Data from FDA - Curated by EPG Health - Last updated 09 October 2017

Indication(s)

1 INDICATIONS AND USAGE Codeine sulfate tablets are 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 [ s ee Warnings and Precautions ( 5.1 ) ], 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. 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. (1) Limitations of Use (1) 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.

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Advisory information

contraindications
4 CONTRAINDICATIONS Codeine sulfate tablets are contraindicated for: All children younger than 12 years of age [see Warnings and Precautions ( 5.3 )]. Post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Warnings and Precautions ( 5.3 )]. Codeine sulfate tablets are also contraindicated in patients with: Significant respiratory depression [see Warnings and Precautions ( 5.2 )]. Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions ( 5.7 )]. Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days [see Warnings and Precautions ( 5.8 ) , Drug Interactions ( 7 ) ] . Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions ( 5.12 )]. Hypersensitivity to codeine (e.g., anaphylaxis) [see Adverse Reactions ( 6 )]. Children younger than 12 years of age. Postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. (4) Significant respiratory depression. (4) Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment. (4) Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days. (4) Known or suspected gastrointestinal obstruction, including paralytic ileus. (4) Hypersensitivity to codeine. (4)
Adverse reactions
6 ADVERSE REACTIONS The following serious adverse reactions are described, or described in greater detail, in other sections: Addiction, Abuse, and Misuse [see Warnings and Precautions ( 5.1 )] Life-Threatening Respiratory Depression [see Warnings and Precautions ( 5.2 )] Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children [see Warnings and Precautions (5.3)] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.4 )] Interactions with Benzodiazepines and Other CNS Depressants [see Warnings and Precautions ( 5.6 )] Adrenal Insufficiency [see Warnings and Precautions ( 5.9 )] Severe Hypotension [see Warnings and Precautions ( 5.10 )] Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.12 )] Seizures [see Warnings and Precautions ( 5.13 )] Withdrawal [see Warnings and Precautions ( 5.14 )] The following adverse reactions associated with the use of codeine were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Serious adverse reactions associated with codeine were respiratory depression and, to a lesser degree, circulatory depression, respiratory arrest, shock, and cardiac arrest. The most frequently observed adverse reactions with codeine administration included drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea, vomiting, sweating, and constipation. Other adverse reactions included allergic reactions, euphoria, dysphoria, abdominal pain, and pruritis. Other less frequently observed adverse reactions expected from opioid analgesics, including codeine sulfate tablets, include: C ardiovascular System: faintness, flushing, hypotension, palpitations, syncope D i gestive System: abdominal cramps, anorexia, diarrhea, dry mouth, gastrointestinal distress, pancreatitis N ervous 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. A drenal Insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. A naphylaxis: Anaphylaxis has been reported with ingredients contained in codeine sulfate tablets. A ndrogen Deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology ( 12.2 ) ]. The most common adverse reactions include: drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea, vomiting, and sweating. (6) To report SUSPECTED ADVERSE REACTIONS, contact Lannett Company, Inc. at 844-834-0530 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals. (2.1) Individualize dosing based on the severity of pain, patient response, prior analgesic experience, and risk factors for addiction, abuse, and misuse. (2.1) Initiate treatment with 15 to 60 mg every 4 hours as needed. (2.2) Do not stop codeine sulfate tablets abruptly in a physically dependent patient. (2.4) 2.1 Important Dosage and Administration Instructions Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions ( 5 ) ] . 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 [see Warnings and Precautions ( 5.1 ) ]. 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 [ see Warnings and Precautions ( 5.2 ) ] . 2.2 Initial Dosage 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. C onversion from Other Opioids to Codeine Sulfate Tablets There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of codeine sulfate tablets. It is safer to underestimate a patient’s 24-hour codeine sulfate tablets dosage than to overestimate the 24-hour codeine sulfate tablets dosage and manage an adverse reaction due to overdose. 2.3 Titration and Maintenance of Therapy Individually titrate codeine sulfate tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving codeine sulfate to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse [see Warnings and Precautions ( 5.1 ) ]. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the codeine sulfate tablets dosage. If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions. 2.4 Discontinuation of Codeine Sulfate Tablets When a patient who has been taking codeine sulfate tablets regularly and may be physically dependent no longer requires therapy with codeine sulfate tablets, taper the dose gradually, by 25% to 50% every 2 to 4 days, while monitoring carefully for signs and symptoms of withdrawal. If the patient develops these signs or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both. Do not abruptly discontinue codeine sulfate tablets in a physically-dependent patient [see Warnings and Precautions ( 5.14 ) , Drug Abuse and Dependence ( 9.3 ) ].
Use in special populations
8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause fetal harm. (8.1) Lactation: Breastfeeding not recommended. (8.2) 8.1 Pregnancy Pregnancy Category C R i sk Summary Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.4)]. Available data with codeine sulfate tablets are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, codeine administration during organogenesis has been shown to produce delayed ossification in the offspring of mice at 1.4 times maximum recommended human dose (MRHD) of 360 mg/day, embryolethal and fetotoxic effects in the offspring of rats and hamsters at approximately 2 to 3 times the MRHD, and cranial malformations/cranioschisis in the offspring of hamsters between 2 and 8 times the MRHD [s ee D ata ]. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. C li n i cal Considerations 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 [ see Warnings and Precautions ( 5.4 ) ]. Labor or Delivery: Opioids cross the 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 tablets are not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including codeine sulfate tablets, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. D ata Animal Data: Studies on the reproductive and developmental effects of codeine have been reported in the published literature in hamsters, rats, mice and rabbits. In a study in which pregnant hamsters were administered 150 mg/kg twice daily of codeine (oral; approximately 7 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m2 basis) during organogenesis cranial malformations (i.e., meningoencephalocele) in several fetuses were reported; as well as the observation of increases in the percentage of resorptions per litter. Doses of 50 and 150 mg/kg, bid resulted in fetotoxicity as demonstrated by decreased fetal body weight. In an earlier study in hamsters, single oral doses of 73 to 360 mg/kg level on Gestation Day 8 (oral; approximately 2 to 8 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m2 basis), reportedly produced cranioschisis in all of the fetuses examined. In studies in rats, doses at the 120 mg/kg level (oral; approximately 3 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m2 basis) during organogenesis, in the toxic range for the adult animal, were associated with an increase in embryo resorption at the time of implantation. In pregnant mice, a single 100 mg/kg dose (subcutaneous; approximately 1.4 times the recommended daily dose of 360 mg/day for adults on a mg/mg2 basis) administered between Gestation Day 7 and 12 reportedly resulted in delayed ossification in the offspring. No teratogenic effects were observed in rabbits administered up to 30 mg/kg (approximately 2 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m2 basis) of codeine during organogenesis. Codeine (30 mg/kg) administered subcutaneously to pregnant rats during pregnancy and for 25 days after delivery increased neonatal mortality at birth. This dose is 0.8 times the maximum recommended human dose of 360 mg/day on a body surface area comparison. 8.2 Lactation R i sk Summary 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. There is no information on the effects of codeine on milk production. Because of the potential for serious adverse reactions, including excess sedation, respiratory depression, and death in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with codeine sulfate tablets [see Warnings and Precautions ( 5.3 )]. C li n i cal Considerations If infants are exposed to codeine sulfate tablets through breast milk, they should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breastfeeding is stopped. 8.3 Females and Males of Reproductive Potential Infertility 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 [ s ee Adverse Reactions ( 6 ) ]. 8.4 Pediatric Use The safety and effectiveness of codeine sulfate tablets in pediatric patients have not been established. Life-threatening respiratory depression and death have occurred in children who received codeine [see Warnings and Precautions ( 5.3 )]. In most of the reported cases, these events followed tonsillectomy and/or adenoidectomy, and many of the children had evidence of being ultra-rapid metabolizers of codeine (i.e., multiple copies of the gene for cytochrome P450 isoenzyme 2D6 or high morphine concentrations). Children with sleep apnea may be particularly sensitive to the respiratory depressant effects of codeine. Because of the risk of life-threatening respiratory depression and death: Codeine sulfate tablets are contraindicated for all children younger than 12 years of age [see Contraindications ( 4 )]. Codeine sulfate tablets are contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications ( 4 )]. 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 unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression [see Warnings and Precautions ( 5.3 )]. 8.5 Geriatric Use Elderly patients (aged 65 years or older) may have increased sensitivity to codeine. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of codeine sulfate tablets slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions ( 5.7 ) ]. Codeine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. 8.6 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. 8.7 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.

Interactions

7 DRUG INTERACTIONS Table 1 includes clinically significant drug interactions with codeine sulfate tablets. Table 1: Clinically Significant Drug Interactions with Codeine Sulfate Tablets Inhibitors of CYP3A4 C li n i cal Impact: 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 [see Warnings and Precautions ( 5.5 ) ]. 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 [see Clinical Pharmacology ( 12.3 ) ], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to codeine. Intervention: If concomitant use of CYP3A4 inhibitor is necessary, consider dosage reduction of codeine sulfate tablets until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the codeine sulfate tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. E xamples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir) CY P 3A4 Inducers C li n i cal Impact: 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 [see Clinical Pharmacology (12.3) ], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence [see Warnings and Precautions ( 5.5 ) ]. 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 [see Clinical Pharmacology (12.3) ], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression. Intervention: If concomitant use of a CYP3A4 inducer is necessary, follow the patient for reduced efficacy and signs of opioid withdrawal and consider increasing the codeine sulfate tablets dosage as needed. If a CYP3A4 inducer is discontinued, consider codeine sulfate tablets dosage reduction and monitor for signs of respiratory depression and sedation at frequent intervals. E xamples: Rifampin, carbamazepine, phenytoin Inhibitors of CYP2D6 C li n i cal Impact: 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 [see Clinical Pharmacology ( 12.3 ) ]. 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 [see Clinical Pharmacology ( 12.3 ) ]. Intervention: If concomitant use with a CYP2D6 inhibitor is necessary, or if a CYP2D6 inhibitor is discontinued after concomitant use, consider dosage adjustment of codeine sulfate tablets and monitor patients closely at frequent intervals. If concomitant use with CYP2D6 inhibitors is necessary, follow the patient for reduced efficacy or signs and symptoms of opioid withdrawal and consider increasing the codeine sulfate tablets as needed. After stopping use of a CYP2D6 inhibitor, consider reducing the codeine sulfate tablets and monitor the patient for signs and symptoms of respiratory depression or sedation. E xamples Paroxetine, fluoxetine, bupropion, quinidine B enzodiazepines and Other Central Nervous System (CNS) Depressants C li n i cal Impact: 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. Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions ( 5.6 ) ]. E xamples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. S erotonergic Drugs C li n i cal Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue codeine sulfate tablets if serotonin syndrome is suspected. E xamples: 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), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) C li n i cal Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.8) ] . Intervention: Do not use codeine sulfate tablets in patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses of other opioids (such as oxycodone, hydrocodone, oxymorphone, or buprenorphine) to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression E xamples: Phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics C li n i cal Impact: May reduce the analgesic effect of codeine sulfate tablets and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. E xamples: Butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants C li n i cal Impact: Codeine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of codeine sulfate tablets and/or the muscle relaxant as necessary. D i u retics C li n i cal Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. A n ticholinergic Drugs C li n i cal Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when codeine sulfate tablets are used concomitantly with anticholinergic drugs. Serotonergic Drugs: Concomitant use may result in serotonin syndrome. Discontinue codeine sulfate if serotonin syndrome is suspected. (7) Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid use with codeine sulfate tablets because they may reduce analgesic effect of codeine sulfate tablets or precipitate withdrawal symptoms. (7)

More information

Category Value
Authorisation number ANDA203046
Agency product number 11QV9BS0CB
Orphan designation No
Product NDC 0527-1727,0527-1698,0527-1699
Date Last Revised 13-09-2017
Type HUMAN PRESCRIPTION DRUG
Marketing authorisation holder Lannett Company, Inc.
Warnings WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE- THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-TREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS Addiction, Abuse, and Misuse Codeine sulfate tablets 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 codeine sulfate tablets, and monitor all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.1)]. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of codeine sulfate tablets. Monitor for respiratory depression, especially during initiation of codeine sulfate tablets or following a dose increase [see Warnings and Precautions (5.2)]. Accidental Ingestion Accidental ingestion of even one dose of codeine sulfate tablets, especially by children, can result in a fatal overdose of codeine [see Warnings and Precautions (5.2)]. 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 the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism [see Warnings and Precautions ( 5.3 )]. 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 [see Contraindications ( 4 )]. 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. Neonatal Opioid Withdrawal Syndrome Prolonged use of codeine sulfate tablets 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 [see Warnings and Precautions ( 5.4 )]. Interactions with Drugs Affecting Cytochrome P450 Isoenzymes 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. [See Warnings and Precautions (5.5), Drug Interactions (7)]. 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 [see Warnings and Precautions (5.6), Drug Interactions (7)]. 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 the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation. W ARNING : ADDICTION, ABUSE, AND MISUSE; LIFE- THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-TREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS See full prescribing information for complete boxed warning. 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. (5.1) Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. (5.2) Accidental ingestion of codeine sulfate tablets, especially by children, can result in a fatal overdose of codeine. (5.2) 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. (5.3) 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. (4) 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 life-threatening 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. ( 5 . 4 ) 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. (5.5, 7) 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. (5.6, 7)