Drug Safety-related Labeling Changes (SrLC)

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DOLOPHINE HYDROCHLORIDE (NDA-006134)

(METHADONE HYDROCHLORIDE)

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

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10/07/2019 (SUPPL-49)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:

5.3 Risk of Life-Threatening Respiratory and Central Nervous System (CNS) Depression

Newly added information to the end of this subsection:

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper.

Additions and/or revisions underlined:

5.9 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of Dolophine Tablets with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

5.15 Withdrawal

Do not abruptly discontinue DOLOPHINE Tablets in a patient physically dependent on opioids. When discontinuing DOLOPHINE Tablets in a physically dependent patient, gradually taper the dosage. Rapid tapering of methadone in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain.

Additionally, avoid the use of mixed agonist/antagonist …

7 Drug Interactions

Clinically Significant Drug Interactions Table

Serotonergic Drugs

Additions and/or revisions underlined:

Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

09/18/2018 (SUPPL-48)

Approved Drug Label (PDF)

Boxed Warning

In the boxed warning title, the following underlined language was added after “ADDICTION, ABUSE, AND MISUSE: RISK EVALUATION AND MITIGATION STRATEGY (REMS)

Addition of the following information:

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 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

  • 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

Addition of the following subsection after the warning regarding addiction, abuse and misuse:

5.2 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 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.

02/01/2018 (SUPPL-45)

Approved Drug Label (PDF)

Boxed Warning

(Additions and/or revisions are underlined)

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 DOLOPHINE Tablets and benzodiazepines or other CNS depressants for use in patients for whom alternatives to benzodiazepines or other CNS depressants are inadequate.

  • Limit dosages and durations to the minimum required for patients being treated for pain.

  • Follow patients for signs and symptoms of respiratory depression and sedation. If the patient is visibly sedated, evaluate the cause of sedation, and consider delaying or omitting the daily methadone dose.

5 Warnings and Precautions

5.6 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

(Additions and/or revisions are underlined)

For Patients Being Treated for Pain

Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

For Patients Being Treated for Opioid Addiction

Concomitant use of methadone and benzodiazepines or other CNS depressants increases the risk of adverse reactions including overdose and death. Medication-assisted treatment of opioid use disorder, however, should not be categorically denied to patients taking these drugs. Prohibiting or creating barriers to treatment can pose an even greater risk of morbidity and mortality due to the opioid use disorder alone.

As a routine part of orientation to methadone treatment, educate patients about the risks of concomitant use of benzodiazepines, sedatives, opioid analgesics, or alcohol.

Develop strategies to manage use of prescribed or illicit benzodiazepines or other CNS depressants at admission to methadone treatment, or if it emerges as a concern during treatment. Adjustments to induction procedures and additional monitoring may be required. There is no evidence to support dose limitations or arbitrary caps of methadone as a strategy to address benzodiazepine use in methadone-treated patients. However, if a patient is sedated at the time of methadone dosing, ensure that a medically-trained healthcare provider evaluates the cause of sedation, and delays or omits the methadone dose if appropriate.

Cessation of benzodiazepines or other CNS depressants is preferred in most cases of concomitant use. In some cases monitoring in a higher level of care for taper may be appropriate. In others, gradually tapering a patient off a prescribed benzodiazepine or other CNS depressant or decreasing to the lowest effective dose may be appropriate.

For patients in methadone treatment, benzodiazepines are not the treatment of choice for anxiety or insomnia. Before co- prescribing benzodiazepines, ensure that patients are appropriately diagnosed and consider alternative medications and non-pharmacologic treatments to address anxiety or insomnia. Ensure that other healthcare providers prescribing benzodiazepines or other CNS depressants are aware of the patient’s methadone treatment and coordinate care to minimize the risks associated with concomitant use.

In addition, take measures to confirm that patients are taking the medications prescribed and not diverting or supplementing with illicit drugs. Toxicology screening should test for prescribed and illicit benzodiazepines.

7 Drug Interactions

 (Table has been revised; please refer to label)

12/16/2016 (SUPPL-40)

Approved Drug Label (PDF)

Boxed Warning

Additions and/or revisions underlined:

WARNING: ADDICTION, ABUSE AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; LIFE-THREATENING QT PROLONGATION; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; and TREATMENT FOR OPIOID ADDICTION

Addiction, Abuse, and Misuse

DOLOPHINE tablets expose patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead …

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression may occur with use of DOLOPHINE Tablets. The peak respiratory depressant effect of methadone occurs later, and persists longer than the peak analgesic effect, especially during the initial dosing period. Monitor for respiratory depression, especially during initiation of DOLOPHINE Tablets or following a dose increase.

Accidental Ingestion

Accidental ingestion of even one dose of DOLOPHINE tablets, especially by children, can result in a fatal overdose of methadone.

Life-Threatening QT Prolongation

… Most cases involve patients being treated for pain with large, multiple daily doses of methadone,

although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. Closely monitor patients with risk factors for development of prolonged QT interval, a history of cardiac conduction abnormalities, and those taking medications affecting cardiac conduction for changes in cardiac rhythm during initiation and titration of DOLOPHINE tablets.

Neonatal Opioid Withdrawal Syndrome

Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of use of DOLOPHINE Tablets during pregnancy. NOWS may be life-threatening if not recognized and treated in the neonate. The

balance between the risks of NOWS and the benefits of maternal DOLOPHINE use may differ based on the

risks associated with the mother’s underlying condition, pain, or addiction. Advise the patient of the risk of NOWS so that appropriate planning for management of the neonate can occur.

Cytochrome P450 Interaction

The concomitant use of DOLOPHINE tablets with all cytochrome P450 3A4, 2B6, 2C19, 2C9 or 2D6 inhibitors may result in an increase in methadone plasma concentrations, which could cause potentially fatal respiratory depression. In addition, discontinuation of concomitantly used cytochrome P450 3A4 2B6, 2C19, or 2C9 inducers may also result in an increase in methadone plasma concentration. Follow patients closely for respiratory depression and sedation, and consider dosage reduction with any changes of concomitant medications that can result in an increase in methadone levels.

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 DOLOPHINE Tablets 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.

    Conditions For Distribution And Use Of Methadone Products For The Treatment Of Opioid Addiction

    For detoxification and maintenance of opioid dependence.

4 Contraindications

Revisions underlined below:

DOLOPHINE tablets are 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

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

5 Warnings and Precautions

5.1 Addiction, Abuse and Misuse

Additions and/or revisions underlined:

Assess each patient’s risk for opioid addiction, abuse, or misuse … Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol addiction or abuse) or mental illness (e.g., major depression).

5.10 Severe Hypotension

Additions and/or revisions underlined:

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

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

Additions and/or revisions underlined:

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) DOLOPHINE Tablets 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 DOLOPHINE Tablets

5.12 Risks of Use in Patients with Gastrointestinal Conditions

Additions and/or revisions underlined:

DOLOPHINE Tablets are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The methadone in DOLOPHINE Tablets may cause spasm of the sphincter of Oddi. Opioids may cause increases in the serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

5.13 Increased Risk of Seizures in Patients with Seizure Disorders

Additions and/or revisions underlined:

The methadone in DOLOPHINE Tablets may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during DOLOPHINE tablets therapy.

5.14 Withdrawal

Additions and/or revisions underlined:

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

When discontinuing DOLOPHINE tablets, gradually taper the dosage. Do not abruptly discontinue DOLOPHINE tablets.

5.15 Risks Driving and Operating Machinery

Additions and/or revisions underlined:

DOLOPHINE Tablets 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 DOLOPHINE Tablets and know how they will react to the medication.

5.16 Laboratory Test Interactions

Newly added information:

False positive urine drug screens for methadone have been reported for several drugs including diphenhydramine, doxylamine, clomipramaine, chlorpromazine, thioridazine, quetiapine, and verapamil.

5.2 Life-Threatening Respiratory Depression

Additions and/or revisions underlined:

Serious, life-threatening, or fatal respiratory depression has been reported with the use of methadone, even when used as recommended. The peak respiratory depressant effect of methadone occurs later, and persists longer than the peak analgesic effect.  Respiratory depression from opioid use, if not immediately recognized and treated …

5.4 Neonatal Opioid Withdrawal Syndrome

Additions and/or revisions underlined:

Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy, whether that use is medically-authorized or illicit. Unlike opioid withdrawal syndrome in adults, NOWS may be life-threatening if not recognized and treated in the neonate. Advise the patient of the risk of NOWS so that appropriate planning for management of the neonate can occur. Healthcare professionals should observe newborns for signs of NOWS and manage accordingly.

The balance between the risks of NOWS and the benefits of maternal DOLOPHINE Tablets use may differ based on the risks associated with the mother’s underlying condition, pain or addiction, and the risks of the alternative treatments.

For management of pain, prescribers should discuss all available treatment options with females. of reproductive potential, including non-opioid and non-pharmacologic options.

  • Untreated opioid addiction often results in continued or relapsing illicit opioid use and is associated with poor pregnancy outcomes. NOWS can result from in utero exposure to opioids regardless of the source. Therefore, prescribers should discuss the importance and benefits of management of opioid addiction throughout pregnancy.
5.5 Risks of Concomitant Use of Cytochrome P450 3A4, 2B6, 2C19, 2C9, or 2D6 Inhibitors or

Newly added information:

Concomitant use of DOLOPHINE Tablets with CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors, may increase plasma concentrations of methadone, prolong opioid adverse reactions, and may cause potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dosage of DOLOPHINE tablets is achieved. Similarly, discontinuation of concomitant CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers in DOLOPHINE Tablets- treated patients may increase methadone plasma concentrations resulting in fatal respiratory depression. Consider dosage reduction of DOLOPHINE Tablets when using concomitant CYP3A4, CYP2B6, CYP2C19, CYP2C9 or CYP2D6 inhibitors or discontinuing CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers in methadone-treated patients, and follow patients closely at frequent intervals for signs and symptoms of respiratory depression and sedation.

Addition of CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers or discontinuation of CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors in patients treated with DOLOPHINE Tablets may decrease methadone plasma concentrations, reducing efficacy and may lead to opioid withdrawal symptoms in patients physically dependent on methadone. When using DOLOPHINE Tablets with CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers or discontinuing CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors, follow patients for signs or symptoms of opioid withdrawal and consider increasing the DOLOPHINE Tablets dosage as needed.

5.6 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Newly added information:

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of DOLOPHINE Tablets 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 DOLOPHINE Tablets 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.

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

Additions and/or revisions underlined:

The use of DOLOPHINE Tablets 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

DOLOPHINE Tablets-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 DOLOPHINE tablets.

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 DOLOPHINE tablets and when DOLOPHINE tablets are given concomitantly with other drugs that depress respiration. Alternatively, consider the use of non-opioid analgesics in these patients.

5.8 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs

Newly added information:

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of DOLOPHINE tablets with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). This may occur within the recommended dosage range.

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue DOLOPHINE tablets if serotonin syndrome is suspected.

5.9 Adrenal Insufficiency

Newly added information:

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.

6 Adverse Reactions

Additions and/or revisions underlined:

  • The following serious adverse reactions are described, or described in greater detail, in other sections:
  • Addiction, Abuse, and Misuse
  • Life Threatening Respiratory Depression
  • QT Prolongation
  • Neonatal Opioid Withdrawal Syndrome
  • Interactions with Benzodiazepines and other CNS Depressants
  • Serotonin Syndrome
  • Adrenal Insufficiency
  • Severe Hypotension
  • Gastrointestinal Adverse Reactions
  • Seizures
  • Withdrawal

The following adverse reactions associated with the use of methadone 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.

Other adverse reactions include the following:

Endocrine: hypogonadism, decreased testosterone

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.

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

7 Drug Interactions

Information has been converted to a table format; please refer to label.

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:


Risk Summary

Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy.

Pregnant women in methadone maintenance programs may have reduced incidence of obstetric and fetal complications and neonatal morbidity and mortality when compared to women using illicit drugs. Untreated opioid addiction in pregnancy is associated with adverse obstetrical outcomes and risk of continued or relapsing illicit opioid use. These risks should be considered in women treated with DOLOPHINE Tablets for maintenance treatment of opioid addiction.

For women treated with DOLOPHINE tablets for pain severe enough to require daily, around-the-clock, long-term opioid treatment, DOLOPHINE tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

There are no adequate and well-controlled studies in pregnant women.


In published animal reproduction studies, methadone administered subcutaneously during the early gestational period produced neural tube defects (i.e., exencephaly and cranioschisis) in the hamster at doses 2 times the human daily oral dose of 120 mg/day on a mg/m2 basis (HDD) and in mice at doses equivalent to the HDD. Administration of methadone to pregnant animals during organogenesis and through lactation resulted decreased litter size, increased pup mortality, decreased pup body weights, developmental delays, and long-term neurochemical changes in the brain of offspring which correlate with altered behavioral responses that persist through adulthood at exposures comparable to and less than the HDD. Administration of methadone to male rodents prior to mating with untreated females resulted in increased neonatal mortality and significant differences in behavioral tests in the offspring at exposures comparable to and less than the HDD. Based on animal data, advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Disease-associated Maternal and Embryo-fetal Risk: Untreated opioid addiction is associated with adverse obstetrical outcomes such as low birth weight, preterm birth, and fetal death. In addition, untreated opioid addiction often results in continued or relapsing illicit opioid use.

Dosage Adjustment During Pregnancy: The disposition of oral methadone has been studied in approximately 30 pregnant patients …

Fetal/neonatal Adverse Reactions: Neonatal opioid withdrawal syndrome may occur in newborn infants of mothers who are receiving treatment with DOLOPHINE Tablets.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and/or failure to gain weight. Signs of neonatal withdrawal usually occur in the first days after birth. The duration and severity of neonatal opioid withdrawal syndrome may vary. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly.

Labor or Delivery: Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Use of DOLOPHINE Tablets as an analgesic is not recommended for pregnant women during or immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including DOLOPHINE can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Data

Human Data: Reported studies have generally compared the benefit of methadone to the risk of untreated addiction to illicit drugs …


Animal Data:  Formal reproductive and developmental toxicology studies for methadone have not been conducted. Exposure margins for the following published study reports are based on a human daily dose (HDD) of 120 mg methadone using a body surface area comparison.

In a published study in pregnant hamsters, a single subcutaneous dose … In a study in pregnant mice, a single subcutaneous dose of 22 to 24 mg/kg methadone (approximately equivalent to the HDD) administered on Gestation Day 9 produced exencephaly in 11% of the embryos. In another study in pregnant mice …

In a second study of pregnant mice dosed with subcutaneous doses up to 28 mg/kg/day methadone from Gestation Day 6 to 15, there was decreased pup viability, delayed onset of development of negative phototaxis and eye opening, increased righting reflexes at 5 mg/kg/day or greater (0.2 times the HDD), and decreased number of live pups at birth and decreased pup weight gain at 20 mg/kg/day or greater (0.8 times the HDD).

No effects were reported in a study of pregnant rats and rabbits at oral doses up to 40 mg/kg (3 and 6 times, respectively, the HDD) administered from Gestation Days 6 to 15 and 6 to 18, respectively.

When pregnant rats were treated with intraperitoneal doses of 2.5, 5, or 7.5 mg/kg methadone from one week prior to mating, through gestation until the end of lactation period, 5 mg/kg or greater (0.4 times the HDD) methadone resulted in decreases in litter size and live pups born and 7.5 mg/kg (0.6 times the HDD) resulted in decreased birth weights. Furthermore, decreased pup viability and pup body weight gain at 2.5 mg/kg or greater (0.2 times the HDD) were noted during the preweaning period.

Additional animal data demonstrates evidence for neurochemical changes in the brains of offspring from methadone- treated pregnant rats, including changes to the cholinergic, dopaminergic, noradrenergic and serotonergic systems at doses below the HDD. Other animal studies have reported that prenatal and/or postnatal exposure to opioids including methadone alters neuronal development and behavior in the offspring including alterations in learning ability, motor activity, thermal regulation, nociceptive responses, and sensitivity to drugs at doses below the HDD. Treatment of pregnant rats subcutaneously with 5 mg/kg methadone from Gestation Day 14 to 19 (0.4 times the HDD) reduced fetal blood testosterone and androstenedione in males.

Published animal data have reported … Examination of uterine contents of methadone-naïve female mice bred to methadone-treated male mice (once a day for three consecutive days) indicated that methadone treatment produced an increase in the rate of preimplantation deaths in all post-meiotic states at 1 mg/kg/day or greater (0.04 times the HDD). Chromosome analysis revealed a dose-dependent increase in the frequency of chromosomal abnormalities at 1 mg/kg/day or greater.

Studies demonstrated that methadone treatment of male rats …

8.2 Lactation

Additions and/or revisions underlined:

Risk Summary

Based on two studies in 22 breastfeeding women maintained on methadone treatment, methadone was present in low levels in human milk, and did not show adverse reactions in breastfed infants. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for methadone and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.

Clinical Considerations

Advise breastfeeding women taking methadone to monitor the infant for increased drowsiness and breathing difficulties.

Data

In a study of ten breastfeeding women maintained on oral methadone doses of 10 to 80 mg/day, methadone concentrations from 50 to 570 mcg/L in milk were reported, which, in the majority of samples …

In a study of twelve breastfeeding women maintained on oral methadone doses of 20 to 80 mg/day, methadone concentrations from 39 to 232 mcg/L in milk were reported. Based on an average milk consumption …

There have been rare cases of sedation and respiratory depression in infants exposed to methadone through breast milk.

8.3 Females and Males of Reproductive Potential

Additions and/or revisions underlined:

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. Reproductive function in human males may be decreased by methadone treatment. Reductions in ejaculate volume and seminal vesicle and prostate secretions have been reported in methadone-treated individuals. In addition, reductions in serum testosterone levels and sperm motility, and abnormalities in sperm morphology have been reported.

In published animal studies, methadone produces a significant regression of sex accessory organs and testes of male mice and rats and administration of methadone to pregnant rats reduced fetal blood testosterone and androstenedione in male offspring.

8.5 Geriatric Use

Additions and/or revisions underlined:

Clinical studies of methadone did not include sufficient numbers of subjects aged 65 and over …

Elderly patients (aged 65 years or older) may have increased sensitivity to methadone.  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 DOLOPHINE tablets slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression.

Methadone 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.

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

MEDICATION GUIDE

Additions and/or revisions underlined:

Important information about DOLOPHINE tablets:

  • Taking DOLOPHINE Tablets with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.

    Tell your healthcare provider if you are:

  • pregnant or plan to become pregnant. If you take DOLOPHINE Tablets while pregnant, your baby may have symptoms of opioid withdrawal or respiratory depression at birth. Talk to your doctor if you are pregnant or plan to become pregnant.

    When taking DOLOPHINE Tablets:

    Do not change your dose. Take DOLOPHINE Tablets exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed.

    Get emergency medical help if you have:

    trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.

     

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined throughout this section:

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

Interactions with Benzodiazepines and Other CNS Depressants

Inform patients and caregivers that potentially fatal additive effects may occur if DOLOPHINE tablets are used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a health care provider..

Serotonin Syndrome

Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications.

MAOI Interaction

Inform patients to avoid taking DOLOPHINE while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking DOLOPHINE.

Adrenal Insufficiency

Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms.

Pregnancy

Neonatal Opioid Withdrawal Syndrome: Advise women that if they are pregnant while being treated with DOLOPHINE Tablets, the baby may have signs of withdrawal at birth and that withdrawal is treatable.

Embryo-Fetal Toxicity: Inform female patients of reproductive potential that DOLOPHINE Tablets can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy.

Infertility

Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible.

Driving or Operating Heavy Machinery

Inform patients that DOLOPHINE Tablets may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication.

Constipation

Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention.

12/16/2016 (SUPPL-41)

Approved Drug Label (PDF)

Boxed Warning

Additions and/or revisions underlined:

WARNING: ADDICTION, ABUSE AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; LIFE-THREATENING QT PROLONGATION; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; and TREATMENT FOR OPIOID ADDICTION

Addiction, Abuse, and Misuse

DOLOPHINE tablets expose patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead …

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression may occur with use of DOLOPHINE Tablets. The peak respiratory depressant effect of methadone occurs later, and persists longer than the peak analgesic effect, especially during the initial dosing period. Monitor for respiratory depression, especially during initiation of DOLOPHINE Tablets or following a dose increase.

Accidental Ingestion

Accidental ingestion of even one dose of DOLOPHINE tablets, especially by children, can result in a fatal overdose of methadone.

Life-Threatening QT Prolongation

… Most cases involve patients being treated for pain with large, multiple daily doses of methadone,

although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. Closely monitor patients with risk factors for development of prolonged QT interval, a history of cardiac conduction abnormalities, and those taking medications affecting cardiac conduction for changes in cardiac rhythm during initiation and titration of DOLOPHINE tablets.

Neonatal Opioid Withdrawal Syndrome

Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of use of DOLOPHINE Tablets during pregnancy. NOWS may be life-threatening if not recognized and treated in the neonate. The

balance between the risks of NOWS and the benefits of maternal DOLOPHINE use may differ based on the

risks associated with the mother’s underlying condition, pain, or addiction. Advise the patient of the risk of NOWS so that appropriate planning for management of the neonate can occur.

Cytochrome P450 Interaction

The concomitant use of DOLOPHINE tablets with all cytochrome P450 3A4, 2B6, 2C19, 2C9 or 2D6 inhibitors may result in an increase in methadone plasma concentrations, which could cause potentially fatal respiratory depression. In addition, discontinuation of concomitantly used cytochrome P450 3A4 2B6, 2C19, or 2C9 inducers may also result in an increase in methadone plasma concentration. Follow patients closely for respiratory depression and sedation, and consider dosage reduction with any changes of concomitant medications that can result in an increase in methadone levels.

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 DOLOPHINE Tablets 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.

    Conditions For Distribution And Use Of Methadone Products For The Treatment Of Opioid Addiction

    For detoxification and maintenance of opioid dependence.

4 Contraindications

Revisions underlined below:

DOLOPHINE tablets are 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

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

5 Warnings and Precautions

5.1 Addiction, Abuse and Misuse

Additions and/or revisions underlined:

Assess each patient’s risk for opioid addiction, abuse, or misuse … Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol addiction or abuse) or mental illness (e.g., major depression).

5.10 Severe Hypotension

Additions and/or revisions underlined:

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

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

Additions and/or revisions underlined:

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) DOLOPHINE Tablets 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 DOLOPHINE Tablets

5.12 Risks of Use in Patients with Gastrointestinal Conditions

Additions and/or revisions underlined:

DOLOPHINE Tablets are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The methadone in DOLOPHINE Tablets may cause spasm of the sphincter of Oddi. Opioids may cause increases in the serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

5.13 Increased Risk of Seizures in Patients with Seizure Disorders

Additions and/or revisions underlined:

The methadone in DOLOPHINE Tablets may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during DOLOPHINE tablets therapy.

5.14 Withdrawal

Additions and/or revisions underlined:

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

When discontinuing DOLOPHINE tablets, gradually taper the dosage. Do not abruptly discontinue DOLOPHINE tablets.

5.15 Risks Driving and Operating Machinery

Additions and/or revisions underlined:

DOLOPHINE Tablets 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 DOLOPHINE Tablets and know how they will react to the medication.

5.16 Laboratory Test Interactions

Newly added information:

False positive urine drug screens for methadone have been reported for several drugs including diphenhydramine, doxylamine, clomipramaine, chlorpromazine, thioridazine, quetiapine, and verapamil.

5.2 Life-Threatening Respiratory Depression

Additions and/or revisions underlined:

Serious, life-threatening, or fatal respiratory depression has been reported with the use of methadone, even when used as recommended. The peak respiratory depressant effect of methadone occurs later, and persists longer than the peak analgesic effect.  Respiratory depression from opioid use, if not immediately recognized and treated …

5.4 Neonatal Opioid Withdrawal Syndrome

Additions and/or revisions underlined:

Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy, whether that use is medically-authorized or illicit. Unlike opioid withdrawal syndrome in adults, NOWS may be life-threatening if not recognized and treated in the neonate. Advise the patient of the risk of NOWS so that appropriate planning for management of the neonate can occur. Healthcare professionals should observe newborns for signs of NOWS and manage accordingly.

The balance between the risks of NOWS and the benefits of maternal DOLOPHINE Tablets use may differ based on the risks associated with the mother’s underlying condition, pain or addiction, and the risks of the alternative treatments.

For management of pain, prescribers should discuss all available treatment options with females. of reproductive potential, including non-opioid and non-pharmacologic options.

  • Untreated opioid addiction often results in continued or relapsing illicit opioid use and is associated with poor pregnancy outcomes. NOWS can result from in utero exposure to opioids regardless of the source. Therefore, prescribers should discuss the importance and benefits of management of opioid addiction throughout pregnancy.
5.5 Risks of Concomitant Use of Cytochrome P450 3A4, 2B6, 2C19, 2C9, or 2D6 Inhibitors or

Newly added information:

Concomitant use of DOLOPHINE Tablets with CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors, may increase plasma concentrations of methadone, prolong opioid adverse reactions, and may cause potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dosage of DOLOPHINE tablets is achieved. Similarly, discontinuation of concomitant CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers in DOLOPHINE Tablets- treated patients may increase methadone plasma concentrations resulting in fatal respiratory depression. Consider dosage reduction of DOLOPHINE Tablets when using concomitant CYP3A4, CYP2B6, CYP2C19, CYP2C9 or CYP2D6 inhibitors or discontinuing CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers in methadone-treated patients, and follow patients closely at frequent intervals for signs and symptoms of respiratory depression and sedation.

Addition of CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers or discontinuation of CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors in patients treated with DOLOPHINE Tablets may decrease methadone plasma concentrations, reducing efficacy and may lead to opioid withdrawal symptoms in patients physically dependent on methadone. When using DOLOPHINE Tablets with CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers or discontinuing CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors, follow patients for signs or symptoms of opioid withdrawal and consider increasing the DOLOPHINE Tablets dosage as needed.

5.6 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Newly added information:

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of DOLOPHINE Tablets 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 DOLOPHINE Tablets 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.

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

Additions and/or revisions underlined:

The use of DOLOPHINE Tablets 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

DOLOPHINE Tablets-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 DOLOPHINE tablets.

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 DOLOPHINE tablets and when DOLOPHINE tablets are given concomitantly with other drugs that depress respiration. Alternatively, consider the use of non-opioid analgesics in these patients.

5.8 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs

Newly added information:

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of DOLOPHINE tablets with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). This may occur within the recommended dosage range.

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue DOLOPHINE tablets if serotonin syndrome is suspected.

5.9 Adrenal Insufficiency

Newly added information:

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.

6 Adverse Reactions

Additions and/or revisions underlined:

  • The following serious adverse reactions are described, or described in greater detail, in other sections:
  • Addiction, Abuse, and Misuse
  • Life Threatening Respiratory Depression
  • QT Prolongation
  • Neonatal Opioid Withdrawal Syndrome
  • Interactions with Benzodiazepines and other CNS Depressants
  • Serotonin Syndrome
  • Adrenal Insufficiency
  • Severe Hypotension
  • Gastrointestinal Adverse Reactions
  • Seizures
  • Withdrawal

The following adverse reactions associated with the use of methadone 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.

Other adverse reactions include the following:

Endocrine: hypogonadism, decreased testosterone

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.

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

7 Drug Interactions

Information has been converted to a table format; please refer to label.

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Risk Summary

Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy.

Pregnant women in methadone maintenance programs may have reduced incidence of obstetric and fetal complications and neonatal morbidity and mortality when compared to women using illicit drugs. Untreated opioid addiction in pregnancy is associated with adverse obstetrical outcomes and risk of continued or relapsing illicit opioid use. These risks should be considered in women treated with DOLOPHINE Tablets for maintenance treatment of opioid addiction.

For women treated with DOLOPHINE tablets for pain severe enough to require daily, around-the-clock, long-term opioid treatment, DOLOPHINE tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

There are no adequate and well-controlled studies in pregnant women.


In published animal reproduction studies, methadone administered subcutaneously during the early gestational period produced neural tube defects (i.e., exencephaly and cranioschisis) in the hamster at doses 2 times the human daily oral dose of 120 mg/day on a mg/m2 basis (HDD) and in mice at doses equivalent to the HDD. Administration of methadone to pregnant animals during organogenesis and through lactation resulted decreased litter size, increased pup mortality, decreased pup body weights, developmental delays, and long-term neurochemical changes in the brain of offspring which correlate with altered behavioral responses that persist through adulthood at exposures comparable to and less than the HDD. Administration of methadone to male rodents prior to mating with untreated females resulted in increased neonatal mortality and significant differences in behavioral tests in the offspring at exposures comparable to and less than the HDD. Based on animal data, advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Disease-associated Maternal and Embryo-fetal Risk: Untreated opioid addiction is associated with adverse obstetrical outcomes such as low birth weight, preterm birth, and fetal death. In addition, untreated opioid addiction often results in continued or relapsing illicit opioid use.

Dosage Adjustment During Pregnancy: The disposition of oral methadone has been studied in approximately 30 pregnant patients …

Fetal/neonatal Adverse Reactions: Neonatal opioid withdrawal syndrome may occur in newborn infants of mothers who are receiving treatment with DOLOPHINE Tablets.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and/or failure to gain weight. Signs of neonatal withdrawal usually occur in the first days after birth. The duration and severity of neonatal opioid withdrawal syndrome may vary. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly.

Labor or Delivery: Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Use of DOLOPHINE Tablets as an analgesic is not recommended for pregnant women during or immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including DOLOPHINE can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Data

Human Data: Reported studies have generally compared the benefit of methadone to the risk of untreated addiction to illicit drugs …


Animal Data:  Formal reproductive and developmental toxicology studies for methadone have not been conducted. Exposure margins for the following published study reports are based on a human daily dose (HDD) of 120 mg methadone using a body surface area comparison.

In a published study in pregnant hamsters, a single subcutaneous dose … In a study in pregnant mice, a single subcutaneous dose of 22 to 24 mg/kg methadone (approximately equivalent to the HDD) administered on Gestation Day 9 produced exencephaly in 11% of the embryos. In another study in pregnant mice …

In a second study of pregnant mice dosed with subcutaneous doses up to 28 mg/kg/day methadone from Gestation Day 6 to 15, there was decreased pup viability, delayed onset of development of negative phototaxis and eye opening, increased righting reflexes at 5 mg/kg/day or greater (0.2 times the HDD), and decreased number of live pups at birth and decreased pup weight gain at 20 mg/kg/day or greater (0.8 times the HDD).

No effects were reported in a study of pregnant rats and rabbits at oral doses up to 40 mg/kg (3 and 6 times, respectively, the HDD) administered from Gestation Days 6 to 15 and 6 to 18, respectively.

When pregnant rats were treated with intraperitoneal doses of 2.5, 5, or 7.5 mg/kg methadone from one week prior to mating, through gestation until the end of lactation period, 5 mg/kg or greater (0.4 times the HDD) methadone resulted in decreases in litter size and live pups born and 7.5 mg/kg (0.6 times the HDD) resulted in decreased birth weights. Furthermore, decreased pup viability and pup body weight gain at 2.5 mg/kg or greater (0.2 times the HDD) were noted during the preweaning period.

Additional animal data demonstrates evidence for neurochemical changes in the brains of offspring from methadone- treated pregnant rats, including changes to the cholinergic, dopaminergic, noradrenergic and serotonergic systems at doses below the HDD. Other animal studies have reported that prenatal and/or postnatal exposure to opioids including methadone alters neuronal development and behavior in the offspring including alterations in learning ability, motor activity, thermal regulation, nociceptive responses, and sensitivity to drugs at doses below the HDD. Treatment of pregnant rats subcutaneously with 5 mg/kg methadone from Gestation Day 14 to 19 (0.4 times the HDD) reduced fetal blood testosterone and androstenedione in males.

Published animal data have reported … Examination of uterine contents of methadone-naïve female mice bred to methadone-treated male mice (once a day for three consecutive days) indicated that methadone treatment produced an increase in the rate of preimplantation deaths in all post-meiotic states at 1 mg/kg/day or greater (0.04 times the HDD). Chromosome analysis revealed a dose-dependent increase in the frequency of chromosomal abnormalities at 1 mg/kg/day or greater.

Studies demonstrated that methadone treatment of male rats …

8.2 Lactation

Additions and/or revisions underlined:

Risk Summary

Based on two studies in 22 breastfeeding women maintained on methadone treatment, methadone was present in low levels in human milk, and did not show adverse reactions in breastfed infants. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for methadone and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.

Clinical Considerations

Advise breastfeeding women taking methadone to monitor the infant for increased drowsiness and breathing difficulties.

Data

In a study of ten breastfeeding women maintained on oral methadone doses of 10 to 80 mg/day, methadone concentrations from 50 to 570 mcg/L in milk were reported, which, in the majority of samples …

In a study of twelve breastfeeding women maintained on oral methadone doses of 20 to 80 mg/day, methadone concentrations from 39 to 232 mcg/L in milk were reported. Based on an average milk consumption …

There have been rare cases of sedation and respiratory depression in infants exposed to methadone through breast milk.

8.3 Females and Males of Reproductive Potential

Additions and/or revisions underlined:

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. Reproductive function in human males may be decreased by methadone treatment. Reductions in ejaculate volume and seminal vesicle and prostate secretions have been reported in methadone-treated individuals. In addition, reductions in serum testosterone levels and sperm motility, and abnormalities in sperm morphology have been reported.

In published animal studies, methadone produces a significant regression of sex accessory organs and testes of male mice and rats and administration of methadone to pregnant rats reduced fetal blood testosterone and androstenedione in male offspring.

8.5 Geriatric Use

Additions and/or revisions underlined:

Clinical studies of methadone did not include sufficient numbers of subjects aged 65 and over …

Elderly patients (aged 65 years or older) may have increased sensitivity to methadone.  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 DOLOPHINE tablets slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression.

Methadone 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.

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

MEDICATION GUIDE

Additions and/or revisions underlined:

Important information about DOLOPHINE tablets:

  • Taking DOLOPHINE Tablets with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.

    Tell your healthcare provider if you are:

  • pregnant or plan to become pregnant. If you take DOLOPHINE Tablets while pregnant, your baby may have symptoms of opioid withdrawal or respiratory depression at birth. Talk to your doctor if you are pregnant or plan to become pregnant.

    When taking DOLOPHINE Tablets:

    Do not change your dose. Take DOLOPHINE Tablets exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed.

    Get emergency medical help if you have:

    trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined throughout this section:          

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

Interactions with Benzodiazepines and Other CNS Depressants

Inform patients and caregivers that potentially fatal additive effects may occur if DOLOPHINE tablets are used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a health care provider..

Serotonin Syndrome

Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications.

MAOI Interaction

Inform patients to avoid taking DOLOPHINE while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking DOLOPHINE.

Adrenal Insufficiency

Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms.

Pregnancy

Neonatal Opioid Withdrawal Syndrome: Advise women that if they are pregnant while being treated with DOLOPHINE Tablets, the baby may have signs of withdrawal at birth and that withdrawal is treatable.

Embryo-Fetal Toxicity: Inform female patients of reproductive potential that DOLOPHINE Tablets can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy.

Infertility

Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible.

Driving or Operating Heavy Machinery

Inform patients that DOLOPHINE Tablets may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication.

Constipation

Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention.

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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