Drug Safety-related Labeling Changes (SrLC)

Get Email Alerts | Guide

CODEINE SULFATE (NDA-202245)

(CODEINE SULFATE)

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

Download Data

Expand all

09/18/2018 (SUPPL-7)

Approved Drug Label (PDF)

Boxed Warning

Boxed Warning

(Additions and/or revisions are underlined)

WARNING: RISK OF MEDICATION ERRORS; ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Risk of Medication Errors

Ensure accuracy when prescribing, dispensing, and administering Codeine Sulfate Oral Solution. Dosing errors due to confusion between mg and mL, and other codeine solutions of different concentrations can result in accidental overdose and death.

 

Addiction, Abuse, and Misuse

Codeine Sulfate Oral Solution exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing Codeine Sulfate Oral Solution, and monitor all patients regularly for the development of these behaviors and conditions.

 

Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS):

To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a REMS for these products.

Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to

  • complete a REMS-compliant education program,
  • counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products,

  • emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist, and

  • consider other tools to improve patient, household, and community safety.

...

5 Warnings and Precautions

5.3 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

(Newly added subsection)

 

To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following:

 

      • Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain.

      • Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG.

      • Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.

      • Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber Responsibilities.

        To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503- 0784, or log on to www.opioidanalgesicrems.com/. The FDA Blueprint can be found at  www.fda.gov/OpioidAnalgesicREMSBlueprint.

     

    08/29/2017 (SUPPL-5)

    Approved Drug Label (PDF)

    Boxed Warning

    WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

    Addition of the following:

    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. Codeine sulfate oral solution are 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 Codeine sulfate 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.

    4 Contraindications

    Additions and/or revisions underlined:

    Codeine sulfate oral solution are contraindicated for:

    • All children younger than 12 years of age

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

    5 Warnings and Precautions

    Newly added subsection:

    5.4 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:

     

    • Codeine sulfate oral solution are contraindicated for all children younger than 12 years of age.

    • Codeine sulfate oral solution are contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy.

    • Avoid the use of Codeine sulfate 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.

    • As with adults, 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 metabolizer of codeine. Breastfeeding is not recommended during treatment with Codeine sulfate oral solution.

    CYP2D6 Genetic Variability: Ultra-Rapid Metabolizers

    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 racial/ethnic groups (i.e., Oceanian, Northern African, Middle Eastern, Ashkenazi Jews, Puerto Rican).

    Therefore, individuals who are ultra-rapid metabolizers should not use Codeine sulfate oral solution.

    6 Adverse Reactions

    Additions and/or revisions underlined:

    The following serious adverse reactions are described, or described in greater detail, in other sections:

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

    8 Use in Specific Populations

    Additions and/or revisions underlined:

    8.2 Lactation

    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 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 Codeine sulfate oral solution.

    8.4 Pediatric Use

    The safety and effectiveness of Codeine sulfate oral solution in pediatric patients have not been established.

    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:

    • Codeine sulfate oral solution are contraindicated for all children younger than 12 years of age.

    • Codeine sulfate oral solution are contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy.

    • Avoid the use of Codeine sulfate 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.

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

    PATIENT COUNSELING INFORMATION

    Additions and/or revisions underlined:

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

    Advise caregivers that Codeine sulfate oral solution are contraindicated in all children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Advise caregivers of children 12 to 18 years of age receiving Codeine sulfate oral solution to monitor for signs of respiratory depression.

    12/16/2016 (SUPPL-4)

    Approved Drug Label (PDF)

    Boxed Warning

     

    (section updated)

     

     

    WARNING: RISK OF MEDICATION ERRORS; ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; DEATH RELATED TO ULTRA-RAPID METABOLISM OF CODEINE TO MORPHINE; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

     

    Risk of Medication Errors

    Ensure accuracy when prescribing, dispensing, and administering Codeine Sulfate Oral Solution. Dosing errors due to confusion between mg and mL, and other codeine solutions of different concentrations can result in accidental overdose and death.

     

    Addiction, Abuse, and Misuse

    Codeine Sulfate Oral Solution exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing Codeine Sulfate Oral Solution, and monitor all patients regularly for the development of these behaviors and conditions.

     

    Life-Threatening Respiratory Depression

    Serious, life-threatening, or fatal respiratory depression may occur with use of Codeine Sulfate Oral Solution. Monitor for respiratory depression, especially during initiation of Codeine Sulfate Oral Solution or following a dose increase.

     

    Accidental Ingestion

    Accidental ingestion of even one dose of Codeine Sulfate Oral Solution, especially by children, can result in a fatal overdose of codeine.

     

    Neonatal Opioid Withdrawal Syndrome

    Prolonged use of Codeine Sulfate Oral Solution during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

     

    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.

     

    Interactions with Drugs Affecting Cytochrome P450 Isoenzymes

    The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with codeine are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with Codeine Sulfate Oral Solution requires careful consideration of the effects on the parent drug, codeine, and the active metabolite, morphine.

     

    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.

     

     

    • Reserve concomitant prescribing of Codeine Sulfate Oral Solution and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.

    • Limit dosages and durations to the minimum required.

     

    • Follow patients for signs and symptoms of respiratory depression and sedation.

    4 Contraindications

    (additions underlined)

     

    Codeine Sulfate Oral Solution is contraindicated in patients with:

     

    • Significant respiratory depression

    • Postoperative pain management in children who have undergone tonsillectomy and/or adenoidectomy Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment

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

     

    • Known or suspected gastrointestinal obstruction, including paralytic ileus

    • Hypersensitivity to codeine (e.g., anaphylaxis)

    5 Warnings and Precautions

    5.1 Risk of Accidental Overdose and Death due to Medication Errors

    (subsection added)

     

    Dosing errors can result in accidental overdose and death. Avoid dosing errors that may result from confusion between mg and mL when prescribing, dispensing, and administering Codeine Sulfate Oral Solution. Ensure that the dose is communicated clearly and dispensed accurately. Always use the enclosed calibrated oral syringe or measuring cup when

    administering Codeine Sulfate Oral Solution to ensure the dose is measured and administered accurately.

     

    Do not use a teaspoon or a tablespoon to measure a dose. A household teaspoon is not an adequate measuring device. Given the inexactitude of the household spoon measure and the risk of mistakenly using a tablespoon instead of a teaspoon, which could lead to overdosage, it is strongly recommended that caregivers obtain and use a calibrated measuring device. Health care providers should recommend a calibrated device that can measure and deliver the prescribed dose accurately, and instruct caregivers to use extreme caution in measuring the dosage.

    5.10 Adrenal Insufficiency

    (subsection added)

     

    Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

    5.11 Severe Hypotension

    Codeine Sulfate Oral Solution may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g. phenothiazines or general anesthetics) .

    Monitor these patients for signs of hypotension after initiating or titrating the dosage of Codeine Sulfate Oral Solution. In patients with circulatory shock, Codeine Sulfate Oral Solution may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Codeine Sulfate Oral Solution in patients with circulatory shock.

    5.12 Impaired Consciousness

    (subsection added)

     

    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), Codeine Sulfate Oral Solution may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with Codeine Sulfate Oral Solution.

     

    Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Codeine Sulfate Oral Solution in patients with impaired consciousness or coma.

    5.13 Risks of Use in Patients with Gastrointestinal Conditions

    (additions underlined)


    Sulfate Oral Solution is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus

     

    The Codeine Sulfate Oral Solution may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitisfor worsening symptoms.

    5.14 Increased Risk of Seizures in Patients with Seizure Disorders

    (additions underlined)

     

    The codeine in Codeine Sulfate Oral Solution may increase the frequency of seizures in patients with disorders, and may increase the risk of seizures occurring in other clinical settings.

    5.15 Withdrawal

    (subsection added)

     

    Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including Codeine Sulfate Oral Solution. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms

     

    When discontinuing Codeine Sulfate Oral Solution, in a physically-dependent patient, gradually taper the dosage.

     Do not abruptly discontinue Codeine Sulfate Oral Solution in these patients.

    5.16 Risks of Driving and Operating Machinery

    (additions underlined)

     

    Codeine Sulfate Oral Solution may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of Codeine Sulfate Oral Solution and know how they will react to the medication.

    5.2 Addiction, Abuse, and Misuse


    (subsection updated)

     

    Codeine Sulfate Oral Solution contains codeine, a Schedule II controlled substance. As an opioid, Codeine Sulfate Oral exposes users to the risks of addiction, abuse, and misuse.

     

    Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Codeine Sulfate Oral Solution. Addiction can occur at recommended dosages and if the drug is misused or abused.

     

    Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing Codeine Sulfate Oral Solution, and monitor all patients receiving Codeine Sulfate Oral Solution for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as Codeine Sulfate Oral Solution, but use in such patients necessitates intensive counseling about the risks and proper use of Codeine Sulfate Oral Solution along with intensive monitoring for signs of addiction, abuse, and misuse.

     

    Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing Codeine Sulfate Oral Solution. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug . Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

    5.3 Life-Threatening Respiratory Depression

    (subsection updated)

     

    Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid

    antagonists, depending on the patient’s clinical status . Carbon dioxide (CO2) retention from opioid- induced respiratory depression can exacerbate the sedating effects of opioids.

     

    While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Codeine Sulfate Oral Solution, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with and following dosage increases of Codeine Sulfate Oral Solution.

     

    To reduce the risk of respiratory depression, proper dosing and titration of Codeine Sulfate Oral Solution are essential.

    Overestimating the Codeine Sulfate Oral Solution dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.

    Accidental ingestion of even one dose of Codeine Sulfate Oral Solution, especially by children, can result in respiratory depression and death due to an overdose of codeine.

    5.4 Neonatal Opioid Withdrawal Syndrome

    (subsection added)

     

    Prolonged use of Codeine Sulfate Oral Solution during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

    5.5 Death Related to Ultra-Rapid Metabolism of Codeine to Morphine

    (addition underlined)

     

    Codeine Sulfate Oral Solution is contraindicated for post-operative pain management in children who have undergone tonsillectomy and/or adenoidectomy.

    5.6 Risks of Interactions with Drugs Affecting Cytochrome P450 Isoenzymes

    (subsection added)

     

    The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with codeine are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with Codeine Sulfate Oral Solution requires careful consideration of the effects on the parent drug, codeine, and the active metabolite, morphine.

     

    • Cytochrome P450 3A4 Interaction

     

    The concomitant use of Codeine Sulfate Oral Solution with all cytochrome P450 3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir) or discontinuation of a cytochrome P450 3A4 inducer such as rifampin, carbamazepine, and phenytoin, may result in an increase in codeine plasma concentrations with subsequently greater metabolism by cytochrome P450 2D6, resulting in greater morphine levels, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression.

    The concomitant use of Codeine Sulfate Oral Solution with all cytochrome P450 3A4 inducers or discontinuation of a cytochrome P450 3A4 inhibitor may result in lower codeine levels, greater norcodeine levels, and less metabolism via 2D6 with resultant lower morphine levels. This may be associated with a decrease in efficacy, and in some patients, may result in signs and symptoms of opioid withdrawal. Follow patients receiving Codeine Sulfate Oral Solution and any CYP3A4 inhibitor or inducer for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when Codeine Sulfate Oral Solution is used in conjunction with inhibitors and inducers of CYP3A4.

     

    If concomitant use of a CYP3A4 inhibitor is necessary or if a CYP3A4 inducer is discontinued, consider dosage reduction of Codeine Sulfate Oral Solution until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.

     

    If concomitant use of a CYP3A4 inducer is necessary or if a CYP3A4 inhibitor is discontinued, consider increasing the Codeine Sulfate Oral Solution dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal

     

    • Risks of Concomitant Use or Discontinuation of Cytochrome P450 2D6 Inhibitors

     

    The concomitant use of Codeine Sulfate Oral Solution with all cytochrome P450 2D6 inhibitors (e.g., amiodarone, quinidine) may result in an increase in codeine plasma concentrations and a decrease in active metabolite morphine plasma concentration which could result in an analgesic efficacy reduction or symptoms of opioid withdrawal.

     

    Discontinuation of a concomitantly used cytochrome P450 2D6 inhibitor may result in a decrease in codeine plasma concentration and an increase in active metabolite morphine plasma concentration which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression.

     

    Follow patients receiving Codeine Sulfate Oral Solution and any CYP2D6 inhibitor for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when Codeine Sulfate Tablets are used in conjunction with inhibitors of CYP2D6.

     

    If concomitant use with a CYP2D6 inhibitor is necessary, follow the patient for signs of reduced efficacy or opioid withdrawal and consider increasing the Codeine Sulfate Oral Solution dosage. After stopping use of a CYP2D6 inhibitor, consider reducing the Codeine Sulfate Oral Solution dosage and follow the patient for signs and symptoms of respiratory depression or sedation.

    5.7 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

    (subsection added)

     

    Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Codeine Sulfate Oral Solution with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

     

    Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics.

     

    If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.

     

    Advise both patients and caregivers about the risks of respiratory depression and sedation when Codeine Sulfate Oral Solution are used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol

    and illicit drugs.

    5.8 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients.


    (additions underlined)


    The use of Codeine Sulfate Oral Solution in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

     

    Patients with Chronic Pulmonary Disease


    Codeine Sulfate Oral Solution-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of Codeine Sulfate Oral Solution.


    Elderly, Cachectic, or Debilitated Patients


    Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients.


    Monitor such patients closely, particularly when initiating and titrating Codeine Sulfate Oral Solution and when Codeine Sulfate Oral Solution is given concomitantly with other drugs that depress respiration.  Alternatively, consider the use of non-opioid analgesics in these patients.

    5.9 Interaction with Monoamine Oxidase Inhibitors

    (subsection added)

    Monoamine oxidase inhibitors (MAOIs) may potentiate the effects of morphine, codeine’s active metabolite, including respiratory depression, coma, and confusion. Codeine Sulfate Oral Solution should not be used in patients taking MAOIs or within 14 days of stopping such treatment.

    6 Adverse Reactions

    (additions underlined)


    The following serious adverse reactions are described, or described in greater detail, in other sections:


    • Addiction, Abuse, and Misuse

    • Life-Threatening Respiratory Depression

    • Neonatal Opioid Withdrawal Syndrome

    • Death Related to Ultra-rapid Metabolizers of Codeine

    • Interactions with Benzodiazepines and Other CNS Depressants

    • Adrenal Insufficiency

    • Severe Hypotension

    • Gastrointestinal Adverse Reactions

    • Seizures

    • Withdrawal

     

     

    The following adverse reactions associated with the use of codeine were identified in clinical studies or postmarketing reports. Because some of these reactions were 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.

     

     

    Serotonin Syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

     

    Adrenal Insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

     

    Anaphylaxis: Anaphylaxis has been reported with ingredients contained in Codeine Sulfate Oral Solution.

     

    Androgen Deficiency: Cases of androgen deficiency have occurred with chronic use of opioids

    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

     

    Codeine is secreted into human milk. In women with normal codeine metabolism (normal CYP2D6 activity), the amount of codeine secreted into human milk is low and dose-dependent. However, some women are ultra-rapid metabolizers of codeine. These women achieve higher-than-expected serum levels of codeine's active metabolite, morphine, leading to higher-than-expected levels of morphine in breast milk and potentially dangerously high serum morphine levels in their breastfed infants. Therefore, maternal use of codeine can potentially lead to serious adverse reactions, including death, in nursing infants.

     

    The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Codeine Sulfate Oral Solution and any potential adverse effects on the breastfed infant from Codeine Sulfate Oral Solution or from the underlying maternal condition.

     

    Clinical Considerations

     

    The risk of infant exposure to codeine and morphine through breast milk should be weighed against the benefits of breastfeeding for both the mother and the baby. Caution should be exercised when codeine is administered to a nursing woman. If a codeine containing product is selected, the lowest dose should be prescribed for the shortest period of time to achieve the desired clinical effect. Infants exposed to codeine sulfate through breast milk should be monitored for excess sedation and respiratory depression. Mothers using codeine should be informed about when to seek immediate medical care and how to identify the signs and symptoms of neonatal toxicity, such as drowsiness or sedation, difficulty breastfeeding, breathing difficulties, and decreased tone, in their baby. Nursing mothers who are ultra-rapid metabolizers may also experience overdose symptoms such as extreme sleepiness, confusion, or shallow breathing. Prescribers should closely monitor mother-infant pairs and notify treating pediatricians about the use of codeine during breast-feeding.

     

    Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.

    8.3 Females and Males of Reproductive Potential

    (PLLR conversion)

     

    Infertility

     

    Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible.

    8.5 Geriatric Use

    (additions underlined)

     

    Elderly patients (aged 65 years or older) may have increased sensitivity to codeine. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

     

    Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of Codeine Sulfate Oral Solution slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression.

     

    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, care should be taken in dose selection, and it may be useful to monitor renal function.

    8.6 Hepatic Impairment

    (additions underlined)

     

    No formal studies have been conducted in patients with hepatic impairment so the pharmacokinetics of codeine in this patient population are unknown. Start these patients with a lower than normal dosage of Codeine Sulfate Oral Solution or with longer dosing intervals and titrate slowly while monitoring signs of respiratory depression, sedation, and hypotension.

    8.7 Renal Impairment

    (additions underlined)

     

    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. Start these patients with a lower than normal dosage of Codeine Sulfate Oral Solution or with longer dosing intervals and titrate slowly while monitoring for signs of respiratory, sedation, and hypotension.

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

    17 PATIENT COUNSELING INFORMATION

    (Extensive revisions, please refer to label)

    Medication Guide

    (Exctensive revisions, please refer to label)

    Other

    (Revisions to the Package Insert to incorporate the opioid analgesic template language)

    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.

    Note: If you need help accessing information in different file formats, see Instructions for Downloading Viewers and Players.
    Language Assistance Available: Español | 繁體中文 | Tiếng Việt | 한국어 | Tagalog | Русский | العربية | Kreyòl Ayisyen | Français | Polski | Português | Italiano | Deutsch | 日本語 | فارسی | English