Dosing & Uses
Dosage Forms & Strengths
tablet: Schedule III
- 15mg/300mg
- 30mg/300mg
- 60mg/300mg
oral suspension: Schedule V
- (12mg/120mg)/5mL
Mild to Moderately Severe Pain
Tablet: 15-60 mg codeine/dose PO q4-6hr; not to exceed 360 mg codeine/day or 4 g acetaminophen/day
Oral solution: 15 mL (36 mg/360 mg) PO q4hr PRN; not to exceed 4 g acetaminophen/day
Dosing considerations
- Based on the dosage strength selected and pain severity/tolerance, the prescriber must determine the number of tablets for each dose and frequency of administration (typically q4-6hr)
Cough (Off-label)
15-30 mg codeine/dose PO q4-6hr; not to exceed 360 mg codeine/day or 4 g acetaminophen/day
Dosage Modifications
Renal impairment: Use caution
Hepatic impairment: May tolerate low-dose therapy in hepatic cirrhosis; avoid chronic use
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 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
tablet: Schedule III
- 15mg/300mg
- 30mg/300mg
- 60mg/300mg
oral suspension: Schedule V
- (12mg/120mg)/5mL
Mild to Moderately Severe Pain
Tablet
- <12 years: Contraindicated
- ≥12 years: 0.5-1 mg codeine/kg/dose PO q4-6hr (not to exceed 5 doses q24hr); 10-15 mg acetaminophen/kg/dose PO q4-6hr (not to exceed 4 g acetaminophen q24hr)
- Alternatively, 15-60 mg/dose for codeine (not to exceed 360 mg q24hr) and 300-1000 mg/dose for acetaminophen (not to exceed 4 g q24hr); may repeat dose q4hr
Oral suspension
- >12 years: 15 mL (36 mg/360 mg) PO q4hr prn
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
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 (40)
- acrivastine
acrivastine and codeine both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate
- amisulpride
amisulpride and codeine both increase sedation. Avoid or Use Alternate Drug.
- asenapine
asenapine and codeine both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate
- asenapine transdermal
asenapine transdermal and codeine both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate
- avapritinib
avapritinib and codeine both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate
- 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.
benzhydrocodone/acetaminophen and codeine both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate - 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.
- brimonidine
brimonidine and codeine both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate
- 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.
- buprenorphine subdermal implant
buprenorphine subdermal implant and codeine both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate
- buprenorphine transdermal
buprenorphine transdermal and codeine both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate
- buprenorphine, long-acting injection
buprenorphine, long-acting injection and codeine both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate
- 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 and codeine both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate - 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 and codeine both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate - fentanyl iontophoretic transdermal system
fentanyl iontophoretic transdermal system and codeine both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate
- 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 transdermal and codeine both increase sedation. Avoid or Use Alternate Drug. Limit use to patients for whom alternative treatment options are inadequate - 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.
- 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.
- 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.
- olopatadine intranasal
codeine and olopatadine intranasal both increase sedation. Avoid or Use Alternate Drug. Coadministration increases risk of CNS depression, which can lead to additive impairment of psychomotor performance and cause daytime impairment.
- 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.
- 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.
- 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
- 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.
- 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. .
Monitor Closely (245)
- 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.
- 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
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.
- atogepant
acetaminophen will increase the level or effect of atogepant 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 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.
- brexpiprazole
brexpiprazole and codeine both increase sedation. Use Caution/Monitor.
- brivaracetam
brivaracetam and codeine both increase sedation. Use Caution/Monitor.
- brompheniramine
brompheniramine and codeine both increase sedation. 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 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.
- 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 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 topical
cocaine topical 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.
- dapsone topical
acetaminophen increases toxicity of dapsone topical by altering metabolism. Modify Therapy/Monitor Closely. May induce methemoglobinemia .
- daridorexant
codeine and daridorexant both increase sedation. Modify Therapy/Monitor Closely. Coadministration increases risk of CNS depression, which can lead to additive impairment of psychomotor performance and cause daytime impairment.
- 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.
- difelikefalin
difelikefalin and codeine both increase sedation. 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.
- eltrombopag
eltrombopag increases levels of acetaminophen by decreasing metabolism. Use Caution/Monitor. UGT inhibition; significance of interaction unclear.
- 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.
- 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.
- 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.
- fenfluramine
codeine increases and fenfluramine decreases sedation. Effect of interaction is not clear, use caution. 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. - 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
- 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.
- 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.
- ganaxolone
codeine and ganaxolone both increase sedation. Use Caution/Monitor.
- 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. - isavuconazonium sulfate
acetaminophen will increase the level or effect of isavuconazonium sulfate 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.
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.
- ivacaftor
acetaminophen increases levels of ivacaftor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Monitor when coadministered with weak CYP3A4 inhibitors .
- 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.
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 codeine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- 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. - levalbuterol
codeine increases and levalbuterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.
- levoketoconazole
levoketoconazole decreases effects of codeine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Prevents conversion of codeine to its active metabolite morphine.
- 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.
- lixisenatide (DSC)
lixisenatide (DSC) 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
codeine and lofepramine both increase sedation. Use Caution/Monitor.
- lofexidine
codeine and lofexidine both increase sedation. 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.
- 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.
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
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
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.
- tazemetostat
acetaminophen will increase the level or effect of tazemetostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. 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.
- tetracaine
tetracaine, acetaminophen. Other (see comment). Use Caution/Monitor. Comment: Monitor for signs of methemoglobinemia when methemoglobin-inducing drugs are coadministered.
- 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.
- tinidazole
acetaminophen will increase the level or effect of tinidazole by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- 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.
- warfarin
acetaminophen increases effects of warfarin by anticoagulation. Use Caution/Monitor.
- xylometazoline
codeine increases and xylometazoline decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.
Minor (70)
- acetazolamide
acetazolamide decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.
- albiglutide
albiglutide decreases levels of acetaminophen by unspecified interaction mechanism. 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.
- asenapine
asenapine will increase the level or effect of codeine by affecting hepatic enzyme CYP2D6 metabolism. 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.
- brimonidine
brimonidine increases effects of codeine by pharmacodynamic synergism. Minor/Significance Unknown. Increased CNS depression.
- carbamazepine
carbamazepine decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.
- cholestyramine
cholestyramine decreases levels of acetaminophen by inhibition of GI absorption. Applies only to oral form of both agents. Minor/Significance Unknown.
- clonazepam
clonazepam decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.
- 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.
- 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.
- disulfiram
disulfiram will increase the level or effect of acetaminophen by affecting hepatic enzyme CYP2E1 metabolism. Minor/Significance Unknown.
- enoxaparin
acetaminophen increases effects of enoxaparin by unknown mechanism. 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.
- eucalyptus
codeine and eucalyptus both increase sedation. Minor/Significance Unknown.
- felbamate
felbamate decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.
- fluoxetine
fluoxetine decreases effects of codeine by decreasing metabolism. Minor/Significance Unknown. Decreased conversion of codeine to active metabolite morphine.
- 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.
- green tea
green tea increases effects of acetaminophen by pharmacodynamic synergism. Minor/Significance Unknown. (Theoretical, due to caffeine content).
- heparin
acetaminophen increases effects of heparin by unknown mechanism. Minor/Significance Unknown.
- 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. - isoniazid
isoniazid increases toxicity of acetaminophen by unknown mechanism. Minor/Significance Unknown.
- lacosamide
lacosamide decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.
- 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.
- liraglutide
liraglutide decreases levels of acetaminophen by unspecified interaction mechanism. Minor/Significance Unknown.
- lorazepam
lorazepam decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.
- 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.
- methsuximide
methsuximide decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.
- metoclopramide
metoclopramide increases levels of acetaminophen by enhancing GI absorption. Applies only to oral form of both agents. Minor/Significance Unknown.
- metronidazole
metronidazole will increase the level or effect of acetaminophen by affecting hepatic enzyme CYP2E1 metabolism. Minor/Significance Unknown.
- nilotinib
nilotinib will increase the level or effect of codeine by affecting hepatic enzyme CYP2D6 metabolism. Minor/Significance Unknown.
- 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.
- oxybutynin topical
oxybutynin topical decreases levels of acetaminophen by unspecified interaction mechanism. Minor/Significance Unknown.
- oxybutynin transdermal
oxybutynin transdermal decreases levels of acetaminophen by unspecified interaction mechanism. 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. - 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.
- phenytoin
phenytoin decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.
- primidone
primidone decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.
- 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. - protamine
acetaminophen increases effects of protamine by unknown mechanism. Minor/Significance Unknown.
- 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.
- rifabutin
rifabutin decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.
- rifampin
rifampin decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.
- rufinamide
rufinamide decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.
- ruxolitinib
acetaminophen will increase the level or effect of ruxolitinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.
- ruxolitinib topical
acetaminophen will increase the level or effect of ruxolitinib topical by affecting hepatic/intestinal enzyme CYP3A4 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.
- 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.
- topiramate
topiramate decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.
- valproic acid
valproic acid decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.
- 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.
- zonisamide
zonisamide decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism increase levels of hepatotoxic metabolites.
Adverse Effects
Frequency Not Defined (Codeine)
Constipation
Drowsiness
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
Decreased urination
Increased LFTs
Burning at injection site
Weakness
Blurred vision
Dyspnea
Histamine release
Frequency Not Defined (Acetaminophen)
Pruritic maculopapular rash
Urticaria
Laryngeal edema
Angioedema
Anaphylactoid reaction
Thrombocytopenia
Leukopenia
Pancytopenia
Neutropenia
Thrombocytopenic purpura
Agranulocytosis
Hepatotoxicity
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, especially by children,can result in a fatal overdose
Addiction, Abuse and Misuse
- 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 the 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 the 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, and 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
Children <12 years
Post-operative management in children <18 years following tonsillectomy and/or adenoidectomy
Patients with significant respiratory depression, 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
Hypersensitivity to codeine, acetaminophen, or ingredients
Hepatitis or severe hepatic/renal impairment
Cautions
Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplantation 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: Risk for rare, but serious skin reactions that can be fatal; these reactions include Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP); symptoms may include skin redness, blisters and rash
Acetaminophen may cause serious an potentially fatal skin reactions
Patients with G6PD deficiency
Use caution in repeated administration in patients with anemia or with cardiovascular, pulmonary, or renal disease
Use caution in patients with history of porphyria
May cause hypotension; use with caution in patients with hypovolemia
Codeine may cause depression; avoid driving car or operating heavy machinery
Use caution in patients with conditions associated with hypoxia, hypercapnia, upper respiratory obstruction, or debilitated patients
May increase respiratory depressant effects; caution with head injury, COPD, or other conditions associated with decreased respiratory drive
Use caution in patients with hypersensitivity reactions to other phenanthrene-derivative opioid agonists including oxymorphone, levorphanol, oxycodone, or hydrocodone
Codeine may cause tolerance/dependency
May obscure diagnosis or clinical course of patients with acute abdominal conditions and may worsen gastrointestinal ileus due to reduced GI motility
Use cuation in adrenal insufficiency, billiary tract impairment, patients susceptible to intracranial effects of CO2 retention, G6PD deficiency, head trauma, prostatic hyperplasia, hepatic/renal impairment, thyroid dysfunction, seizure disorder, or respiratory disease (COPD)
Codeine may cause or exacerbate constipation; chronic use may result in obstructive bowel disease, especially in patients with existing intestinal motility disorders; reduce potential for constipation by taking preventive measures, including the increase of fiber intake and the use of stool softeners
Long-term use in patients with adrenal insufficiency may cause secondary hypogonadism, which may lead to sexual dysfunction, infertility, mood disorders, and osteoporosis
Use with caution in patients with biliary tract dysfunction, including pancreatitis; may increase amylase/lipase levels and may cause constriction of sphincter of Oddi
Healthcare providers should choose lowest effective dose for shortest period of time and inform patients and caregivers about these risks and the signs of morphine overdose
Death reported in 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
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
(eg, phenothiazines or general anesthetics); monitor for signs of hypotension after initiating or titrating dosage; in patients with circulatory shock, drug may cause vasodilatation that can further reduce cardiac output and blood pressure; avoid use in circulatory shock
Therapy may obscure diagnosis or clinical course in patients with acute abdominal conditions; therapy 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
Codeine 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 therapy
Do not abruptly discontinue drug in a patient physically dependent on opioids; when discontinuing therapy in a physically dependent patient, gradually taper the dosage
Addiction potential
- Therapy exposes users to the risks of addiction, abuse, and misuse; addiction can occur in patients appropriately prescribed therapy and can occur at recommended dosages; assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing therapy; risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (eg, major depression)
- Patients at increased risk may be prescribed opioids, but use in such patients necessitates intensive counseling about risks and proper use of drug along with intensive monitoring for signs of addiction, abuse, and misuse
Adrenal insufficiency
- Cases of adrenal insufficiency reported with opioid use, more often following > 1 month of use; presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure
- If adrenal insufficiency suspected, confirm diagnosis with diagnostic testing as soon as possible; 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
Respiratory depression
- Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended; respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death; management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on patient’s clinical status; carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids
- 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 the opioid dosage using best practices for opioid taper
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; codeine is subject to variability in metabolism based upon CYP2D6 genotype, which can lead to an increased exposure to active metabolite morphine
- Based upon post-marketing reports, children <12 years appear to be more susceptible to respiratory depressant effects of codeine, particularly if there are risk factors for respiratory depression; for example, many reported cases of death occurred in the post-operative period following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being ultra-rapid metabolizers of codeine
- Children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to its respiratory depressant effects
- Avoid use in adolescents 12-18 years of age who have other risk factors that may increase their sensitivity to respiratory depressant effects of codeine unless benefits outweigh risks; risk factors include conditions associated with hypoventilation, such as post-operative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression
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
Drug interaction overview
- Concomitant use with all CYP3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (eg, ketoconazole), and protease inhibitors (e.g., ritonavir) or discontinuation of CYP3A4 inducer such as rifampin, carbamazepine, and phenytoin, may increase codeine plasma concentrations with subsequently greater metabolism by CYP2D6, resulting in greater morphine levels, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression
- Concomitant use with all CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor may result in lower codeine levels, greater norcodeine levels, and less metabolism via CYP2D6 with resultant lower morphine levels; this may be associated with a decrease in efficacy, and in some patients, may result in signs and symptoms of opioid withdrawal; follow patients receiving the drug and any CYP3A4 inhibitor or inducer for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when used in combination with inhibitors and inducers of CYP3A4
- If concomitant use of a CYP3A4 inhibitor is necessary or if a CYP3A4 inducer is discontinued, consider dosage reduction until stable drug effects are achieved; monitor patients for respiratory depression and sedation at frequent intervals; if concomitant use of a CYP3A4 inducer is necessary or if a CYP3A4 inhibitor is discontinued, consider increasing the dosage of the drug until stable drug effects are achieved; monitor for signs of opioid withdrawal
- Concomitant use with Codeine with all CYP2D6 inhibitors (eg, amiodarone, quinidine) may result in an increase in codeine plasma concentrations and a decrease in active metabolite morphine plasma concentration which could result in analgesic efficacy reduction or symptoms of opioid withdrawal; discontinuation of a concomitantly used CYP2D6 inhibitor may result in a decrease in codeine plasma concentration and an increase in active metabolite morphine plasma concentration which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression
- Follow patients receiving CYP2D6 inhibitor for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when administered in conjunction with inhibitors of CYP2D6
- If concomitant use with a CYP2D6 inhibitor necessary, follow patient for signs of reduced efficacy or opioid withdrawal and consider increasing
- Dosage; after stopping use of a CYP2D6 inhibitor, consider reducing dosage and follow the patient for signs and symptoms of respiratory depression or sedation
Pregnancy & Lactation
Pregnancy
There are no adequate and well-controlled studies in pregnant women; use during pregnancy only if potential benefit justifies potential risk to fetus
Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in neonate and neonatal opioid withdrawal syndrome shortly after birth
Inform female patients of reproductive potential that prolonged use of drug during pregnancy can result in neonatal opioid withdrawal syndrome,which may be life-threatening if not recognized and treated
Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight; onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of drug by newborn; observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly
Inform female patients of reproductive potential that therapy can cause fetal harm and for patient to inform prescriber of a known or suspected pregnancy
Inform patients that chronic use of opioids may cause reduced fertility; it is not known whether these effects on fertility are reversible
Labor and delivery
- Not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate; opioid analgesics, including can prolong labor through actions which temporarily reduce strength, duration, and frequency of uterine contractions
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 on milk production; because of potential for serious adverse reactions, including excess sedation, respiratory depression, and death in a breastfed infant, advise patients that breastfeeding is not recommended during treatment
Limited published studies report that acetaminophen passes rapidly into human milk with similar levels in milk and plasma; average and maximum neonatal doses of 1% and 2%, respectively, of weight-adjusted maternal dose are reported after a single oral administration of 1 gram APAP; there is one well documented report of rash in a breast-fed infant that resolved when mother stopped acetaminophen use and recurred when she resumed acetaminophen use
If infants are exposed to drug through breast milk, they should be monitored for excess sedation and respiratory depression; withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breastfeeding is stopped
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.Pharmacology
Mechanism of Action
Codeine: Opioid agonist; analgesia; blocks pain impulse generation and inhibits ascending pain pathways, thus altering the perception and response to pain; inhibits cough by acting centrally in the medulla; causes CNS depression
Acetaminophen: Nonopioid, nonsalicylate analgesic; may work peripherally to block pain impulse generation; acts on hypothalamus to produce antipyresis
Absorption
Bioavailability: Codeine (53%); acetaminophen (100%)
Onset: 0.5-1 hr
Duration: 4-6 hr
Peak effect: 1-1.5 hr
Distribution
Protein bound: Codeine (<25%); acetaminophen (10-25%), higher with toxic concentrations
Vd: Codeine (3-6 L/kg); acetaminophen (1 L/kg)
Metabolism
Codeine
- Via hepatic UGT2B7 and UGT2B4 to codeine-6-glucuronide
- 10% of codeine is metabolized in liver to morphine by CYP2D6; the active morphine metabolite has a higher affinity for opioid receptors; also via CYP3A4 to norcodeine
- CYPD2D6 poor metabolizers may not achieve adequate analgesia
- Ultrarapid metabolizers (up to 7% of whites and up to 30% of Asian and African populations) may experience increased toxicity due to rapid conversion to morphine
Acetaminophen
- Metabolized in liver by microsomal enzyme systems
- 80-85% conjugated principally with glucuronic acid and to a lesser extent with sulfuric acid and cysteine
- 4% metabolized by CYP450 to toxic metabolite (N acetyl-p-benzoquinoneimine, N-acetylimidoquinone [NAPQI]), which is further detoxified by conjugation with glutathione; high doses may deplete fixed amount of glutathione in body, causing NAPQI accumulation
Elimination
Codeine
- Half-life: 3 hr
- Excretion: Urine (90%)
Acetaminophen
- Half-life: 2-4 hr
- Excretion: Urine (90-100%; principally as acetaminophen glucuronide with acetaminophen sulfate/mercaptate)
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Formulary
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To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.
Adding plans allows you to:
- View the formulary and any restrictions for each plan.
- Manage and view all your plans together – even plans in different states.
- Compare formulary status to other drugs in the same class.
- Access your plan list on any device – mobile or desktop.
