CODEINE SULFATE tablets, CII
Codeine Sulfate Tablets USP contain codeine, an opioid agonist, available for oral administration containing either 15 mg, 30 mg, or 60 mg of codeine sulfate USP. The chemical name is morphinan-6-ol,7,8-didehydro-4,5-epoxy-3-methoxy-17-methyl-(5α,6α)-, sulfate (2:1) (salt), trihydrate. Its molecular formula is (C18H21NO3)2 • H2SO4 • 3H2O and its molecular weight is 750.85 g/mol.
The inactive ingredients in Codeine Sulfate Tablets USP include: colloidal silicon dioxide, microcrystalline cellulose, pregelatinized starch and stearic acid.
Indications and usage
Codeine Sulfate Tablets are an opioid agonist, indicated for the management of mild to moderate pain, where treatment with an opioid is appropriate and for which alternative treatments are inadequate.
Limitations of Use: Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, reserve Codeine Sulfate Tablets for use in patients for whom alternative treatment options [e.g., non-opioid analgesics or opioid combination products]:
- Have not been tolerated, or are not expected to be tolerated.
- Have not provided adequate analgesia, or are not expected to provide adequate analgesia.
Mechanism of Action
Codeine sulfate is an opioid agonist relatively selective for the mu-opioid receptor, but with a much weaker affinity than morphine. The analgesic properties of codeine have been speculated to come from its conversion to morphine, although the exact mechanism of analgesic action remains unknown.
Dosage and administration
- Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals
- Initiate the dosing regimen for each patient individually, taking into account the patient’s severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse
- Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy and following dosage increases with Codeine Sulfate Tablets and adjust the dosage accordingly
Initiating Treatment with Codeine Sulfate Tablets: Initiate treatment with Codeine Sulfate Tablets in a dosing range of 15 to 60 mg every 4 hours as needed for pain. Adult doses of Codeine Sulfate Tablets higher than 60 mg provide no further efficacy but are associated with greater adverse reactions. The maximum 24 hour dose is 360 mg.
Codeine Sulfate Tablets are contraindicated for:
- All children younger than 12 years of age.
- Post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy
- Significant respiratory depression.
- Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment.
- Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days.
- Known or suspected gastrointestinal obstruction, including paralytic ileus.
- Hypersensitivity to codeine (e.g., anaphylaxis)
Cardiovascular System: faintness, flushing, hypotension, palpitations, syncope
Digestive System: abdominal cramps, anorexia, diarrhea, dry mouth, gastrointestinal distress, pancreatitis
Nervous System: anxiety, drowsiness, fatigue, headache, insomnia, nervousness, shakiness, somnolence, vertigo, visual disturbances, weakness
Skin and Appendages: rash, sweating, urticaria
Serotonin Syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.
Adrenal Insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.
Anaphylaxis: Anaphylaxis has been reported with ingredients contained in Codeine Sulfate Tablets.
Androgen Deficiency: Cases of androgen deficiency have occurred with chronic use of opioids
Warnings and precautions
- Codeine Sulfate Tablets exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient’s risk before prescribing and monitor regularly for these behaviors and conditions.
- To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products.
- Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase.
- Accidental ingestion of Codeine Sulfate Tablets, especially by children, can result in a fatal overdose of codeine.
- Life-threatening respiratory depression and death have occurred in children who received codeine; most cases followed tonsillectomy and/or adenoidectomy and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism.
- Codeine Sulfate Tablets are contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of Codeine Sulfate Tablets in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine. • Prolonged use of Codeine Sulfate Tablets during pregnancy can result in neonatal opioid withdrawal syndrome which may be lifethreatening if not recognized and treated. If prolonged opioid use is required in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.
- The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with codeine are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with Codeine Sulfate Tablets requires careful consideration of the effects on the parent drug, codeine, and the active metabolite, morphine.
- 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 for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation.
Inhibitors of CYP3A4: The concomitant use of Codeine Sulfate Tablets with CYP3A4 inhibitors, may result in an increase in codeine plasma concentrations with subsequently greater metabolism by cytochrome CYP2D6, resulting in greater morphine levels, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of Codeine Sulfate Tablets is achieved
After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, it may result in lower codeine levels, greater norcodeine levels, and less metabolism via CYP2D6 with resultant lower morphine levels, resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to codeine.
Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers: The concomitant use of Codeine Sulfate Tablets and CYP3A4 inducers can result in lower codeine levels, greater norcodeine levels, and less metabolism via 2D6 with resultant lower morphine levels, resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
After stopping a CYP3A4 inducer, as the effects of the inducer decline, codeine plasma concentrations may increase with subsequently greater metabolism by cytochrome CYP2D6, resulting in greater morphine levels, which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Examples: Rifampin, carbamazepine, phenytoin
Inhibitors of CYP2D6: Codeine is metabolized by CYP2D6 to form morphine. The concomitant use of Codeine Sulfate Tablets and CYP2D6 inhibitors can increase the plasma concentration of codeine, but can decrease the plasma concentration of active metabolite morphine, which could result in reduced analgesic efficacy or symptoms of opioid withdrawal, particularly when an inhibitor is added after a stable dose of Codeine Sulfate Tablets is achieved
After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the codeine plasma concentration will decrease but the active metabolite morphine plasma concentration will increase, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression
Examples: Paroxetine, fluoxetine, bupropion, quinidine.
Benzodiazepines and Other Central Nervous System (CNS) Depressants: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs): MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma). Examples: Phenelzine, tranylcypromine, linezolid.
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: May reduce the analgesic effect of Codeine Sulfate Tablets and/or precipitate withdrawal symptoms. Examples: Butorphanol, nalbuphine, pentazocine, buprenorphine.
Muscle Relaxants: Codeine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Examples: Cyclobenzaprine, metaxalone.
Diuretics: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Monitor patients for signs of urinary retention or reduced gastric motility when Codeine Sulfate Tablets are used concomitantly with anticholinergic drugs.
Use in specific populations
Pregnancy: Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome. Available data with Codeine Sulfate Tablets are insufficient to inform a drug-associated risk for major birth defects and miscarriage.
Fetal/Neonatal Adverse Reactions: 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.
Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly
Lactation: Codeine and its active metabolite, morphine, are present in human milk. There are published studies and cases that have reported excessive sedation, respiratory depression, and death in infants exposed to codeine via breast milk. Women who are ultra-rapid metabolizers of codeine achieve higher than expected serum levels of morphine, potentially leading to higher levels of morphine in breast milk that can be dangerous in their breastfed infants. In women with normal codeine metabolism (normal CYP2D6 activity), the amount of codeine secreted into human milk is low and dose-dependent.
Hepatic Impairment: No formal studies have been conducted in patients with hepatic impairment so the pharmacokinetics of codeine in this patient population are unknown. Start these patients with a lower than normal dosage of Codeine Sulfate Tablets or with longer dosing intervals and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension.
Renal Impairment: Codeine pharmacokinetics may be altered in patients with renal failure. Clearance may be decreased and the metabolites may accumulate to much higher plasma levels in patients with renal failure as compared to patients with normal renal function. Start these patients with a lower than normal dosage of Codeine Sulfate Tablets or with longer dosing intervals and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension.
Drug abuse and dependence
Controlled Substance: Codeine Sulfate Tablets contain codeine, a Schedule II controlled substance.
Abuse: Codeine Sulfate Tablets contains codeine, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol. Codeine Sulfate Tablets can be abused and is subject to misuse, addiction, and criminal diversion
All patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carry the risk of addiction even under appropriate medical use.
Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.
Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.
Dependence: Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.
Physical dependence is a physiological state in which the body adapts to the drug after a period of regular exposure, resulting in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine).
Acute overdose with Codeine Sulfate Tablets can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations
Treatment of Overdose: In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support techniques.
Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to opioid overdose, administer an opioid antagonist.
In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist.