codeine (Rx)

Brand and Other Names:
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet: Schedule II

  • 15mg
  • 30mg
  • 60mg

Pain

15-60 mg PO q4-6hr PRN; not to exceed 360 mg/day in naive patients

Dosing considerations

  • Patients with prior opioid exposure may require higher initial doses
  • Titrate dose to pain relief; use lowest effective dose for shortest period of time

Cough (Off-label)

7.5-30 mg PO q4-6hr PRN

Dosing Consideration

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 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

tablet: Schedule II

  • 15mg
  • 30mg
  • 60mg

oral solution: Schedule II

  • 30mg/mL (has not been available for over 1 year)

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

Pain (Off-label)

<12 years:Contraindicated

≥12 years: 0.5-1 mg/kg PO q4-6hr PRN; not to exceed 60 mg/dose; titrate dose to pain relief; use lowest effective dose for shortest period of time  

Alternatively, 15-60 mg PO q4-6hr PRN; not to exceed 360 mg/day in naive patients

Dosing considerations

  • See Black Box Warnings and Contraindications sections for warning regarding postoperative use following tonsillectomy and/or adenoidectomy

Cough (Off-label)

<12 years: Not recommended  

≥ 12 years: 7.5-30 mg PO q4-6hr PRN;titrate dose to pain relief; use lowest effective dose for shortest period of time

Dosing Consideration

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 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)

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Interactions

Interaction Checker

and codeine

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            Contraindicated (1)

            • 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.

            Serious - Use Alternative (35)

            • benzhydrocodone/acetaminophen

              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.

            • 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.

            • 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.

            • 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.

            • clonidine

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

            • 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.

            • 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.

            • 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. .

            • fentanyl

              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 transdermal

              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.

            • 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.

            • hydrocodone

              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.

            • 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.

            • 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.

            • 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

            • 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.

            • 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.

            • 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.

            • pentazocine

              pentazocine, 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.

            • phenelzine

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

            • prasugrel

              codeine will decrease the level or effect of prasugrel by inhibition of GI absorption. Applies only to oral form of both agents. Avoid or Use Alternate Drug. Co-administration of opioid agonists delay and reduce absorption of prasugrel and its active metabolite presumably by slowing gastric emptying; consider the use of a parenteral anti-platelet agent in acute coronary syndrome patients requiring co-administration of opioid agonists

            • procarbazine

              procarbazine increases toxicity of codeine by unknown mechanism. Avoid or Use Alternate Drug. MAOIs may potentiate CNS depression and hypotension. Do not use within 14 days of MAOI use. .

            • rasagiline

              rasagiline increases toxicity of codeine by unknown mechanism. Avoid or Use Alternate Drug. Risk of hypotension, hyperpyrexia, somnolence, or death.

            • selegiline transdermal

              selegiline transdermal increases toxicity of codeine by unknown mechanism. Avoid or Use Alternate Drug. Risk of hypotension, hyperpyrexia, somnolence, or death.

            • selinexor

              selinexor, codeine. unspecified interaction mechanism. Avoid or Use Alternate Drug. Patients treated with selinexor may experience neurological toxicities. Avoid taking selinexor with other medications that may cause dizziness or confusion.

            • sodium oxybate

              codeine, sodium oxybate. 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.

            • sufentanil SL

              sufentanil SL, codeine. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Coadministration may result in hypotension, profound sedation, respiratory depression, coma, and death. 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.

            • ticagrelor

              codeine will decrease the level or effect of ticagrelor by inhibition of GI absorption. Applies only to oral form of both agents. Avoid or Use Alternate Drug. Co-administration of opioid agonists delay and reduce absorption of ticagrelor and its active metabolite presumably by slowing gastric emptying; consider the use of a parenteral anti-platelet agent in acute coronary syndrome patients requiring co-administration of opioid agonists

            • tramadol

              tramadol, codeine. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

            • tranylcypromine

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

            • valerian

              valerian and codeine both increase sedation. Avoid or Use Alternate Drug.

            Monitor Closely (221)

            • 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.

            • albuterol

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

            • alfentanil

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

            • alprazolam

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

            • amiodarone

              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

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

            • amobarbital

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

            • amoxapine

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

            • apomorphine

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

            • arformoterol

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

            • aripiprazole

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

            • armodafinil

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

            • artemether/lumefantrine

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

            • azelastine

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

            • baclofen

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

            • belladonna and opium

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

            • benperidol

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

            • benzphetamine

              codeine increases and benzphetamine 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.

            • brompheniramine

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

            • buprenorphine

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

            • buprenorphine buccal

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

            • buprenorphine, long-acting injection

              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.

            • bupropion

              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.

            • butabarbital

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

            • butalbital

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

            • butorphanol

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

            • caffeine

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

            • carbinoxamine

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

            • carisoprodol

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

            • celecoxib

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

            • cenobamate

              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.

            • chlordiazepoxide

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

            • chlorpromazine

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

              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

            • chlorzoxazone

              chlorzoxazone and codeine both increase sedation. 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.

            • cinnarizine

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

            • clemastine

              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

              codeine 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

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

            • clorazepate

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

            • clozapine

              codeine and clozapine both increase sedation. 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.

            • cyclizine

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

            • cyclobenzaprine

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

            • cyproheptadine

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

            • dantrolene

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

            • darifenacin

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

            • desflurane

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

            • desipramine

              codeine and desipramine both increase sedation. 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.

            • 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

            • deutetrabenazine

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

            • dexchlorpheniramine

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

            • dexfenfluramine

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

            • dexmedetomidine

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

            • dexmethylphenidate

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

            • dextroamphetamine

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

            • dextromoramide

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

            • diamorphine

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

            • diazepam

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

            • diethylpropion

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

            • difenoxin hcl

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

            • dimenhydrinate

              dimenhydrinate and codeine 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.

            • diphenoxylate hcl

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

            • dipipanone

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

            • dobutamine

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

            • dopamine

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

            • dopexamine

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

            • dosulepin

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

            • doxepin

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

            • doxylamine

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

            • 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.

            • duloxetine

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

            • 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.

            • ephedrine

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

            • epinephrine

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

            • epinephrine racemic

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

            • esketamine intranasal

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

            • estazolam

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

            • ethanol

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

            • etomidate

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

            • 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.

            • fenfluramine

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

            • flibanserin

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

            • 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

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

            • flurazepam

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

            • formoterol

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

            • 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.

            • haloperidol

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

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

            • hydromorphone

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

            • hydroxyzine

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

            • iloperidone

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

            • imipramine

              codeine and imipramine both increase sedation. 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.

            • 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.

            • ketamine

              ketamine and codeine 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.

            • 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.

            • 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

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

            • levorphanol

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

            • lisdexamfetamine

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

            • lofepramine

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

            • lofexidine

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

            • lopinavir

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

            • loprazolam

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

            • lorazepam

              lorazepam and codeine both increase sedation. 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.

            • loxapine

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

            • loxapine inhaled

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

            • lumefantrine

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

            • lurasidone

              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

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

            • marijuana

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

            • melatonin

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

            • meperidine

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

            • meprobamate

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

            • metaproterenol

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

            • metaxalone

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

            • methadone

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

            • methamphetamine

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

            • methocarbamol

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

            • methylenedioxymethamphetamine

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

            • midazolam

              midazolam and codeine 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.

            • midodrine

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

            • mirabegron

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

            • mirtazapine

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

            • modafinil

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

            • morphine

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

            • motherwort

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

            • moxonidine

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

            • nabilone

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

            • nalbuphine

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

            • norepinephrine

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

            • nortriptyline

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

            • olanzapine

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

            • oliceridine

              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

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

            • orphenadrine

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

            • oxazepam

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

            • oxycodone

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

            • oxymorphone

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

            • paliperidone

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

            • papaveretum

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

            • papaverine

              codeine and papaverine both increase sedation. 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.

            • 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.

            • pentazocine

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

            • pentobarbital

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

            • perampanel

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

            • perphenazine

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

            • phendimetrazine

              codeine 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.

            • phentermine

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

            • phenylephrine

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

            • phenylephrine PO

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

            • pholcodine

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

            • pimozide

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

            • pirbuterol

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

            • primidone

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

            • prochlorperazine

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

            • promethazine

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

            • propofol

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

            • propylhexedrine

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

            • protriptyline

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

            • quazepam

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

            • quetiapine

              codeine and quetiapine both increase sedation. 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.

            • ramelteon

              codeine and ramelteon both increase sedation. 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.

            • ribociclib

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

            • risperidone

              codeine and risperidone both increase sedation. 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.

            • 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

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

            • scullcap

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

            • secobarbital

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

            • selegiline

              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.

            • sertraline

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

            • sevoflurane

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

            • shepherd's purse

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

            • 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.

            • sufentanil

              codeine and sufentanil both increase sedation. 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

            • tapentadol

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

            • temazepam

              temazepam and codeine both increase 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.

            • terbutaline

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

            • 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.

            • thiothixene

              codeine 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.

            • topiramate

              codeine and topiramate both increase sedation. Modify Therapy/Monitor Closely.

            • tramadol

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

            • tranylcypromine

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

            • trazodone

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

            • triazolam

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

            • triclofos

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

            • trifluoperazine

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

            • trimipramine

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

            • triprolidine

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

            • venlafaxine

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

            • xylometazoline

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

            • yohimbine

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

            • ziconotide

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

            • ziprasidone

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

            • zotepine

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

            Minor (21)

            • asenapine

              asenapine will increase the level or effect of codeine by affecting hepatic enzyme CYP2D6 metabolism. Minor/Significance Unknown.

            • brimonidine

              brimonidine increases effects of codeine by pharmacodynamic synergism. Minor/Significance Unknown. Increased CNS depression.

            • dextroamphetamine

              dextroamphetamine increases effects of codeine by unspecified interaction mechanism. Minor/Significance Unknown.

            • eucalyptus

              codeine and eucalyptus both increase sedation. Minor/Significance Unknown.

            • fluoxetine

              fluoxetine decreases effects of codeine by decreasing metabolism. Minor/Significance Unknown. Decreased conversion of codeine to active metabolite morphine.

            • imatinib

              imatinib will increase the level or effect of codeine by affecting hepatic enzyme CYP2D6 metabolism. Minor/Significance Unknown.

              imatinib decreases effects of codeine by decreasing metabolism. Minor/Significance Unknown. Decreased conversion of codeine to active metabolite morphine.

            • lidocaine

              lidocaine increases toxicity of codeine by pharmacodynamic synergism. Minor/Significance Unknown. Risk of increased CNS depression.

            • 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.

            • nilotinib

              nilotinib will increase the level or effect of codeine by affecting hepatic enzyme CYP2D6 metabolism. Minor/Significance Unknown.

            • parecoxib

              parecoxib will increase the level or effect of codeine by affecting hepatic enzyme CYP2D6 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.

            • propafenone

              propafenone will increase the level or effect of codeine by affecting hepatic enzyme CYP2D6 metabolism. Minor/Significance Unknown.

              propafenone decreases effects of codeine by decreasing metabolism. Minor/Significance Unknown. Decreased conversion of codeine to active metabolite morphine.

            • 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.

            • ranolazine

              ranolazine will increase the level or effect of codeine by affecting hepatic enzyme CYP2D6 metabolism. Minor/Significance Unknown.

            • sage

              codeine and sage both increase sedation. Minor/Significance Unknown.

            • sertraline

              sertraline decreases effects of codeine by decreasing metabolism. Minor/Significance Unknown. Decreased conversion of codeine to active metabolite morphine.

            • thioridazine

              thioridazine decreases effects of codeine by decreasing metabolism. Minor/Significance Unknown. Decreased conversion of codeine to active metabolite morphine.

            • tipranavir

              tipranavir will increase the level or effect of codeine by affecting hepatic enzyme CYP2D6 metabolism. Minor/Significance Unknown.

            • venlafaxine

              venlafaxine decreases effects of codeine by decreasing metabolism. Minor/Significance Unknown. Decreased conversion of codeine to active metabolite morphine.

            • ziconotide

              ziconotide, codeine. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Additive decreased GI motility. Additive analgesia. Ziconotide does NOT potentiate opioid induced respiratory depression.

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            Adverse Effects

            >10%

            Constipation

            Drowsiness

            1-10%

            Hypotension

            Tachycardia or bradycardia

            Confusion

            Dizziness

            False feeling of well-being

            Headache

            Lightheadedness

            Malaise

            Paradoxical CNS stimulation

            Restlessness

            Rash, urticaria

            Anorexia

            Nausea, vomiting

            Xerostomia

            Ureteral spasm, urination decreased

            LFTs increased

            Burning at injection site

            Weakness

            Blurred vision

            Dyspnea

            Histamine release

            <1%

            Hypotension, with IV use

            Anaphylactoid reaction (rare)

            Seizure, with excessive doses

            Respiratory depression

            Postmarketing Reports

            Severe hypotension

            Life-threatening respiratory depression

            Neonatal opioid withdrawal syndrome

            Death related to ultra-rapid metabolizers of codeine

            Adrenal insufficiency

            Gastrointestinal adverse reactions

            Seizures

            Euphoria

            Dysphoria

            Abdominal pain

            Pruritus

            Sweating

            Serotonin syndrome

            Anaphylaxis

            Androgen deficiency

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            Warnings

            Black Box Warnings

            Opioid analgesic risk evaluation and mitigation strategy (REMS)

            • Drug exposes patients and other users to the risks of opioid addiction, abuse and misuse, which can lead to overdose and death; assess each patient’s risk prior to prescribing drug, and monitor all patients regularly for the development of these behaviors and conditions
            • 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

            Life-Threatening Respiratory Depression

            • Serious, life-threatening, or fatal respiratory depression may occur with therapy
            • Monitor for respiratory depression, especially during initiation of therapy or following a dose increase
            • Respiratory depression and death reported following tonsillectomy and/or adenoidectomy in patients that appeared to be rapid metabolizers of codeine due to CYP2D6 polymorphism

            Ultra-rapid metabolism of codeine and other risk factors for life-threatening respiratory depression in children

            • Life-threatening respiratory depression and death have occurred in children who received codeine; most of reported cases occurred following tonsillectomy and/or adenoidectomy and many of the children had evidence of being ultra-rapid metabolizers of codeine due to a cytochrome P450 (CYP) 2D6 polymorphism
            • Avoid use of in adolescents 12-18 years of age who have other risk factors that may increase their sensitivity to respiratory depressant effects of codeine

            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 patient of risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available

            Interactions with Drugs Affecting Cytochrome P450 Isoenzymes

            • The effects of concomitant use or discontinuation of CYP3A4 inducers, CYP3A4 inhibitors, or CYP2D6 inhibitors with codeine are complex; use of CYP3A4 inducers, CYP3A4 inhibitors, or CYP2D6 inhibitors with drug requires careful consideration of 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 with
            • 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 codeine

            Significant respiratory depression

            Children younger than 12 years

            Postoperative pain management in children (<18 years) who have undergone tonsillectomy and/or adenoidectomy

            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 last 14 days

            Known or suspected gastrointestinal obstruction, including paralytic ileus

            Cautions

            Codeine sulfate tablets contain codeine, a schedule II controlled substance; as an opioid, codeine sulfate tablets exposes users to risks of addiction, abuse, and misuse; addiction can occur at recommended dosages and if drug is misused or abused; assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing codeine sulfate tablets, and monitor; risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression); potential for these risks should not prevent proper management of pain in any given patient; patients at increased risk may be prescribed opioids such as codeine sulfate tablets, but use in such patients necessitates intensive counseling about risks and proper use of codeine sulfate along with intensive monitoring for signs of addiction, abuse, and misuse; prescribe the drug in smallest appropriate quantity and advise patient on proper disposal of unused drug

            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

            Therapy 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 (e.g., phenothiazines or general anesthetics); monitor patients for signs of hypotension after initiating or titrating dosage; in patients with circulatory shock, therapy may cause vasodilation that can further reduce cardiac output and blood pressure; avoid therapy in patients with circulatory shock

            In patients who may be susceptible to intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), therapy may reduce respiratory drive, and resultant CO2 retention can further increase intracranial pressure; monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy; opioids may obscure clinical course in a patient with a head injury; avoid the use in patients with impaired consciousness or coma

            Contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus; may cause spasm of sphincter of Oddi; opioids may cause increases in serum amylase; monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms

            Therapy 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 history of seizure disorders for worsened seizure control during therapy

            Avoid use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic; mixed agonist/antagonist and partial agonist analgesics may reduce analgesic effect and/or precipitate withdrawal symptoms; when discontinuing therapy in physically-dependent patient, gradually taper dosage; do not abruptly discontinue therapy in these patients

            Warn patients not to drive or operate dangerous machinery unless they are tolerant to effects of drug and know how they will react to medication

            While serious, life-threatening, or fatal respiratory depression can occur at any time during therapy, risk is greatest during initiation of therapy or following dosage increase; monitor patients closely for respiratory depression, especially within first 24 to 72 hr of initiating therapy with and following dosage increases; accidental ingestion of even one dose, especially by children, can result in respiratory depression and death due to overdose of codeine

            Deaths have occurred in nursing infants exposed to high levels of morphine in breast milk because mothers were ultra-rapid metabolizers of codeine

            Do not abruptly discontinue buprenorphine 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

            Profound sedation, respiratory depression, coma, and death may result from concomitant administration with benzodiazepines or other CNS depressants (eg, non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol); because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate; if concomitant use with benzodiazepine or muscle relaxant warranted, consider prescribing naloxone for the emergency treatment of opioid overdose

            If an opioid analgesic is initiated in a patient already taking a benzodiazepine, a muscle relaxant, or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response; follow patients closely for signs and symptoms of respiratory depression and sedation

            Use in patients with acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment is contraindicated; patients with significant chronic obstructive pulmonary disease or cor pulmonale, and with substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages

            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; monitor closely

            Monoamine oxidase inhibitors (MAOIs) may potentiate effects of morphine, codeine’s active metabolite, including respiratory depression, coma, and confusion; therapy should not be administered within 14 days of taking MAOIs

            Cases of adrenal insufficiency reported with opioid use, more often following greater than one month of use; symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure; if adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids; wean patient off of opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers; other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency

            Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible

            Use caution when selecting dosage for an elderly patient, usually starting at low end of dosing range, reflecting greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy; because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and may be useful to monitor renal function

            Codeine pharmacokinetics may be altered in patients with renal failure; clearance may be decreased and metabolites may accumulate much higher plasma levels in patients with renal failure as compared to patients with normal renal function; start with a lower than normal dosage or with longer dosing intervals and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension

            Use caution in cardiac arrhythmias, drug abuse/dependence, emotional lability, gallbladder disease, head injury, hepatic impairment, hypothyroidism, increased ICP, prostatic hypertrophy, renal impairment, seizures with epilepsy, urethral stricture, urinary tract surgeryLife-threatening respiratory depression and death reported in children who received codeine; codeine is subject to variability in metabolism based upon CYP2D6 genotype (described below), which can lead to an increased exposure to active metabolite morphine; based upon post-marketing reports, children younger than 12 years old appear to be more susceptible to the respiratory depressant effects of codeine, particularly if there are risk factors for respiratory depression; children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to respiratory depressant effect

            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 signs of morphine overdose

            At least one death reported in a nursing infant exposed to high levels of morphine in breast milk because mother was an ultra-rapid metabolizer of codeine; breastfeeding is not recommended during treatment with codeine sulfate oral solution

            Risk of life-threatening side effects in nursing infants, especially if mother is an ultra-rapid metabolizer of codeine

            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 Risk Evaluation and Mitigation Strategy (REMS) for these products
            • Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed; use the following link to obtain the Patient Counseling Guide (PCG): www.fda.gov/OpioidAnalgesicREMSPCG
            • Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them
            • Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities
            • To obtain further information on opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com; the FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint

            Postoperative pain in children

            • Prescribe an alternate analgesic for postoperative pain control in children undergoing tonsillectomy and/or adenoidectomy
            • Deaths have occurred in children with obstructive sleep apnea who received codeine for postoperative pain following tonsillectomy and/or adenoidectomy
            • Codeine is converted to morphine by the liver; these children had evidence of being ultra-rapid metabolizers (via CYP2D6) of codeine, which is an inherited (genetic) ability that causes codeine to be converted rapidly into life-threatening or fatal amounts of 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 for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth; observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly; opioids cross placenta and may produce respiratory depression and psycho-physiologic effects in neonates; an opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate; codeine sulfate is not recommended for use 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 strength, duration, and frequency of uterine contractions

            Lactation: Codeine is secreted into human milk; in women with normal codeine metabolism (normal CYP2D6 activity), amount of codeine secreted into human milk is low and dose-dependent; some women are ultra-rapid metabolizers of codeine; these women achieve higher-than-expected serum levels of codeine's active metabolite, morphine, leading to higher-than-expected levels of morphine in breast milk and potentially dangerously high serum morphine levels in their breastfed infants that can potentially lead to serious adverse reactions, including death, in nursing infants; there is no information on effects of codeine on milk production

            Developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy and any potential adverse effects on breastfed infant from therapy or from underlying maternal condition

            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

            Narcotic agonist analgesic with antitussive activity, mu receptor agonist

            Absorption

            Onset: 30-60 min (PO); 10-30 min (IM)

            Duration: 4-6 hr

            Peak plasma time: 0.5-1 hr

            Distribution

            Protein bound: 25%

            Vd: 3.5 L/kg (PO); 2.6 L/kg (IM)

            Metabolism

            Prodrug metabolized to morphine by CYP2D6; demethylated/conjugated in liver (undergoes O-demethylation, N-demethylation, and partial conjugation with glucuronic acid)

            Elimination

            Half-life: 3-4 hr

            Excretion: Urine, feces

            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
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
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            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
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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.