknown.

            • protriptyline

              butalbital, protriptyline. Other (see comment). Minor/Significance Unknown. Comment: Barbiturates may increase adverse effects, including respiratory depression, produced by toxic doses of TCAs. With therapeutic doses of TCAs, barbiturates increase metabolism and decrease blood concentrations of TCAs.

            • quinacrine

              quinacrine will increase the level or effect of codeine by affecting hepatic enzyme CYP2D6 metabolism. Minor/Significance Unknown.

              quinacrine decreases effects of codeine by decreasing metabolism. Minor/Significance Unknown. Decreased conversion of codeine to active metabolite morphine.

            • quinine

              butalbital will decrease the level or effect of quinine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • rabeprazole

              butalbital will decrease the level or effect of rabeprazole by affecting hepatic enzyme CYP2C19 metabolism. Minor/Significance Unknown.

              butalbital will decrease the level or effect of rabeprazole by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • ramelteon

              butalbital will decrease the level or effect of ramelteon by affecting hepatic enzyme CYP2C9/10 metabolism. Minor/Significance Unknown.

              butalbital will decrease the level or effect of ramelteon by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • ranolazine

              ranolazine will increase the level or effect of codeine by affecting hepatic enzyme CYP2D6 metabolism. Minor/Significance Unknown.

            • rifabutin

              rifabutin decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

            • rifampin

              rifampin will decrease the level or effect of caffeine by affecting hepatic enzyme CYP1A2 metabolism. Minor/Significance Unknown.

              rifampin decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

            • riluzole

              butalbital will decrease the level or effect of riluzole by affecting hepatic enzyme CYP1A2 metabolism. Minor/Significance Unknown.

            • rufinamide

              rufinamide decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

            • rose hips

              butalbital decreases levels of rose hips by increasing elimination. Minor/Significance Unknown.

            • ruxolitinib

              acetaminophen will increase the level or effect of ruxolitinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • sage

              sage increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Minor/Significance Unknown.

              codeine and sage both increase sedation. Minor/Significance Unknown.

              butalbital and sage both increase sedation. Minor/Significance Unknown.

            • saxagliptin

              butalbital will decrease the level or effect of saxagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • secobarbital

              secobarbital will decrease the level or effect of caffeine by affecting hepatic enzyme CYP1A2 metabolism. Minor/Significance Unknown.

            • sertraline

              sertraline decreases effects of codeine by decreasing metabolism. Minor/Significance Unknown. Decreased conversion of codeine to active metabolite morphine.

            • selegiline transdermal

              selegiline transdermal increases levels of butalbital by decreasing metabolism. Minor/Significance Unknown. Theoretical interaction.

            • Siberian ginseng

              Siberian ginseng increases effects of butalbital by pharmacodynamic synergism. Minor/Significance Unknown. May enhance CNS depression.

            • smoking

              smoking will decrease the level or effect of caffeine by affecting hepatic enzyme CYP1A2 metabolism. Minor/Significance Unknown.

            • sufentanil

              butalbital will decrease the level or effect of sufentanil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • sulfamethoxazole

              butalbital will decrease the level or effect of sulfamethoxazole by affecting hepatic enzyme CYP2C9/10 metabolism. Minor/Significance Unknown.

            • tamoxifen

              butalbital will decrease the level or effect of tamoxifen by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • thiamine

              caffeine decreases levels of thiamine by inhibition of GI absorption. Applies only to oral form of both agents. Minor/Significance Unknown. Coffee, tea are high in anti-thiamine factors.

            • thioridazine

              thioridazine decreases effects of codeine by decreasing metabolism. Minor/Significance Unknown. Decreased conversion of codeine to active metabolite morphine.

              thioridazine decreases levels of butalbital by unspecified interaction mechanism. Minor/Significance Unknown.

            • thyroid desiccated

              butalbital decreases levels of thyroid desiccated by increasing metabolism. Minor/Significance Unknown.

            • tiagabine

              tiagabine decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

            • tipranavir

              tipranavir will increase the level or effect of codeine by affecting hepatic enzyme CYP2D6 metabolism. Minor/Significance Unknown.

            • tibolone

              butalbital decreases levels of tibolone by increasing metabolism. Minor/Significance Unknown. Theoretical interaction.

            • tobacco use

              tobacco use will decrease the level or effect of caffeine by affecting hepatic enzyme CYP1A2 metabolism. Minor/Significance Unknown.

            • tolbutamide

              butalbital will decrease the level or effect of tolbutamide by affecting hepatic enzyme CYP2C9/10 metabolism. Minor/Significance Unknown.

            • topiramate

              topiramate decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

              butalbital decreases levels of topiramate by increasing metabolism. Minor/Significance Unknown.

            • tranylcypromine

              tranylcypromine increases levels of butalbital by decreasing metabolism. Minor/Significance Unknown. Theoretical interaction.

            • valproic acid

              valproic acid decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

            • trazodone

              butalbital, trazodone. Other (see comment). Minor/Significance Unknown. Comment: Barbiturates may increase adverse effects, including respiratory depression, produced by toxic doses of TCAs. With therapeutic doses of TCAs, barbiturates increase metabolism and decrease blood concentrations of TCAs.

            • trimipramine

              butalbital, trimipramine. Other (see comment). Minor/Significance Unknown. Comment: Barbiturates may increase adverse effects, including respiratory depression, produced by toxic doses of TCAs. With therapeutic doses of TCAs, barbiturates increase metabolism and decrease blood concentrations of TCAs.

            • venlafaxine

              venlafaxine decreases effects of codeine by decreasing metabolism. Minor/Significance Unknown. Decreased conversion of codeine to active metabolite morphine.

            • verapamil

              verapamil will increase the level or effect of caffeine by affecting hepatic enzyme CYP1A2 metabolism. Minor/Significance Unknown.

            • vinblastine

              butalbital will decrease the level or effect of vinblastine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • vincristine

              butalbital will decrease the level or effect of vincristine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • vincristine liposomal

              butalbital will decrease the level or effect of vincristine liposomal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • vinorelbine

              butalbital will decrease the level or effect of vinorelbine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • voriconazole

              butalbital will decrease the level or effect of voriconazole by affecting hepatic enzyme CYP2C19 metabolism. Minor/Significance Unknown.

              voriconazole increases levels of caffeine by decreasing metabolism. Minor/Significance Unknown.

              butalbital will decrease the level or effect of voriconazole by affecting hepatic enzyme CYP2C9/10 metabolism. Minor/Significance Unknown.

            • warfarin

              butalbital will decrease the level or effect of warfarin by affecting hepatic enzyme CYP2C19 metabolism. Minor/Significance Unknown.

            • yerba mate

              yerba mate increases effects of caffeine by pharmacodynamic synergism. Minor/Significance Unknown.

            • zaleplon

              butalbital will decrease the level or effect of zaleplon by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • ziconotide

              ziconotide, codeine. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Additive decreased GI motility. Additive analgesia. Ziconotide does NOT potentiate opioid induced respiratory depression.

            • zileuton

              zileuton will increase the level or effect of caffeine by affecting hepatic enzyme CYP1A2 metabolism. Minor/Significance Unknown.

            • ziprasidone

              butalbital will decrease the level or effect of ziprasidone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • zonisamide

              zonisamide decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism increase levels of hepatotoxic metabolites.

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            Adverse Effects

            >10%

            Codeine

            • Drowsiness
            • Constipation

            1-10%

            Codeine

            • Bradycardia, hypotension, tachycardia
            • Confusion, dizziness, false feeling of well being, headache, lightheadedness, malaise, paradoxical CNS stimulation, restlessness, weakness
            • Rash, urticaria
            • Anorexia, nausea, vomiting, xerostomia
            • LFT's increased
            • Ureteral spasm, urination decreased
            • Dyspnea
            • Burning at injection site, blurred vision, histamine release

            Frequency Not Defined

            Acetaminophen

            • Angioedema, laryngeal edema
            • Pruritic maculopapular rash, urticaria
            • Agranulocytosis, leukopenia, neutropenia, pancytopenia, thrombocytopenia, thrombocytopenic purpura
            • Hepatotoxicity
            • Anaphylactoid reaction

            Butalbital

            • Drowsiness, dizziness, intoxicated feeling, lightheadedness, sedation
            • Abdominal pain, nausea, vomiting
            • Shortness of breath

            Caffeine

            • Tachycardia, palpitations (dose dependent)
            • Insomnia, irritability restlessness, nervousness, tremor, tinnitus
            • Diarrhea, nausea, vomiting
            • Diuresis
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            Warnings

            Black Box Warnings

            Hepatotoxicity may occur with acetaminophen doses that exceed 4 g/day; take into account all acetaminophen-containing products that the patient is taking, including PRN doses and OTC products

            Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplantation or death

            New dosage limit allows no more than 325 mg/dosage unit for prescription medications that contain acetaminophen

            Healthcare professionals can direct patients to take 1 or 2 tablets, capsules, or other dosage units of a prescription product containing 325 mg of acetaminophen up to 6 times a day (12 dosage units) and still not exceed the maximum daily dose of acetaminophen of 4 g/day

            Accidental ingestion of butalbital, acetaminophen, caffeine, and codeine phosphate capsules, especially by children, can result in fatal overdose; keep out of reach of children

            Opioid analgesic risk evaluation and mitigation strategy (REMS)

            • To ensure that benefits of opioid analgesics outweigh risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a REMS for these products; under requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers
            • Healthcare providers are strongly encouraged to:
              • Complete a REMS-compliant education program
              • Counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products
              • Emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist
              • Consider other tools to improve patient, household, and community safety

            Addiction, abuse, and misuse

            • Risk of opioid addiction, abuse, and misuse, which can lead to overdose and death; assess each patient’s risk prior to prescribing and monitor all patients regularly for the development of these behaviors or conditions

            Life-threatening respiratory depression

            • Serious, life-threatening, or fatal respiratory depression may occur
            • Monitor for respiratory depression, especially during initiation or following a dose increase

            Accidental ingestion

            • Accidental ingestion of even 1 dose, especially by children, can result in a fatal overdose

            Neonatal opioid withdrawal syndrome

            • Prolonged use during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts
            • If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available

            Ultra-rapid metabolism of codeine and other risk factors for life-threatening respiratory depression in children

            • Respiratory depression and death reported in children who received codeine following tonsillectomy and/or adenoidectomy that were also ultra-rapid metabolizers of codeine due to CYP2D6 polymorphism
            • Contraindicated in children <12 years and in children <18 years following tonsillectomy and/or adenoidectomy; avoid use in adolescents 12-18 years who have risk factors that may increase sensitivity to respiratory depressant effects of codeine

            Interactions with drugs affecting cytochrome P450 isoenzymes

            • Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors requires careful consideration of the effects on parent drug, codeine, and active metabolite, morphine

            Risks from concomitant use with benzodiazepines or other CNS depressants

            • Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death
            • Reserve concomitant prescribing of codeine sulfate tablets and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate
            • Limit dosages and durations to minimum required
            • Follow patients for signs and symptoms of respiratory depression and sedation

            Contraindications

            Hypersensitivity to drug or components

            Hepatitis or severe hepatic/renal impairment

            Repeated administration in patients with anemia, cardiovascular, pulmonary, or renal disease porphyria

            Children <12 years

            Postoperative management in children <18 years following tonsillectomy and/or adenoidectomy (see Black Box Warnings)

            Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment

            Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days

            Significant respiratory depression

            Known or suspected gastrointestinal obstruction, including paralytic ileus

            Cautions

            As Butalbital, acetaminophen, caffeine, and codeine phosphate capsules contain butalbital and codeine, they expose users to the risks of addiction, abuse, and misuse; assess each patient’s risk for addiction, abuse, or misuse prior to prescribing therapy, and monitor all patients receiving drug for development of addiction behaviors and conditions

            Acetaminophen associated with cases of acute liver failure, at times resulting in liver transplant and death; risk increases in individuals with underlying liver disease, alcohol ingestion, and/or use of more than 1 acetaminophen-containing product (see Black Box Warnings)

            Acetaminophen may cause rare serious skin reactions (eg, acute generalized exanthematous pustulosis, Stevens-Johnson Syndrome, toxic epidermal necrolysis), which can be fatal; discontinued at the first appearance of skin rash

            Use caution in patients withG6PD deficiency

            Avoid driving car or operating machinery

            May increase respiratory depressant effects; caution with head injury, COPD, or other conditions with decreased respiratory drive

            Codeine may cause tolerance/dependency

            Life-threatening respiratory depression and death have occurred in children who received codeine; codeine is subject to variability in metabolism based upon CYP2D6 genotype, which can lead to an increased exposure to active metabolite morphine; children < 12 years appear to be more susceptible to respiratory depressant effects of codeine, particularly if there are risk factors for respiratory depression; many reported cases of death occurred in postoperative period following tonsillectomy and/or adenoidectomy, and many of children had evidence of being ultra-rapid metabolizers of codeine

            Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia; opioid use increases risk of CSA in a dose-dependent fashion; in patients who present with CSA, consider decreasing opioid dosage using best practices for opioid taper

            Avoid use of capsules in adolescents 12-18 years of age who have other risk factors that may increase sensitivity to respiratory depressant effects of codeine unless benefits outweigh risks; risk factors include conditions associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression; when prescribing codeine for adolescents, healthcare providers should choose lowest effective dose for shortest period of time and inform patients and caregivers about risks and the signs of morphine overdose

            Concomitant use of opioids with benzodiazepines or another central nervous system (CNS) depressants, including alcohol or muscle relaxant, may result in profound sedation, respiratory depression, coma, and death; if concomitant use with benzodiazepine warranted, consider prescribing naloxone for emergency treatment of opioid overdose

            Accidental ingestion of butalbital, acetaminophen, caffeine, and codeine phosphate capsules, especially by children, can result in fatal overdose; keep out of reach of children

            Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with codeine sulfate requires careful consideration of effects on parent drug, codeine, and active metabolite, morphine

            Serious, life-threatening, or fatal respiratory depression may occur; monitor closely, especially upon initiation or following a dose increase

            Do not abruptly discontinue therapy in a patient physically dependent on opioids; when discontinuing therapy, in a physically dependent patient, gradually taper the dosage; rapid tapering in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain

            Adrenal Insufficiency may occur; if diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid

            In patients who may be susceptible to intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), butalbital, acetaminophen, caffeine, and codeine phosphate capsules may reduce respiratory drive, and resultant CO2 retention can further increase intracranial pressure; monitor for sedation and respiratory depression

            Opioids may obscure clinical course in patient with a head injury; avoid use of butalbital, acetaminophen, caffeine, and codeine phosphate capsules in patients with impaired consciousness or coma

            Butalbital, acetaminophen, caffeine, and codeine phosphate capsules may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients; there is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs; monitor these patients for signs of hypotension after initiating or titrating dosage

            The codeine in butalbital, acetaminophen, caffeine, and codeine phosphate capsules may increase frequency of seizures in patients with seizure disorders and may increase risk of seizures occurring in other clinical settings associated with seizures; monitor patients with a history of seizure disorders for worsened seizure control during butalbital, acetaminophen, caffeine, and codeine phosphate capsules

            Rarely, acetaminophen may cause serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal; patients should be informed about signs of serious skin reactions, and use of drug should be discontinued at first appearance of skin rash or any other sign of hypersensitivity

            Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients

            Effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with codeine are complex; use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules require careful consideration of effects on codeine and active metabolite, morphine

            Patient access to naloxone for emergency treatment of opioid overdose

            • Assess potential need for naloxone; consider prescribing for emergency treatment of opioid overdose
            • Consult on availability and ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines
            • Educate patients regarding the signs and symptoms of respiratory depression and to call 911 or seek immediate emergency medical help in the event of a known or suspected overdose
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            Pregnancy & Lactation

            Pregnancy

            Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome; available data in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage

            Labor and delivery

            • Use of codeine during labor may lead to respiratory depression in the neonate; opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates; an opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate; use is not recommended in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate; opioid analgesics, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions; however, this effect is not consistent and may be offset by increased rate of cervical dilation, which tends to shorten labor; monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression

            Lactation

            Codeine and its active metabolite, morphine, are present in human milk; there are published studies and cases that have reported excessive sedation, respiratory depression, and death in infants exposed to codeine via breast milk; women who are ultra-rapid metabolizers of codeine achieve higher than expected serum levels of morphine, potentially leading to higher levels of morphine in breast milk that can be dangerous in their breastfed infants; in women with normal codeine metabolism (normal CYP2D6 activity), the amount of codeine secreted into human milk is low and dose-dependent

            There is no information on effects of codeine milk production; because of potential for serious adverse reactions, including excess sedation, respiratory depression, and death in a breastfed infant, breastfeeding is not recommended during treatment

            Withdrawal seizures in newborns whose mothers had taken butalbital-containing drug during pregnancy reported

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Codeine: Opioid agonist; analgesia

            Acetaminophen: Acts on hypothalamus to produce analgesia and antipyresis

            Butalbital: Barbiturate; elicits generalized CNS depressant effects

            Caffeine: Vasoconstrictive properties of cerebral blood vessels may be helpful when treating headaches

            Pharmacogenomics

            10% of codeine is metabolized to morphine by CYP2D6; the active morphine metabolite has a higher affinity for opioid receptors

            CYP2D6 poor metabolizers may not achieve adequate analgesia

            Ultra-rapid metabolizers (up to 7% of Caucasians and up to 30% of Asian and African populations) may have increased toxicity due to rapid conversion

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            Patient Handout

            A Patient Handout is not currently available for this monograph.
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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
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            QL Quantity Limits
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.