VA Class:RE301

ATC Class:R05DA04

AHFS Class:

• Antitussives 48:08

Generic Name(s):

• Codeine Phosphate

• Codeine Sulfate

• Codeine Sulfate

• Guaifenesin and Codeine Phosphate

Codeine is a phenanthrene-derivative opiate agonist antitussive agent.

Cough

Codeine is used, alone or in combination with other antitussives or expectorants, in the symptomatic relief of nonproductive cough. Since the cough reflex may be a useful physiologic mechanism which clears the respiratory passages of foreign material and excess secretions and may aid in preventing or reversing atelectasis, cough suppressants should not be used indiscriminately.

Antitussives containing codeine should not be used in patients younger than 18 years of age.710 (See Cautions: Pediatric Precautions.)

Pain

For use of codeine as an analgesic, see 28:08.08.

Administration

Codeine sulfate and codeine phosphate are administered orally as antitussives.

Dosage

Cough

Codeine preparations should be given in the smallest effective dose and as infrequently as possible to minimize the development of tolerance and physical dependence. Reduced dosage is indicated in poor-risk patients and in very old patients.

The usual oral antitussive dosage of codeine phosphate or codeine sulfate conventional (immediate-release) preparations in adults is 10-20 mg every 4-6 hours, not to exceed 120 mg daily.

Adverse Effects

Adverse reactions occur infrequently with usual oral antitussive doses of codeine. Nausea, vomiting, constipation with repeated doses, dizziness, sedation, palpitation, pruritus, and, rarely, excessive perspiration and agitation have been reported. Although equianalgesic doses of codeine and morphine produce similar degrees of respiratory depression, respiratory depression seldom occurs with oral antitussive doses of codeine.

Precautions and Contraindications

Codeine is contraindicated in children younger than 12 years of age for the management of cough and cold.705 In addition, FDA states that use of antitussives containing codeine is not recommended in pediatric patients younger than 18 years of age.710 (See Cautions: Pediatric Precautions.)

Individuals who are ultrarapid metabolizers of cytochrome P-450 (CYP) 2D6 substrates are likely to have higher than expected serum concentrations of morphine, the active metabolite of codeine; therefore, FDA states that codeine should not be used in such patients.705 (See Pharmacokinetics: Pharmacogenomics.)

Because concomitant use of opiate agonists and benzodiazepines or other CNS depressants may result in profound sedation, respiratory depression, coma, and death, opiate antitussives should be avoided in patients receiving CNS depressants.700,704 (See Drug Interactions.) Patients receiving codeine and/or their caregivers should be apprised of the risks associated with concomitant therapeutic or illicit use of benzodiazepines, alcohol, or other CNS depressants.700,703

When preparations containing codeine in fixed combination with other drugs are used, the cautions, precautions, and contraindications applicable to each ingredient must be considered.

In patients with asthma or pulmonary emphysema, the indiscriminate use of antitussives may precipitate respiratory insufficiency resulting from increased viscosity of bronchial secretions and suppression of the cough reflex.

Tolerance and physical dependence may occur following prolonged administration of codeine. Patients should be warned that codeine may impair their ability to perform activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle). Codeine should be used with caution in debilitated patients. The drug should also be used with caution in patients who have undergone thoracotomies or laparotomies, since suppression of the cough reflex may lead to retention of secretions postoperatively in these patients.

FDA states that use of codeine is not recommended in nursing women, especially those who have evidence of ultrarapid metabolism of CYP2D6 substrates.705 Serious adverse events (i.e., excessive sedation, difficulty nursing, respiratory depression), including death, have been reported in nursing infants exposed to codeine.705 One case of opiate toxicity resulting in neonatal death has been reported in the nursing infant of a woman receiving codeine; genetic testing of the woman indicated that she was an ultrarapid metabolizer of codeine.104,105,107,113,705 (See Pharmacokinetics: Pharmacogenomics.) Higher than expected concentrations of morphine were found in breast milk and in the blood of the infant.104,106,107,705 Somnolence also has been reported more frequently in nursing infants whose mothers received codeine in combination with acetaminophen compared with those whose mothers received acetaminophen alone; evidence of ultrarapid metabolism of CYP2D6 substrates was identified in some of these women.705 Concentrations of morphine in breast milk are low and dose dependent in women who are normal metabolizers of codeine.705 Although not routinely used in clinical practice, FDA-approved tests (e.g., AmpliChip^® CYP450 Test) are available to identify an individual's CYP2D6 genotype.106,111,113 However, testing alone may not adequately predict the risk of adverse reactions.104,113 Infants exposed to codeine through breast milk should be monitored closely for clinical manifestations of opiate toxicity (e.g., sedation, difficulty breast-feeding or breathing, hypotonia).104,105,106,113,705 If such manifestations occur, caregivers should seek immediate medical treatment for the infant.705

Codeine is contraindicated in patients with known hypersensitivity to the drug.

For additional information on the usual precautions of opiate agonist therapy, see Cautions in the Opiate Agonists General Statement 28:08.08.

Pediatric Precautions

Pediatric patients receiving codeine for the management of cough and cold, especially those who are obese, have obstructive sleep apnea or severe lung disease, or have evidence of ultrarapid metabolism of CYP2D6 substrates, are at increased risk of respiratory depression.705 Between January 1969 and May 2015, the FDA Adverse Event Reporting System (AERS) received 64 reports of respiratory depression, including 24 reports of death, worldwide that were associated with codeine use in pediatric patients younger than 18 years of a in all 10 of the reports that provided information about CYP2D6 metabolizer status, the patients were ultrarapid or extensive metabolizers of CYP2D6 substrates.705 (See Pharmacokinetics: Pharmacogenomics.) Most of the cases of respiratory depression, including most of the deaths, occurred in children younger than 12 years of age.705 Respiratory depression may occur despite serum concentrations of codeine or morphine being within the therapeutic ran one patient who had concentrations within the therapeutic range died following use of codeine for management of pain after tonsillectomy and adenoidectomy.705 In addition, a review initiated by the European Medicines Agency (EMA) in 2014 identified 14 cases of morphine toxicity, including 4 deaths, in children 17 days to 6 years of age receiving codeine for relief of symptoms of upper respiratory tract infection (e.g., cough).126

Because the risks of respiratory depression, misuse, abuse, addiction, overdosage, and death outweigh the potential benefit in pediatric patients, FDA states that antitussive agents containing opiates, including codeine, should not be used in pediatric patients younger than 18 years of age.710 In addition, use of codeine for the management of cough is contraindicated in children younger than 12 years of age.705 FDA is requiring inclusion of this warning against antitussive use of codeine in pediatric patients younger than 18 years of age and this contraindication to antitussive use of codeine in children younger than 12 years of age in the labeling of codeine-containing cough and cold preparations available by prescription; FDA also is considering additional regulatory action for fixed-combination codeine-containing cough and cold preparations available without a prescription in some states.705,710 FDA and EMA consider that cough and cold generally are self-limiting conditions and that evidence of codeine's efficacy in the management of these conditions in children is limited.125,126

Serious adverse events, including deaths, also have been reported in children receiving codeine for management of pain.117,118,119,122,123,124,705 For additional information on precautions and contraindications associated with the use of codeine as an analgesic in pediatric patients, see Cautions: Pediatric Precautions in Codeine 28:08.08.

Concomitant use of opiate agonists and benzodiazepines or other CNS depressants (e.g., anxiolytics, sedatives, hypnotics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opiate agonists, alcohol) may result in profound sedation, respiratory depression, coma, and death.416,417,418,700,701,702,703,704 Opiate agonist antitussives should be avoided in patients taking benzodiazepines, other CNS depressants, or alcohol.700,704 Concomitant use of opiate agonists with serotonergic drugs can cause serotonin syndrome.400 (See Drug Interactions in the Opiate Agonists General Statement 28:08.08.)

Acute Toxicity

Toxic doses of codeine may produce exhilaration, excitement, seizures, delirium, hypotension, miosis, slow pulse, tachycardia, narcosis, flushed facies, tinnitus, lassitude, muscular weakness, and circulatory collapse or respiratory paralysis. Codeine should be discontinued if any of the aforementioned effects occur. Respiratory arrest, coma, and death have occurred in young children receiving oral codeine doses of 5-12 mg/kg.100,101,102 Severe respiratory depression resulting from acute toxicity may be reversed by administration of an opiate antagonist (i.e., naloxone hydrochloride).

Pharmacology

Codeine causes suppression of the cough reflex by a direct effect on the cough center in the medulla of the brain and appears to exert a drying effect on respiratory tract mucosa and to increase viscosity of bronchial secretions. On a weight basis, antitussive activity of codeine is less than that of morphine. Codeine also has mild analgesic and sedative effects.

Pharmacokinetics

Codeine is well absorbed from the GI tract. Following oral administration, peak antitussive effects usually occur within 1-2 hours and antitussive activity may persist for 4 hours. Codeine is distributed into milk.

Like other phenanthrene derivatives, codeine is metabolized in the liver. The drug undergoes O -demethylation (by cytochrome P-450 [CYP] isoenzyme 2D6), N -demethylation (by CYP3A4), and partial conjugation with glucuronic acid and is excreted in the urine as norcodeine and morphine in the free and conjugated forms. Negligible amounts of codeine and its metabolites are found in the feces.

Codeine is metabolized by the CYP microsomal enzyme system, principally by CYP3A4, and to a lesser extent by CYP2D6 (debrisoquine hydroxylase).110,112 Although the CYP2D6 isoenzyme accounts for only 10% of the metabolism of codeine, it plays an essential role in converting the drug to its active O -demethylated metabolite, morphine.108,109,110,112

Pharmacogenomics: Metabolism of certain drugs, including codeine, is influenced by CYP2D6 polymorphism.108,109,110,112,114 Individuals who lack functional alleles of the CYP2D6 gene are described as poor metabolizers, those with one or two functional alleles are described as extensive metabolizers, and those who carry a duplicate or amplified gene are described as ultrarapid metabolizers.108,109,110,114 Genetically determined differences in drug metabolism can affect an individual's response to a drug or risk of having an adverse event.108,109,110,112,114 Individuals who are poor metabolizers experience no analgesic effects of codeine;109 individuals who are ultrarapid metabolizers are likely to have higher than expected serum concentrations of morphine.107,109,110,112

Variations in CYP2D6 polymorphism occur at different frequencies among subpopulations of different ethnic or racial origin.107,108,109,110,114 Approximately 1-7% of Caucasians and 10-30% of Ethiopians and Saudi Arabians carry the genotype associated with ultra-rapid metabolism of CYP2D6 substrates.107,108,110,114

Chemistry and Stability

Chemistry

Codeine is a phenanthrene-derivative opiate agonist antitussive agent. Codeine occurs as colorless or white crystals or as a white, crystalline powder and is slightly soluble in water and freely soluble in alcohol. The phosphate and sulfate salts of codeine occur as white, needle-shaped crystals or white, crystalline powders. Codeine phosphate is freely soluble in water and slightly soluble in alcohol. Codeine sulfate is soluble in water and very slightly soluble in alcohol. Because of its greater water solubility, codeine phosphate is most frequently used for extemporaneous compounding.

Stability

Codeine sulfate tablets should be stored in well-closed, light-resistant containers at a temperature less than 40°C, preferably between 15-30°C.

Additional Information

For further information on chemistry and stability, pharmacology, pharmacokinetics, uses, cautions, and dosage and administration of codeine, see 28:08.08. See also the Opiate Agonists General Statement 28:08.08.

Only references cited for selected revisions after 1984 are available electronically.

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