Tuxarin

TUXARIN- codeine phosphate and chlorpheniramine maleate tablet, extended release
Mainpointe Pharmaceuticals

WARNING ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN And RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

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 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. [See Warnings and Precautions (5.1)]. TUXARIN ER is 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 TUXARIN ER 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. [See Warnings and Precautions (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.

1 INDICATIONS AND USAGE

TUXARIN ER is indicated for the relief of cough and symptoms associated with upper respiratory allergies or a common cold in adults 18 years of age and older.

Important Limitations of Use

Not indicated for pediatric patients under 18 years of age [see Use in Special Population (8.4)]

2 DOSAGE AND ADMINISTRATION

2.1 Adults 18 Years of Age and Older

TUXARIN ER should be administered orally at a dosage of one tablet every 12 hours, not to exceed 2 tablets in 24 hours.

3 DOSAGE FORMS AND STRENGTHS

Extended release tablets: Each tablet contains 54.3 mg of codeine phosphate (equivalent to 40 mg of codeine) and 8 mg of chlorpheniramine maleate (equivalent to 5.6 mg of chlorpheniramine). Each tablet is white to off-white, uncoated, round, debossed with MP on one side and CC on the other side.

4 CONTRAINDICATIONS

  • TUXARIN ER is contraindicated for:
  • All children younger than 12 years of age [see Warnings and Precautions (5.1)].
  • Postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Warnings and Precautions (5.1)].
  • Patients with known hypersensitivity to codeine, chlorpheniramine or any of the inactive ingredients of TUXARIN ER. Persons known to be hypersensitive to certain other opioids may exhibit cross-sensitivity to codeine.

5 WARNINGS AND PRECAUTIONS

5.1 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. Codeine is subject to variability in metabolism based upon CYP2D6 genotype (described below), which can lead to an increased exposure to the active metabolite morphine. Based upon post-marketing reports, children less than 12 years old appear to be more susceptible to the respiratory depressant effects of codeine, particularly if there are risk factors for respiratory depression. For example, many reported cases of death occurred in the post-operative period following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being ultra-rapid metabolizers of codeine. Furthermore, children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to its respiratory depressant effect. Because of the risk of life-threatening respiratory depression and death:

  • TUXARIN ER is contraindicated in all children younger than 12 years of age [see Contraindications (4)].
  • TUXARIN ER is 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 TUXARIN ER 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. 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.
  • When prescribing codeine for adolescents, healthcare providers 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 Overdosage (10)].

Nursing Mothers

At least one death was reported in a nursing infant who was exposed to high levels of morphine in breast milk because the mother was an ultra-rapid metabolizer of codeine. Breastfeeding is not recommended during treatment with TUXARIN ER [see Use in Specific Populations (8.3)].

CYP2D6 Genetic Variability: Ultra-rapid metabolizer

Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (e.g., gene duplications denoted as *1/*1×N or *1/*2×N). The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 1 to 10% for Whites (European, North American), 3 to 4% for Blacks (African Americans), 1 to 2% for East Asians (Chinese, Japanese, Korean), and may be greater than 10% in certain ethnic groups (i.e., Oceanian, Northern African, Middle Eastern, Ashkenazi Jews, Puerto Rican). 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)]. Therefore, individuals who are ultra-rapid metabolizers should not use TUXARIN ER.

5.2 Risks from Concomitant Use with Benzodiazepines or other CNS Depressants

Concomitant use of opioids, including TUXARIN ER, 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 TUXARIN ER 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 TUXARIN ER, 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 TUXARIN ER because of the potential for respiratory depression. If respiratory depression occurs, discontinue TUXARIN ER and use naloxone hydrochloride when indicated to antagonize the effect and other supportive measures as necessary. [see Overdosage (10)].

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