Drug Safety-related Labeling Changes (SrLC)

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TUZISTRA XR (NDA-207768)

(CHLORPHENIRAMINE POLISTIREX; CODEINE POLISTIREX)

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

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06/28/2018 (SUPPL-7)

Approved Drug Label (PDF)

Boxed Warning

(extensive additions, please refer to label)

4 Contraindications

(additions underlined)

TUZISTRA XR is contraindicated for:

  • All children younger than 12 years of age.

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

TUZISTRA XR 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 TUZISTRA XR.Persons known to be hypersensitive to certain other opioids may exhibit cross-reactivity to codeine.

5 Warnings and Precautions

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

(additions underlined)

Avoid the use of TUZISTRA XR 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), TUZISTRA XR 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.

5.6 Risk of Accidental Overdose and Death due to Medication Errors

(additions underlined)

Dosing errors can result in accidental overdose and death. To reduce the risk of overdose and respiratory depression, ensure that the dose of TUZISTRA XR is communicated clearly and dispensed accurately.

(The following 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

5.8 Risks of Interactions with Drugs Affecting Cytochrome P450 Isoenzymes

5.10 Risks of Use in Patients with Gastrointestinal Conditions

5.12 Increased Risk of Seizures in Patients with Seizure Disorders

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 TUZISTRA XR 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 TUZISTRA XR 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 TUZISTRA XR in patients who are taking benzodiazepines or other CNS depressants.

7.7 Monoamine Oxidase Inhibitors (MAOIs)

(additions underlined)

TUZISTRA XR 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).

(Then 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 TUZISTRA XR, 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)

TUZISTRA XR 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 TUZISTRA XR 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 TUZISTRA XR in geriatric populations.

 When considering the use of TUZISTRA XR 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 TUZISTRA XR. 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 TUZISTRA XR 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, TUZISTRA XR should be used with caution in patients with severe impairment of renal function, and patients should be monitored closely for signs of codeine 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 TUZISTRA XR 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, TUZISTRA XR should be used with caution in patients with severe impairment of hepatic function, and patients should be monitored closely for signs of codeine 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-6)

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

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. Tuzistra XR 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 TUZISTRA XR 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.

RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS …

4 Contraindications

Additions and/or revisions underlined:

TUZISTRA XR 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 …

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:

Addition of the following:

  • TUZISTRA XR is contraindicated in all children younger than 12 years of age.

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

  • Avoid the use of TUZISTRA XR 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

Additions and/or revisions underlined:

Nursing Mothers

At least one death was reported in a nursing infant who was exposed to high levels of morphine in breast milk because t the mother was an ultra-rapid metabolizer of codeine. Breastfeeding is not recommended during treatment with TUZISTRA XR.

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 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) …

Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience of signs of overdose (such as extreme sleepiness, confusion, or shallow breathing) Therefore, individuals who are ultra-rapid metabolizers should not use TUZISTRA XR.

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 …

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 TUZISTRA XR.

If infants are exposed to TUZISTRA XR 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.

Chlorpheniramine is excreted in human milk …

8.4 Pediatric Use

Addition of the following:

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:

  • TUZISTRA XR is contraindicated in all children younger than 12 years of age.

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

  • Avoid the use of TUZISTRA XR 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 of the following:

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 TUZISTRA XR in children younger than 18 years of age. Advise patients that TUZISTRA XR 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.

Lactation

Advise women that breastfeeding is not recommended during treatment with TUZISTRA XR.

01/13/2017 (SUPPL-4)

Approved Drug Label (PDF)

Boxed Warning

(additions underlined)

DEATH RELATED TO ULTRA-RAPID METABOLISM OF CODEINE TO MORPHINE

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.

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. 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

(New subsection added)

 

Concomitant use of opioids, including TUZISTRA XR, with benzodiazepines, or other CNS depressants, including alcohol, may results 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.

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 TUZISTRA XR 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 TUZISTRA XR because serious adverse events such as respiratory depression may occur with overdosage

 

Dosing

 

Administer TUZISTRA XR by the oral route only. Pharmacists and prescribers should ensure patients have an oral dosing dispenser that measures the appropriate volume in milliliters. Counsel patients on how to utilize an oral dosing dispenser and correctly measure the oral suspension as prescribed.

TUZISTRA XR should not be diluted with fluids or mixed together with other drugs.

Interactions with Benzodiazepines and Other Central Nervous System Depressants

Inform patients and caregivers that potentially fatal additive effects may occur if TUZISTRA XR is used with benzodiazepines or other CNS depressants, including, alcohol. Because of this risk, patients should avoid concomitant use of TUZISTRA XR with benzodiazepines or other CNS depressants, including alcohol.

MEDICATION GUIDE

(Extensive 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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