FDA label 6feb059d-5153-42a5-9306-6b05429ca86d

WARNING DEATH RELATED TO ULTRA-RAPID METABOLISM OF CODEINE TO MORPHINE and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS Ultra-Rapid Metabolism Respiratory depression and death have occurred in children who received codeine following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine due to a CYP2D6 polymorphism. ( 5.1) Concomitant Use with Benzodiazepines, 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 Warning and Precautions ( 5.2) Drug Interactions ( 7.1 ). Avoid use of opioid cough medications in patients taking benzodiazepines, other CNS depressants, or alcohol. WARNING DEATH RELATED TO ULTRA-RAPID METABOLISM OF CODEINE TO MORPHINE and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS Ultra-Rapid Metabolism Respiratory depression and death have occurred in children who received codeine following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine due to a CYP2D6 polymorphism. ( 5.1 ) Concomitant Use with Benzodiazepines, 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 Warning and Precautions ( 5.2 ) Drug Interactions ( 7.1 ). Avoid use of opioid cough medications in patients taking benzodiazepines, other CNS depressants, or alcohol.

5 WARNINGS AND PRECAUTIONS • Risk of death in ultra-rapid metabolizers: Conversion of codeine into its active metabolite, morphine, may occur more rapidly and completely resulting in higher than expected morphine levels and respiratory depression or death. ( 5.1 ) • Risks using with Benzodiazepines or other CNS Depressants. ( 5.2 ) • Dose-related respiratory depression. Use with caution. ( 5.3 ) • Drug dependence: Prescribe with caution that is appropriate to the use of other opioids. ( 5.4 ) • Head injury, intra-cranial lesions, or increased intracranial pressure: Avoid in patients with head injury, intra-cranial lesions, or increased intracranial pressure. ( 5.5 ) • Activities requiring mental alertness: Avoid engaging in hazardous tasks requiring complete mental alertness such as driving or operating machinery. Avoid concurrent use of alcohol or other central nervous system depressants.. ( 5.6 ) • Prolonged use may cause Obstructive Bowel Disease ( 5.7 ) • Acute abdominal conditions: Use caution in patients with acute abdominal conditions. ( 5.8 ) • Special risk patients: Caution in elderly patients and those with asthma, persistent or chronic cough, hypothyroidism, Addison’s disease, prostatic hypertrophy or urethral stricture. ( 5.9 ) 5.1 Death Related to Ultra-Rapid Metabolism of Codeine to Morphine Respiratory depression and death have occurred in children who received codeine in the post-operative period following tonsillectomy and/or adenoidectomy and 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). Deaths have also occurred in nursing infants who were exposed to high levels of morphine in breast milk because their mothers were ultra-rapid metabolizers of codeine. [see Use in Specific Populations (8.3) ] Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (gene duplications denoted as *1/*1xN or *1/*2xN). The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5 to 1% in Chinese and Japanese, 0.5 to 1% in Hispanics, 1 to 10% in Caucasians, 3% in African Americans, and 16 to 28% in North Africans, Ethiopians, and Arabs. Data are not available for other ethnic groups. These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing). [see Overdosage (10) ] Children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to the respiratory depressant effects of codeine that has been rapidly metabolized to morphine. CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE is contraindicated for post-operative pain management in all pediatric patients undergoing tonsillectomy and/or adenoidectomy [see Contraindications (4) ]. When prescribing codeine-containing drugs, healthcare professionals should choose the lowest effective dose for the shortest period of time and inform patients and caregivers about these risks and the signs of morphine overdose. [see Use in Specific Populations (8), Overdosage (10) ] 5.2 Risks from Concomitant Use with Benzodiazepines or other CNS Depressants Concomitant use of opioids, including CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE, with benzodiazepines, or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death . Because of these risks, avoid use of opioid cough medications in patients taking Benzodiazepines, other CNS depressants, or alcohol [ see Drug Interactions (7.1) ]. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. Because of similar pharmacologic properties, it is reasonable to expect similar risk with concomitant use of opioid cough medications and benzodiazepines, other CNS depressants, or alcohol. Advise both patients and caregivers about the risks of respiratory depression and sedation if CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE is used with benzodiazepines, alcohol, or other CNS depressants. [ see Patient Counseling Information (17)] 5.3 Respiratory Depression Codeine, one of the active ingredients in CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE, produces dose-related respiratory depression by directly acting on brain stem respiratory centers. Overdose of codeine in adults has been associated with fatal respiratory depression, and the use of codeine in children has been associated with fatal respiratory depression. Exercise caution when administering CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE because of the potential for respiratory depression. If respiratory depression occurs, discontinue CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE and use naloxone hydrochloride when indicated to antagonize the effect and other supportive measures as necessary. [see Overdosage (10) ]. 5.4 Drug Dependence Codeine can produce drug dependence of the morphine type and, therefore, has the potential for being abused. Psychological dependence, physical dependence, and tolerance may develop upon repeated administration of CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE. Prescribe and administer CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE with the same degree of caution appropriate to the use of other opioid drugs. [see Drug Abuse and Dependence (9.2 , 9.3) ] 5.5 Head Injury and Increased Intracranial Pressure The respiratory depression effects of opioids and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions, or a pre-existing increase in intracranial pressure. Furthermore, opioids produce adverse reactions that may obscure the clinical course of patients with head injuries. The use of CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE should be avoided in these patients. 5.6 Activities Requiring Mental Alertness Codeine and chlorpheniramine, the active ingredients in CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE, may produce marked drowsiness and impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. Advise patients to avoid engaging in hazardous tasks requiring mental alertness and motor coordination after ingestion of CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE. Concurrent use of CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE with alcohol or other central nervous system depressants should be avoided because additional impairment of central nervous system performance may occur. 5.7 Obstructive Bowel Disease Chronic use of opioids, including codeine, may result in obstructive bowel disease especially in patients with underlying intestinal motility disorders. Codeine may cause or aggravate constipation. Use with caution in patients with underlying intestinal motility disorders. 5.8 Acute Abdominal Conditions CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE should be used with caution in patients with acute abdominal conditions since the administration of codeine may obscure the diagnosis or clinical course of patients with acute abdominal conditions. The concurrent use of other anticholinergics with codeine may produce paralytic ileus. [see Drug Interactions (7.3) ] 5.9 Special Risk Patients As with other opioids, CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE should be used with caution in elderly or debilitated patients and those with asthma, persistent or chronic cough, hypothyroidism, Addison's disease, prostatic hypertrophy or urethral stricture. The usual precautions should be observed and the possibility of respiratory depression should be kept in mind.

6 ADVERSE REACTIONS Use of codeine, an opioid, may result in the following: • Respiratory depression [see Warnings and Precautions (5.3) and Overdosage (10) ] • Drug dependence [see Warnings and Precautions (5.4) ] • Increased intracranial pressure [see Warnings and Precautions (5.5) ] • Decreased mental alertness with impaired mental and/or physical abilities [see Warnings and Precautions (5.6) ] • Paralytic ileus [see Warnings and Precautions (5.7) ] Use of chlorpheniramine, an antihistamine, may result in: • Decreased mental alertness with impaired mental and/or physical abilities [see Warnings and Precautions (5.6) ] Adverse reactions listed below have been reported in the literature for codeine and chlorpheniramine and may be expected to occur with CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE. Also included are events that occurred during clinical pharmacokinetic studies (in a total of 66 healthy adult volunteers with either single or multiple dose exposure) with CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE and judged by the investigator to be related to study treatment. Because these reactions may be 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. Allergic : Allergic laryngospasm, nasal stuffiness, bronchospastic allergic reaction, hives, itching, swelling of face. Body as a whole : Asthenia, feeling of relaxation, redness or flushing of the face, unusual tiredness, weakness. Cardiovascular : Fast, or slow heartbeat, hypertension, hypotension, orthostatic hypotension, palpitations, shock-like state, syncope. Dermatological System : Skin rash, pruritus, erythema, urticaria, excessive perspiration, dermatitis. Endocrine System : Changes in glucose utilization, decreased lactation, early menses, glycosuria, gynecomastia, hypoglycemia, increased appetite, increased libido, pheochromocytoma stimulation. Gastrointestinal System : Nausea and vomiting,, constipation, abdominal distension, abdominal pain, acute pancreatitis, dry mouth, dyspepsia, epigastric distress, loss of appetite, diarrhea, gastro-esophageal reflux, gastrointestinal hypomotility. Genitourinary System : Ureteral spasm, urinary retention, dysuria, urinary frequency, urinary hesitancy, irritative bladder symptom. Nervous System : Blurred vision, diplopia, visual disturbances, confusion, dizziness, depression, drowsiness, sedation, headache, euphoria, facial dyskinesia, false sense of well-being, feeling faint, lightheadedness, general feeling of discomfort or illness, excitability nervousness, agitation, restlessness, somnolence, insomnia, dyskinesia, irritability, tremor. Respiratory : Dryness of the pharynx and respiratory passages, laryngismus, atelectasis, wheezing, troubled breathing, respiratory depression, hiccups. Special Senses : labyrinthitis, tinnitus, vertigo, hypermetropia, lacrimation increased, mydriasis, photophobia. Common adverse reactions of CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE include: Nausea and vomiting, constipation, abdominal distension, abdominal pain, blurred vision, diplopia, visual disturbances, confusion, dizziness, depression, drowsiness, sedation, headache, euphoria, facial dyskinesia, feeling faint, light-headedness, general feeling of discomfort or illness, excitability, nervousness, agitation, restlessness, somnolence, insomnia, dyskinesia, irritability, tremor. (6) To report SUSPECTED ADVERSE REACTIONS, contact Nexgen Pharma, Inc. at 888-710-0006 or go to www.nexgenpharma.com or FDA at 1-800-FDA-1088