ACETAMINOPHEN AND CODEINE PHOSPHATE- acetaminophen and codeine phosphate tablet
Preferred Pharmaceuticals, Inc.
WARNING: ADDICTION, ABUSE, AND MISUSE:RISK EVALUATION AND MITIGATION STRATEGY (REMS), LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; DEATH RELATED TO ULTRA-RAPID METABOLISM OF CODEINE TO MORPHINE;HEPATOTOXICITY; CYTOCHROME P450 2D6 INTERACTION; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
Addiction, Abuse and Misuse
Acetaminophen and codeine phosphate tablets expose 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 acetaminophen and codeine phosphate tablets, and monitor all patients regularly for the development of these behaviors and conditions [see WARNINGS].
Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS):
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 REMS for these products [see Warnings]. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to
• complete a REMS-compliant education program,
• counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products,
• emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist, and
• Consider other tools to improve patient, household, and community safety.
Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression may occur with use of acetaminophen and codeine phosphate tablets. Monitor for respiratory depression, especially during initiation of acetaminophen and codeine phosphate tablets or following a dose increase [see WARNINGS].
Accidental ingestion of acetaminophen and codeine phosphate tablets, especially by children, can result in a fatal overdose of acetaminophen and codeine phosphate tablets [see WARNINGS].
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 cases following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizers of codeine due to a CYP2D6 polymorphism. Codeine is contraindicated in children younger than twelve years of age and in children of any age who are undergoing tonsillectomy and/or adenoidectomy. Avoid the use of acetaminophen and codeine phosphate 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 acetaminophen and codeine phosphate 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 [see WARNINGS].
Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4,000 milligrams per day, and often involve more than one acetaminophen-containing product [see WARNINGS].
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 Acetaminophen and Codeine Phosphate Tablets requires careful consideration of the effects on the parent drug, codeine, and the active metabolite, morphine.
• Cytochrome P450 3A4 Interaction
The concomitant use of Acetaminophen and Codeine Phosphate Tablets with all cytochrome P450 3A4 inhibitors or discontinuation of a cytochrome P450 3A4 inducer may result in an increase in codeine plasma concentrations with subsequently greater metabolism by cytochrome P450 2D6, resulting in greater morphine levels, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression.
The concomitant use of Acetaminophen and Codeine Phosphate Tablets with all cytochrome P450 3A4 inducers or discontinuation of a cytochrome P450 3A4 inhibitor may result in lower codeine levels, greater norcodeine levels, and less metabolism via 2D6 with resultant lower morphine levels. This may be associated with a decrease in efficacy, and in some patients, may result in signs and symptoms of opioid withdrawal.
Follow patients receiving Acetaminophen and Codeine Phosphate Tablets and any CYP3A4 inhibitor or inducer for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when Acetaminophen and Codeine Phosphate Tablets are used in conjunction with inhibitors and inducers of CYP3A4 [see Warnings, Precautions, Drug Interactions].
• Cytochrome P450 2D6 Interaction
The concomitant use of Acetaminophen and Codeine Phosphate Tablets with all cytochrome P450 2D6 inhibitors may result in an increase in codeine plasma concentrations and a decrease in the plasma concentration of the active metabolite, morphine, which could result in an analgesic efficacy reduction or symptoms of opioid withdrawal.
The discontinuation of a cytochrome P450 2D6 inhibitor may result in a decrease in codeine plasma concentrations and an increase in the plasma concentration of the active metabolite, morphine, which could which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression.
Follow patients receiving Acetaminophen and Codeine Phosphate Tablets and any CYP2D6 inhibitor for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when Acetaminophen and Codeine Phosphate Tablets are used in conjunction with inhibitors of CYP2D6 [see WARNINGS, PRECAUTIONS, DRUG INTERACTIONS].
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, PRECAUTIONS, Drug Interactions].
• Reserve concomitant prescribing of acetaminophen and codeine phosphate 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.
Acetaminophen and codeine phosphate tablets, USP are for oral administration.Acetaminophen, 4’-hydroxyacetanilide, a slightly bitter, white, odorless, crystalline powder, is a non-opiate, non-salicylate analgesic and antipyretic. It has the following structural formula:
Codeine phosphate, 7,8-didehydro-4,5α-epoxy-3-methoxy-17-methylmorphinan-6α-ol phosphate (1:1) (salt) hemihydrate, a white crystalline powder, is a narcotic analgesic and antitussive. It has the following structural formula:
Each tablet contains:
Codeine Phosphate……………………15 mg
(Warning: May be habit forming)
Codeine Phosphate……………………30 mg
(Warning: May be habit forming)
Codeine Phosphate……………………60 mg
(Warning: May be habit forming)
In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, crospovidone, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch, sodium lauryl sulfate, and stearic acid.
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