codeine (Rx)

Brand and Other Names:
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet: Schedule II

  • 15mg
  • 30mg
  • 60mg
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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

Dosage Forms & Strengths

tablet: Schedule II

  • 15mg
  • 30mg
  • 60mg

oral solution: Schedule II

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

12 years: 0.5-1 mg/kg PO q4-6hr PRN; not to exceed 30 mg/dose; titrate dose to pain relief; use lowest effective dose for shortest period of time  

12-17 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

Dosing considerations

  • See Black Box Warnings and Contraindications sections for warning regarding postoperative use following tonsillectomy and/or adenoidectomy
  • Potential toxic dose <6 years: 2 mg/kg

Cough (Off-label)

<12 years: Not recommended 

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

Dosing considerations

  • Potential toxic dose <6 years: 2 mg/kg
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Interactions

Interaction Checker

and codeine

No Results

     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse Effects

            >10%

            Constipation

            Drowsiness

            1-10%

            Hypotension

            Tachycardia or bradycardia

            Confusion

            Dizziness

            False feeling of well-being

            Headache

            Lightheadedness

            Malaise

            Paradoxical CNS stimulation

            Restlessness

            Rash, urticaria

            Anorexia

            Nausea, vomiting

            Xerostomia

            Ureteral spasm, urination decreased

            LFTs increased

            Burning at injection site

            Weakness

            Blurred vision

            Dyspnea

            Histamine release

            <1%

            Hypotension, with IV use

            Anaphylactoid reaction (rare)

            Seizure, with excessive doses

            Respiratory depression

            Postmarketing Reports

            Severe hypotension

            Life-threatening respiratory depression

            Neonatal opioid withdrawal syndrome

            Death related to ultra-rapid metabolizers of codeine

            Adrenal insufficiency

            Gastrointestinal adverse reactions

            Seizures

            Euphoria

            Dysphoria

            Abdominal pain

            Pruritus

            Sweating

            Serotonin syndrome

            Anaphylaxis

            Androgen deficiency

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            Warnings

            Black Box Warnings

            Addiction, abuse, and misuse

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

            Life-threatening respiratory depression

            • Serious, life-threatening, or fatal respiratory depression may occur
            • Monitor for respiratory depression, especially during initiation or following a dose increase

            Accidental ingestion

            • Accidental ingestion of even 1 dose, especially by children, can result in a fatal overdose

            Neonatal opioid withdrawal syndrome

            • Prolonged use during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts
            • If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available

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

            • Respiratory depression and death reported in children who received codeine following tonsillectomy and/or adenoidectomy that were also ultra-rapid metabolizers of codeine  due to CYP2D6 polymorphism
            • Contraindicated in children <12 years and in children <18 years following tonsillectomy and/or adenoidectomy; avoid use in adolescents 12-18 years who have risk factors that may increase sensitivity to respiratory depressant effects of codeine

            Interactions with drugs affecting cytochrome P450 isoenzymes

            • Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors requires careful consideration of the effects on parent drug, codeine, and active metabolite, morphine

            Risks from concomitant use with benzodiazepines or other CNS depressants

            • Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death
            • Reserve concomitant prescribing of codeine sulfate tablets and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate
            • Limit dosages and durations to minimum required
            • Follow patients for signs and symptoms of respiratory depression and sedation

            Contraindications

            Hypersensitivity to 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

            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

            Profound sedation, respiratory depression, coma, and death may result from concomitant administration with benzodiazepines or other CNS depressants (e.g., 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

            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

            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
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            Pregnancy & Lactation

            Pregnancy: Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth; observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly; opioids cross placenta and may produce respiratory depression and psycho-physiologic effects in neonates; an opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate; codeine sulfate is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate; opioid analgesics can prolong labor through actions which temporarily reduce strength, duration, and frequency of uterine contractions

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

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

            Pregnancy Categories

            A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA:Information not available.

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            Pharmacology

            Mechanism of Action

            Narcotic agonist analgesic with antitussive activity, mu receptor agonist

            Absorption

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

            Duration: 4-6 hr

            Peak plasma time: 0.5-1 hr

            Distribution

            Protein bound: 25%

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

            Metabolism

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

            Elimination

            Half-life: 3-4 hr

            Excretion: Urine, feces

            Pharmacogenomics

            10% of codeine is metabolized to morphine by CYP2D6; the active morphine metabolite has a higher affinity for opioid receptors

            CYP2D6 poor metabolizers may not achieve adequate analgesia

            Ultra-rapid metabolizers (up to 7% of Caucasians and up to 30% of Asian and African populations) may have increased toxicity due to rapid conversion

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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
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            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
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            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
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            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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