Drug Safety-related Labeling Changes (SrLC)

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CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE (NDA-206323)

(CHLORPHENIRAMINE MALEATE; CODEINE PHOSPHATE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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06/28/2018 (SUPPL-6)

Approved Drug Label (PDF)

Boxed Warning

(extensive additions, please refer to label)

4 Contraindications

(additions underlined)

TUXARIN ER is contraindicated for:

  • All children younger than 12 years of age [see Warnings and Precautions .
  • Postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy.

TUXARIN ER is also contraindicated in patients with:

  • Significant respiratory depression.
  • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment.
  • Known or suspected gastrointestinal obstruction, including paralytic ileus.
  • Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within 14 days.
  • Hypersensitivity to codeine, chlorpheniramine, or any of the inactive ingredients in TUXARIN ER. Persons known to be hypersensitive to certain other opioids may exhibit cross-reactivity to codeine.

5 Warnings and Precautions

5.10 Risks of Use in Patients with Gastrointestinal Conditions

(additions underlined)

TUXARIN ER is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The use of codeine in TUXARIN ER may obscure the diagnosis or clinical course of patients with acute abdominal conditions. 

The concurrent use of anticholinergics with TUXARIN ER may produce paralytic ileus.

The codeine in TUXARIN ER may result in constipation or obstructive bowel disease, especially in patients with underlying intestinal motility disorders. Use with caution in patients with underlying intestinal motility disorders.

The codeine in TUXARIN ER may cause spasm of the sphincter of Oddi, resulting in an increase in biliary tract pressure. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms.

5.11 Risks of Use in Patients with Head Injury, Impaired Consciousness, Increased Intracranial Pressure, or Brain Tumors

(additions underlined)

Avoid the use of TUXARIN ER in patients with head injury, intracranial lesions, or a pre-existing increase in intracranial pressure.  In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), TUXARIN ER may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Furthermore, opioids produce adverse reactions that may obscure the clinical course of patients with head injuries.

5.12 Increased Risk of Seizures in Patients with Seizure Disorders

(additions underlined)

The codeine and chlorpheniramine in TUXARIN ER may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during TUXARIN ER therapy.

(The following new subsections added, please refer to label for more information)

5.1 Addiction, Abuse, and Misuse

5.2 Life-Threatening Respiratory Depression

5.4 Risks with Use in Pediatric Populations

5.5 Risks with Use in Other At-Risk Populations

5.6 Risk of Accidental Overdose and Death due to Medication Errors

5.8 Risks of Interactions with Drugs Affecting Cytochrome P450 Isoenzymes

5.13 Co-administration with Monoamine Oxidase Inhibitors (MAOIs)

5.14 Severe Hypotension

5.15 Neonatal Opioid Withdrawal Syndrome

5.16 Adrenal Insufficiency

5.17 Drug/Laboratory Test Interactions

6 Adverse Reactions

(extensive additions, please refer to label)

7 Drug Interactions

7.10 Anticholinergic Drugs

(additions underlined)

The concomitant use of anticholinergic drugs with TUXARIN ER 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 TUXARIN ER is used concomitantly with anticholinergic drugs.

Additive adverse effects resulting from cholinergic blockade (e.g., xerostomia, blurred vision, or constipation) may occur when anticholinergic drugs are administered with chlorpheniramine.

7.5 Benzodiazepines and Other CNS Depressants

(additions underlined)

Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Avoid the use of TUXARIN ER in patients who are taking benzodiazepines or other CNS depressants.

7.7 Monoamine Oxidase Inhibitors (MAOIs)

(additions underlined)

TUXARIN ER is contraindicated in patients who are taking MAOIs (i.e., certain drugs used for depression, psychiatric or emotional conditions, or Parkinson’s disease) or have taken MAOIs within 14 days.

MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).

(The following new subsections added, please refer to label for more information)

7.1 Inhibitors of CYP3A4

7.2 CYP3A4 Inducers

7.3 Phenytoin

7.4 Inhibitors of CYP2D6

7.6 Serotonergic Drugs

7.8 Muscle Relaxants

7.9 Diuretics

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion, please refer to label)

8.2 Lactation

(PLLR conversion, please refer to label)

8.3 Females and Males of Reproductive Potential

(PLLR conversion)

Infertility

Chronic use of opioids, such as codeine, a component of TUXARIN ER, may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible.

8.4 Pediatric Use

(additions underlined)

TUXARIN ER is not indicated for use in patients younger than 18 years of age because the benefits of symptomatic treatment of cough associated with allergies or the common cold do not outweigh the risks for use of codeine in these patients.

Because of the risk of life-threatening respiratory depression and death:

  • 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 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.
8.5 Geriatric Use

(additions underlined)

Clinical studies have not been conducted with TUXARIN ER in geriatric populations. 

Use caution when considering the use of TUXARIN ER in patients 65 years of age or older.  Elderly patients may have increased sensitivity to codeine; greater frequency of decreased hepatic, renal, or cardiac function; or concomitant disease or other drug therapy.

Respiratory depression is the chief risk for elderly patients treated with opioids, including TUXARIN ER. Respiratory depression has occurred after large initial doses of opioids were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration.

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, monitor these patients closely for respiratory depression, sedation, and hypotension.

8.6 Renal Impairment

(additions underlined)

The pharmacokinetics of TUXARIN ER has not been characterized in patients with 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. Chlorpheniramine is cleared substantially by the kidney. As such, impaired renal function could potentially lead to the risk of decreased clearance and thereby increased retention or systemic levels of chlorpheniramine. Therefore, TUXARIN ER should be used with caution in patients with severe impairment of renal function, and patients should be monitored closely for signs of hydrocodone toxicity (respiratory depression, sedation, and hypotension) and chlorpheniramine toxicity.

8.7 Hepatic Impairment

(additions underlined)

No formal studies have been conducted in patients with hepatic impairment so the pharmacokinetics of TUXARIN ER in this patient population are unknown. Chlorpheniramine is extensively metabolized by liver before elimination from the body. As such, impaired hepatic function could potentially lead to the risk of decreased metabolism and thereby increased systemic levels of chlorpheniramine. Therefore, TUXARIN ER should be used with caution in patients with severe impairment of hepatic function, and patients should be monitored closely for signs of hydrocodone toxicity (respiratory depression, sedation, and hypotension) and chlorpheniramine toxicity.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(extensive additions, please refer to label)

PATIENT COUNSELING INFORMATION

(extensive additions, please refer to label)

08/29/2017 (SUPPL-5)

Approved Drug Label (PDF)

Boxed Warning

Additions and/or revisions underlined:

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. 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. 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.

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. Avoid use of opioid cough medications in patients taking benzodiazepines, other CNS depressants, or alcohol.

4 Contraindications

Additions and/or revisions underlined:

TUXARIN ER is contraindicated for:

  • All children younger than 12 years of age

  • Postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy.

  • 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

Additions and/or revisions underlined:

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 younger 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.

  • XARIN ER is contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy.

  • 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.

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 metabolizers of codeine metabolizer of codeine. Breastfeeding is not recommended during treatment with TUXARIN ER.

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/*1xN or *1/*2xN). The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5 to 1% in 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  …

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). Therefore, individuals who are ultra-rapid metabolizers should not use TUXARIN ER.

Newly added subsection:

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. 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.

7 Drug Interactions

7.1 Benzodiazepines, Opioids, Antihistamines, Antipsychotics, Anti-anxiety Agents, or Other CNS Depressants (Including Alcohol)

Additions and/or revisions underlined:

The use of benzodiazepines, opioids, antihistamines, antipsychotics, anti-anxiety agents, or other CNS depressants (including alcohol) concomitantly with TUXARIN ER may cause an additive CNS depressant effect, profound sedation, respiratory depression, coma, and death and should be avoided.

8 Use in Specific Populations

8.3 Nursing Mothers

Additions and/or revisions underlined:

Risk 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 the 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 TUXARIN ER.

Clinical Considerations

If infants are exposed to TUXARIN ER 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 breast-feeding is stopped

8.4 Pediatric Use

Newly added information:

… Life-threatening respiratory depression and death have occurred in children who received codeine. 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:

  • TUXARIN ER is contraindicated in all children younger than 12 years of age.

  • TUXARIN ER is contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy.

  • 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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-threatening Respiratory Depression in Children: Advise patients of the risks of respiratory depression and death with TUXARIN ER in children younger than 18 years of age. Advise patients that TUXARIN ER should not be used in children younger than 12 years of age or in a child younger than 18 years of age for treatment after tonsillectomy and/or adenoidectomy.

Overdosage:

Interactions with Benzodiazepines and Other Central Nervous System Depressants: Inform patients and caregivers that potentially fatal additive effects may occur if TUXARIN ER is used with benzodiazepines or other CNS depressants, including alcohol. Because of this risk, patients should avoid concomitant use of TUXARIN ER with benzodiazepines or other CNS depressants, including alcohol

Lactation: Advise women that breastfeeding is not recommended during treatment with TUXARIN ER.

Other

TUXARIN ER replaces all instances of CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE ER.

01/13/2017 (SUPPL-4)

Approved Drug Label (PDF)

Boxed Warning

(additions underlined)

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 andpolymorphism.

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.

Avoid use of opioid cough medications in patients taking benzodiazepines, other

CNS depressants, or alcohol.

5 Warnings and Precautions

5.2 Risks from Concomitant Use with Benzodiazepines or other CNS Depressants

(subsection added)

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.

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.

7 Drug Interactions

7.1 Benzodiazepines, Opioids, Antihistamines, Antipsychotics, Anti-anxiety Agents, or Other CNS Depressants (Including Alcohol)

(subsection revised, additions underlined)

The use of benzodiazepines, opioids, antihistamines, antipsychotics, anti-anxiety agents, or other CNS depressants (including alcohol) concomitantly with TUXARIN ER may cause an additive CNS depressant effect, profound sedation, respiratory depression, coma, and death and should be avoided.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(additions underlined)

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Overdosage:  Advise patients not to increase the dose or dosing frequency of TUXARIN ER because serious adverse events such as respiratory depression may occur with overdosage.

 

Interactions with Benzodiazepines and Other Central Nervous System Depressants: Inform patients and caregivers that potentially fatal additive effects may occur if TUXARIN ER is used with benzodiazepines or other CNS depressants, including alcohol. Because of this risk, patients should avoid concomitant use of TUXARIN ER with benzodiazepines or other CNS depressants, including alcohol.

Activities Requiring Mental Alertness:  Caution patients that TUXARIN ER 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.

Controlled Substance Status/Potential for Abuse and Dependence:  Caution patients that TUXARIN ER contains codeine and can produce drug dependence.

MEDICATION GUIDE

(additions, please refer to label)

Questions related to the drug data in these files should be directed to the Center for Drug Evaluation and Research, Division of Drug Information
druginfo@fda.hhs.gov.

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