Administration 
Codeine sulfate and codeine phosphate are administered orally.
Dosage
Codeine salts should be given at the lowest effective dosage and for the shortest duration of therapy consistent with the treatment goals of the patient.411,413,431,432,435 Reduced dosage is indicated in poor-risk patients and in very old patients. If concomitant therapy with other CNS depressants is required, the lowest effective dosages and shortest possible duration of concomitant therapy should be used.700,703
When opiate analgesics are administered in fixed combination with nonopiate analgesics, the opiate dosage may be limited by the nonopiate component.117,119,120,121 Because commercially available preparations contain codeine and nonopiate analgesics in various fixed ratios and because these nonopiate analgesics also are available in many other prescription and OTC preparations, care should be taken to ensure that therapy is not duplicated and that dosage of the nonopiate drug does not exceed maximum recommended dosages.117,118,119,121
The initial dosage must be individualized, taking into account the patient's prior opiate use; concurrent drug therapy; degree of opiate tolerance; medical condition; type and severity of pain; and risk factors for addiction, abuse, and misuse.122,123
For the relief of mild to moderate pain in adults, the usual oral dosage of codeine phosphate or codeine sulfate is 30 mg every 4 hours as necessary; the usual dose range is 15-60 mg. Adult dosage should not exceed 360 mg daily.122,123
Children may receive 3 mg/kg or 100 mg/m2 daily in 6 divided doses. Alternatively, children may be given 0.5 mg/kg or 15 mg/m2 every 4-6 hours. (See Cautions: Pediatric Precautions.)
For acute pain not related to trauma or surgery, the prescribed quantity should be limited to the amount needed for the expected duration of pain severe enough to require opiate analgesia (generally 3 days or less and rarely more than 7 days).411,433,434,435 When opiate analgesics are used for the management of chronic noncancer pain, the US Centers for Disease Control and Prevention (CDC) recommends that primary care clinicians carefully reassess individual benefits and risks before prescribing dosages equivalent to 50 mg or more of morphine sulfate daily (approximately 330 mg or more of codeine phosphate or codeine sulfate daily) and avoid dosages equivalent to 90 mg or more of morphine sulfate daily or carefully justify their decision to titrate the dosage to such levels.411 Other experts recommend consulting a pain management specialist before exceeding a dosage equivalent to 80-120 mg of morphine sulfate daily.423,431 For further information on the management of opiate analgesic therapy, see Dosage and Administration: Dosage, in the Opiate Agonists General Statement 28:08.08.
Precautions and Contraindications
Codeine shares the toxic potentials of the opiate agonists, and the usual precautions of opiate agonist therapy should be observed. (See Cautions in the Opiate Agonists General Statement 28:08.08.)
Codeine is contraindicated in children younger than 12 years of age for the management of pain705 and in pediatric patients younger than 18 years of age for the management of postoperative pain following tonsillectomy and/or adenoidectomy.122,123,124,130,705 In addition, FDA states that use of codeine for the management of pain is not recommended in pediatric patients 12-18 years of age who are obese or have conditions such as obstructive sleep apnea or compromised respiratory function.705 (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.)
FDA also 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 (e.g., 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.104,106,107,113,705 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
When preparations containing codeine in fixed combination with other drugs are administered, the cautions, precautions, and contraindications applicable to each ingredient must be considered.
Pediatric Precautions
Pediatric patients receiving codeine for the management of pain, 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.122,123,130,705 Serious adverse events, including deaths, have been reported during postmarketing experience in pediatric patients receiving codeine.122,123,124,125,126,127,705 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.124,705 (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
To minimize the risk of serious adverse events in pediatric patients, FDA states that codeine-containing preparations must not be used for the management of pain in children younger than 12 years of age or for the management of postoperative pain following tonsillectomy and/or adenoidectomy in pediatric patients younger than 18 years of age, and that use of codeine for the management of pain is not recommended in pediatric patients 12-18 years of age who are obese or have conditions such as obstructive sleep apnea or compromised respiratory function (because of potentially greater susceptibility to the respiratory depressant effects of the drug).705 If codeine is used for the management of pain in pediatric patients 12-18 years of age, caregivers should closely monitor the child for clinical manifestations of opiate toxicity (e.g., shallow, difficult, or noisy breathing; confusion; unusual sleepiness) and seek immediate medical treatment for the child if such manifestations occur.705
Serious adverse events, including deaths, also have been reported in children receiving codeine for relief of symptoms of upper respiratory tract infection.131,705 For additional information on precautions and contraindications associated with the use of codeine as an antitussive in pediatric patients, see Cautions: Pediatric Precautions, in Codeine 48:08.
Pharmacology
Equianalgesic parenteral doses of codeine phosphate and morphine sulfate have produced similar degrees of respiratory depression. Codeine has good antitussive activity, although on a weight basis antitussive activity of codeine is less than that of morphine.
Pharmacokinetics
Codeine and its salts are well absorbed following oral administration. Following oral administration, onset of action occurs in 15-30 minutes and analgesia is maintained for 4-6 hours. Codeine is distributed into milk. Codeine is metabolized mainly in the liver where it undergoes O -demethylation (by cytochrome P-450 [CYP] isoenzyme 2D6), N -demethylation (by CYP3A4), and partial conjugation with glucuronic acid; the drug is excreted mainly in urine as norcodeine and free and conjugated morphine.110 Negligible amounts of codeine and its metabolites are found in 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 1 or 2 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 ultrarapid metabolism of CYP2D6 substrates.107,108,110,114
Chemistry and Stability
Chemistry
Codeine is a phenanthrene-derivative opiate agonist. Codeine occurs as colorless or white crystals or as a white, crystalline powder; the drug is slightly soluble in water and freely soluble in alcohol. Codeine phosphate occurs as fine, white, needle-shaped crystals or as a white, crystalline powder and is freely soluble in water and slightly soluble in alcohol. Codeine sulfate occurs as white crystals, usually needle-like, or as a white, crystalline powder and is soluble in water and very slightly soluble in alcohol.
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, pharmacology, uses, cautions, chronic toxicity, acute toxicity, drug interactions, and dosage and administration of codeine, see the Opiate Agonists General Statement 28:08.08.
Only references cited for selected revisions after 1984 are available electronically.
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