Drug Safety-related Labeling Changes (SrLC)

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PHENERGAN W/ CODEINE (NDA-008306)

(CODEINE PHOSPHATE; PROMETHAZINE HYDROCHLORIDE)

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

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06/28/2018 (SUPPL-34)

Approved Drug Label (PDF)

Boxed Warning

(extensive additions, please refer to label)

4 Contraindications

(additions underlined)

Promethazine HCl and Codeine Phosphate Oral Solution 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.

       

      Promethazine HCl and Codeine Phosphate Oral Solution 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.

    • A history of an idiosyncratic reaction to promethazine or to other phenothiazines

    • Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within 14 days.

    • Hypersensitivity to codeine, promethazine, or any of the inactive ingredients in Promethazine HCl and Codeine Phosphate Oral Solution.Persons known to be hypersensitive to certain other opioids may exhibit cross-reactivity to codeine.

5 Warnings and Precautions

(PLR conversion: subsections created as below, see label for complete information)

5.1         Addiction, Abuse, and Misuse

5.2       Life-Threatening Respiratory Depression

5.3       Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children

5.4       Promethazine and Respiratory Depression

5.5       Risks with Use in Pediatric Populations

5.6       Risks with Use in Other At-Risk Populations

5.7       Risk of Accidental Overdose and Death due to Medication Errors

5.8       Activities Requiring Mental Alertness: Risks of Driving and Operating Machinery

5.9       Risks of Interactions with Drugs Affecting Cytochrome P450 Isoenzymes

5.10   Risks from Concomitant Use with Benzodiazepines or other CNS Depressants

5.11   Risks of Use in Patients with Gastrointestinal Conditions

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

5.13   Risk of Neuroleptic Malignant Syndrome

5.14   Risk of Paradoxical Reactions, including Dystonias

5.15   Increased Risk of Seizures in Patients with Seizure Disorders

5.16   Co-administration with Monoamine Oxidase Inhibitors (MAOIs)

5.17   Bone-Marrow Depression

5.18   Severe Hypotension

5.19   Neonatal Opioid Withdrawal Syndrome

5.20   Adrenal Insufficiency

5.21   Drug/Laboratory Test Interactions

6 Adverse Reactions

(revisions and additions, please refer to label)

7 Drug Interactions

(extensive additions, please refer to label)

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion, please refer to label)

8.2 Lactation

 

(PLLR conversion)

Risk Summary

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 Promethazine HCl and Codeine Phosphate Oral Solution.

There are no data on the presence of Promethazine HCl and Codeine Phosphate Oral Solution in human milk, the effects of Promethazine HCl and Codeine Phosphate Oral Solution on the breastfed infant, or the effects of Promethazine HCl and Codeine Phosphate Oral Solution on milk production; however, data are available with codeine and promethazine.

Codeine

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 one infant) 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.

Promethazine

There are no data on the presence of promethazine in human milk. However, direct oral administration of promethazine has been associated with respiratory depression, including fatalities, in pediatric patients. Promethazine has been shown to decrease basal prolactin levels in non- nursing women, and therefore may affect milk production.

Clinical Considerations

Infants exposed to Promethazine HCl and Codeine Phosphate Oral Solution through breast milk should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid is stopped, or when breastfeeding is stopped.

8.3 Females and Males of Reproductive Potential

(PLLR conversion)

Infertility

Chronic use of opioids, such as codeine, a component of Promethazine HCl and Codeine Phosphate Oral Solution, 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)

Promethazine HCl and Codeine Phosphate Oral Solution 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.

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.

Life-threatening respiratory depression and death have also occurred in children who received promethazine.

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

      • Promethazine HCl and Codeine Phosphate Oral Solution is contraindicated for all children younger than 12 years of age.

      • Promethazine HCl and Codeine Phosphate Oral Solution is contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy.

        Avoid the use of Promethazine HCl and Codeine Phosphate Oral Solution 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 Promethazine HCl and Codeine Phosphate Oral Solution in geriatric populations.

Use caution when considering the use of Promethazine HCl and Codeine Phosphate Oral Solution 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 Promethazine HCl and Codeine Phosphate Oral Solution. 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

(new subsection added)

The pharmacokinetics of Promethazine HCl and Codeine Phosphate Oral Solution 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. Promethazine HCl and Codeine Phosphate Oral Solution should be used with caution in patients with severe impairment of renal function, and patients should be monitored closely for respiratory depression, sedation, and hypotension.

8.7 Hepatic Impairment

(new subsection added)

No formal studies have been conducted in patients with hepatic impairment so the pharmacokinetics of Promethazine HCl and Codeine Phosphate Oral Solution in this patient population are unknown. Promethazine HCl and Codeine Phosphate Oral Solution should be used with caution in patients with impairment of hepatic function, and patients should be monitored closely for respiratory depression, sedation, and hypotension.

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

MEDICATION GUIDE

(additions and revisions, please refer to label)

PATIENT COUNSELING INFORMATION

(new subsection added, please refer to label)

Other

(PLR conversion)

08/29/2017 (SUPPL-33)

Approved Drug Label (PDF)

Boxed Warning

(additions underlined)

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 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. Promethazine HCl and Codeine Phosphate Oral Solution 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). Avoid the use of Promethazine HCl and Codeine Phosphate Oral Solution 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

  • Ultra-Rapid Metabolism of Codeine and Respiratory Depression).

     

    Promethazine and Respiratory Depression in Children

    Postmarketing cases of respiratory depression, including fatalities have been reported with use of promethazine in pediatric patients. Children may be particularly sensitive to the additive respiratory depressant effects when promethazine is combined with other respiratory depressants, including codeine. (See WARNINGS – Promethazine and Respiratory Depression in Children).

4 Contraindications

(additions underlined)

 Promethazine HCl and Codeine Phosphate Oral Solution is contraindicated in all children younger than 12 years of age.

Promethazine HCl and Codeine Phosphate Oral Solution is contraindicated for postoperative management in children younger than 18 years of age who have undergone tonsillectomy and/or adenoidectomy.

Codeine is contraindicated in patients with a known hypersensitivity to the drug.

Promethazine is contraindicated in comatose states, and in individuals known to be hypersensitive or to have had an idiosyncratic reaction to promethazine or to other phenothiazines.

Antihistamines and codeine are both contraindicated for use in the treatment of lower respiratory tract symptoms, including asthma.

5 Warnings and Precautions

WARNINGS

(additions 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. 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 postoperative 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:

  • Promethazine HCl and Codeine Phosphate Oral Solution is contraindicated in all children younger than 12 years of age.

  • Promethazine HCl and Codeine Phosphate Oral Solution is contraindicated for postoperative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy.

  • Avoid the use of Promethazine HCl and Codeine Phosphate Oral Solution 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

    (additions underlined)

    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 Promethazine HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution.

    CYP2D6 Genetic Variability: Ultra-rapid metabolizer

    (additions underlined)

    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).

     

    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). Therefore, individuals who are ultra-rapid metabolizers should not use Promethazine HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution.

     

    Promethazine and Respiratory Depression

    (additions underlined)

  • Children

    Postmarketing cases of respiratory depression, including fatalities have been reported with use of promethazine in pediatric patients. Concomitant administration with other respiratory depressants may increase the risk of respiratory depression. Children may be particularly sensitive to the additive respiratory depressant effects when promethazine is combined with other respiratory depressants, including codeine. See WARNINGS - Ultra-Rapid Metabolism of Codeine and Respiratory Depression for limitations on the use of Promethazine HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution in children.

    Excessively large dosages of antihistamines, including promethazine hydrochloride, in pediatric patients may cause sudden death.

  • Concomitant Conditions and Other Risk Factors

    Avoid use of promethazine in patients at risk for respiratory depression. 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 Use in Specific Populations

Nursing Mothers

(additions underlined)

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 Promethazine HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution.

If infants are exposed to Promethazine HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution 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.

It is not known whether phenylephrine or promethazine are excreted in human milk.

Pediatric Use

(subsection revised, additions underlined)

Life threatening respiratory depression and death have occurred in children who received codeine. Postmarketing cases of respiratory depression, including fatalities have been reported with use of promethazine in pediatric patient.   Because of the risk of life-threatening respiratory depression and death:

  • Promethazine HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution is contraindicated in all children younger than 12 years of age.

  • Promethazine HCL, Phenylephrine HCl and Codeine Phosphate Oral Solution is contraindicated in pediatric patients younger than 18 years of age following tonsillectomy and/ or adenoidectomy

  • Avoid the use of Promethazine HCl, Phenylephrine HCl and Codeine Phosphate Oral Solution in adolescents 12 to 18 years of age who have other risk factors that may 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.

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

PATIENT COUNSELING INFORMATION

Information for Patients

(additions underlined)

Advise patients of the risks of respiratory depression and death with Promethazine HCl and Codeine Phosphate Oral Solution in children younger than 18 years of age. Advise patients that Promethazine HCl and Codeine Phosphate Oral Solution 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. Advise caregivers of children ages 12 to 18 receiving Promethazine HCl and Codeine Phosphate Oral Solution to monitor for signs of respiratory depression.

  Advise women that breastfeeding is not recommended during treatment with Promethazine    HCl and Codeine Phosphate Oral Solution.

Patients should be advised to measure Promethazine HCl and Codeine Phosphate Oral Solution with an accurate measuring device. A household teaspoon is not an accurate measuring device and could lead to overdosage, especially when a half a teaspoon is measured. A pharmacist can recommend an appropriate measuring device and can provide instructions for measuring the correct dose.

01/13/2017 (SUPPL-32)

Approved Drug Label (PDF)

Boxed Warning

(additions underlined)

WARNING: RESPIRATORY DEPRESSION IN CHILDREN; DEATH RELATED TO ULTRA RAPID METABOLISM OF CODEINE TO MORPHINE and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Respiratory Depression in Children

The combination of promethazine hydrochloride and codeine phosphate is contraindicated in pediatric patients less than 6 years of age. Concomitant administration of promethazine products with other respiratory depressants has an association with respiratory depression, and sometimes death, in pediatric patients.

Postmarketing cases of respiratory depression, including fatalities, have been reported with use of promethazine hydrochloride in pediatric patients less than 2 years of age. A wide range of weight-based doses of promethazine hydrochloride have resulted in respiratory depression in these patients.

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

WARNINGS

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

(New section added)

Concomitant use of opioids, including Promethazine HCl and Codeine Phosphate Oral Solution, 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 Promethazine HCl and Codeine Phosphate Oral Solution is used with benzodiazepines, alcohol, or other CNS depressants.

Promethazine

CNS Depression

(additions underlined)

Promethazine may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a vehicle or operating machinery. The impairment may be amplified by concomitant use of other central-nervous-system depressants such as alcohol, sedatives/hypnotics (including barbiturates), narcotics, narcotic analgesics, general anesthetics, tricyclic antidepressants, and tranquilizers; therefore avoid use of Promethazine HCl  and Codeine Phosphate Oral Solution in patients on these medications.

7 Drug Interactions

Codeine

(additions underlined)

In patients receiving MAO inhibitors, an initial small test dose is advisable to allow observation of any excessive narcotic effects or MAOI interaction.

The use of benzodiazepines, opioids, antihistamines, antipsychotics, anti-anxiety agents, or other CNS depressants concomitantly with Promethazine HCl and Codeine Phosphate Oral Solution 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)

Information for Patients

(additions underlined)

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

MEDICATION GUIDE

 (New section added, 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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