Dosing & Uses
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: 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)
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 (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.
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
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
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.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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Formulary
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- View the formulary and any restrictions for each plan.
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- Compare formulary status to other drugs in the same class.
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