Drug Safety-related Labeling Changes (SrLC)

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METHADOSE (NDA-017116)

(METHADONE HYDROCHLORIDE)

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

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12/22/2025 (SUPPL-48)

Approved Drug Label (PDF)

Boxed Warning

Subsection title revised:

. . .

Managing Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants 

Concomitant use with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, is a risk factor for respiratory depression and death [see Warnings and Precautions (5.2)].

• Reserve concomitant prescribing of benzodiazepines or other CNS depressants in patients in methadone treatment to those for whom alternatives to benzodiazepines or other CNS depressants are inadequate.
• 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 daily methadone dosing.

. . .

5 Warnings and Precautions

5.1 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. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with a “sighing” pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. Management of respiratory depression may include close observation, supportive measures, and use of opioid overdose reversal agents, depending on the patient’s clinical status [see Overdosage (10)].

. . .

Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose

Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene) and discuss the importance of having access to an opioid overdose reversal agent. Because patients being treated with methadone may be at risk for opioid overdose during initiation or titration, or in the case of relapse to illicit use, strongly consider recommending or prescribing an opioid overdose reversal agent for the emergency treatment of an opioid overdose, both when initiating and renewing treatment with METHADOSE. Also consider recommending or prescribing such an agent if the patient has household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose [see Dosage and Administration (2.3)].

Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).

There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent.

Advise patients and caregivers that an opioid overdose reversal agent, such as naloxone or nalmefene, may also be administered for a known or suspected overdose with METHADOSE itself [see Overdosage (10)].

Educate patients and caregivers on how to recognize respiratory depression and how to use an opioid overdose reversal agent for the emergency treatment of opioid overdose. Emphasize the importance of calling 911 or getting emergency medical help, even if an opioid overdose reversal agent is administered.

5.2 Managing Risks from Concomitant Use of Benzodiazepines or Other CNS Depressants with Methadone

Additions and/or revisions underlined:

Concomitant use of methadone and benzodiazepines and/or other CNS depressants (e.g., alcohol, non- benzodiazepine sedative/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids), 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.

. . .

If concomitant use is warranted, strongly consider recommending or prescribing an opioid overdose reversal agent, as is recommended for all patients on methadone treatment for opioid use disorder [see Warnings and Precautions (5.1)].

. . .

5.13 Risks of Gastrointestinal Complications

Subsection title revised.

Additions and/or revisions underlined:

. . .

Cases of opioid-induced esophageal dysfunction (OIED) have been reported in patients taking opioids. The risk of OIED may increase as the dose and/or duration of opioids increases. Regularly evaluate patients for signs and symptoms of OIED (e.g., dysphagia, regurgitation, non-cardiac chest pain) and, if necessary, adjust opioid therapy as clinically appropriate [see Clinical Pharmacology (12.2)].

5.15 Withdrawal

Additions and/or revisions underlined:

. . .

When discontinuing METHADOSE, gradually taper the dosage [see Dosage and Administration (2.6, 2.7)]. Do not abruptly rapidly reduce or discontinue METHADOSE [see Drug Abuse and Dependence (9.3)].

6 Adverse Reactions

Additions and/or revisions underlined:

. . .

Opioid-induced esophageal dysfunction (OIED): Cases of OIED have been reported in patients taking opioids and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term [see Warnings and Precautions (5.13)].

7 Drug Interactions

Additions and/or revisions underlined for Intervention section of Benzodiazepines and Other Central Nervous System (CNS) Depressants of table; please refer to table for complete information:

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 of a prescribed benzodiazepine or other CNS depressant or decreasing to the lowest effective dose may be appropriate.

Before co-prescribing benzodiazepines for anxiety or insomnia, ensure that patients are appropriately diagnosed and consider alternative medications and non-pharmacologic treatments [see Warnings and Precautions (5.2)].

If concomitant use is warranted, strongly consider recommending or prescribing an opioid overdose reversal agent, as is recommended for all patients in treatment for opioid use disorder [see Warnings and Precautions (5.1)].

Additions and/or revisions underlined for Examples section of Benzodiazepines and Other Central Nervous System (CNS) Depressants of table; please refer to table for complete information:

Alcohol, benzodiazepines, and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin), other opioids.

Additions and/or revisions underlined for Intervention section of Muscle Relaxants of table; please refer to table for complete information:

Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of METHADOSE and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, strongly consider recommending or prescribing an opioid overdose reversal agent, as is recommended for all patients in treatment for opioid use disorder [see Dosage and Administration (2.3), Warnings and Precautions (5.1, 5.2)].

Newly added Examples section of Muscle Relaxants of table; please refer to table for complete information:

Cyclobenzaprine, metaxalone

8 Use in Specific Populations

8.3 Females and Males of Reproductive Potential

Additions and/or revisions underlined:

Infertility

The effect of METHADOSE on fertility is unknown. Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6), Clinical Pharmacology (12.2), Nonclinical Toxicology (13)]. 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 [see Nonclinical Toxicology (13)].

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

. . .

Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene) and discuss the importance of having access to an opioid overdose reversal agent. Because patients being treated with methadone may be at risk for opioid overdose during initiation or titration, or in the case of relapse to illicit use, discuss the importance of having access to an opioid overdose reversal agent. Also discuss the importance of having access to an opioid overdose reversal agent if the patient has household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose.

Discuss with the patient the options for obtaining an opioid overdose reversal agent (e.g., prescription, over- the-counter (some products), or as part of a community-based program) [see Dosage and Administration (2.3), Warnings and Precautions (5.1)].

There are important differences among the opioid overdose reversal agents. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent.

Educate patients and caregivers on how to recognize the signs and symptoms of an opioid overdose.

Explain to patients and caregivers that effects of opioid overdose reversal agents like naloxone and nalmefene are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if an opioid overdose reversal agent is administered. Repeat administration may be necessary, particularly for overdose involving METHADOSE [see Dosage and Administration (2.3), Warnings and Precautions (5.1), Overdosage (10)].

Advise patients and caregivers:

• how to treat with an opioid overdose reversal agent in the event of an opioid overdose.
• to tell family and friends about their opioid overdose reversal agent, and to keep it in a place where family and friends can access it in an emergency.
• to read the Patient Information (or other educational material) that will come with their opioid overdose reversal agent. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do.

Interactions with Benzodiazepines and Other CNS Depressants

Inform patients and caregivers that potentially fatal additive effects may occur if METHADOSE is used with benzodiazepines or other CNS depressants (e.g., alcohol, non-benzodiazepine sedative/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids), and not to use these concomitantly unless supervised by a healthcare provider [see Warnings and Precautions (5.2), Drug Interactions (7)].

. . .

Infertility

Advise patients that use of opioids, such as METHADOSE, for an extended period of time may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Populations (8.3)].

. . .

12/15/2023 (SUPPL-45)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.17 Hypoglycemia

Newly added subsection:

Cases of methadone-associated hypoglycemia have been reported, some resulting in hospitalization. In many cases, patients had predisposing risk factors (e.g., diabetes). The relationship between methadone and hypoglycemia is not fully understood but may be dose dependent. If hypoglycemia is suspected, monitor blood glucose levels, and manage the patient as clinically appropriate.

6 Adverse Reactions

Additions and revisions underlined:

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

• Respiratory Depression [see Warnings and Precautions (5.1)]

• Interactions with Benzodiazepines and other CNS Depressants [see Warnings and Precautions (5.2)]

• QT Prolongation [see Warnings and Precautions (5.3)]

• Serotonin Syndrome [see Warnings and Precautions (5.9)]

• Adrenal Insufficiency [see Warnings and Precautions (5.10)]

• Severe Hypotension [see Warnings and Precautions (5.11)]

• Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.13)]

• Seizures [see Warnings and Precautions (5.14)]

• Withdrawal [see Warnings and Precautions (5.15)]

• Hypoglycemia [see Warnings and Precautions (5.15)]

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

PATIENT COUNSELING INFORMATION

Newly added information:

Hypoglycemia

Inform patients that methadone may cause hypoglycemia. Instruct patients how to recognize the symptoms of low blood glucose and to contact their health care provider if these symptoms occur [see Warnings and Precautions (5.17)].

09/13/2021 (SUPPL-43)

Approved Drug Label (PDF)

Other

(PLR conversion; please refer to label)

 

06/02/2021 (SUPPL-41)

Approved Drug Label (PDF)

5 Warnings and Precautions

Precautions

(Newly added information)

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose (see WARNINGS, Life-Threatening Respiratory Depression).

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

Because patients being treated for opioid use disorder are at risk for relapse, discuss the importance of having access to naloxone with the patient and  caregiver.  Also discuss the importance of having access to naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose.

Inform patients and caregivers of the options for obtaining naloxone as permitted by individual state naloxone dispensing and prescribing requirements and guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program).

Educate patients and caregivers on how to recognize the signs and symptoms of an opioid overdose.

Explain to patients and caregivers that naloxone’s effects are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if naloxone is administered (see WARNINGS, Life- Threatening Respiratory Depression, DOSAGE AND ADMINISTRATION, Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose).

If naloxone is prescribed, also advise patients and caregivers:

• How to treat with naloxone in the event of an opioid overdose

• To tell family and friends about their naloxone and to keep it in a place where family and friends can access it in an emergency

To read the Patient Information (or other educational material) that will come with their naloxone. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do.

Warnings

(Newly added information)

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose (see PRECAUTIONS, Information for Patients).

Patient Access to Nalox one for the Emergenc y Treatment of Opioid Overdose

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver. Because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with METHADOSE.  Also  consider  prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose (see DOSAGE AND ADMINISTRATION, Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose).

Advise patients and caregivers that naloxone may also be administered for a known or suspected overdose with METHADOSE itself (see OVERDOSAGE).

Inform patients and caregivers of their options for obtaining naloxone as permitted by individual state naloxone  dispensing  and  prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and, if naloxone is prescribed, how to treat with naloxone. Emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered (see PRECAUTIONS, Information for Patients).

If concomitant use is warranted, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, as is recommended for all patients in methadone treatment for opioid use disorder (see WARNINGS, Life-Threatening Respiratory Depression).

6 Adverse Reactions

(Newly added information)

Central Nervous System – agitation, confusion, disorientation, dysphoria, euphoria, insomnia, hallucinations, seizures, visual disturbances, congenital oculomotor disorders (nystagmus, strabismus)

8 Use in Specific Populations

Females and Males of Reproductive Potential Infertility

(Additions and/or revisions underlined)

The effect of METHADOSE on fertility is unknown. 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 (see ADVERSE REACTIONS and CLINICAL PHARMACOLOGY).

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.

Infertility

(Newly added information)

Advise patients that chronic use of opioids, such as METHADOSE, may cause reduced fertility. It is not known whether these effects on fertility are reversible (see ADVERSE REACTIONS and CLINICAL PHARMACOLOGY).

Lactation

(Additions and/or revisions underlined)

Risk Summary

Based on two small clinical studies, methadone was present in low levels in human milk, but the exposed infants in these studies did not show adverse reactions. Based on an average milk consumption of 150 mL/kg/day, an infant would consume approximately 17.4 mcg/kg/day which is approximately 2 to 3% of the oral maternal dose. There have been rare case reports of sedation and respiratory  depression in infants exposed to methadone through breast milk (see Data). Monitor infants exposed to METHADOSE through breastmilk for excess sedation and respiratory depression. 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.

Data

(Additions and/or revisions underlined)

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, were lower than maternal serum drug concentrations at steady state. Peak methadone levels in milk occur approximately 4 to 5 hours after an oral dose.

(Newly added information)

Advise women who are breastfeeding to monitor the infant for increased sleepiness (more than usual), difficulty breathing or limpness.

Pregnancy Risk Summary

(Updated section title)

(Additions and/or revisions underlined)

The majority of available data from clinical trials, observational studies, case series, and case reports on methadone use in pregnancy do not indicate an increased risk of major malformations specifically due to methadone. Pregnant women involved in methadone maintenance programs have been reported to have improved prenatal care leading to reduced incidence of obstetric and fetal complications and neonatal morbidity and mortality when compared to women using illicit drugs. Several factors, including maternal use of illicit drugs, nutrition, infection and psychosocial circumstances, complicate the interpretation of investigations of the children of women who take methadone during pregnancy. Information is limited regarding dose and duration of methadone use during pregnancy, and most maternal exposure in these studies appears to occur after the first trimester of pregnancy (see Data).

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

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 (see Data). 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 in pregnancy 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

Dosage adjustment using higher doses or administering the daily dose in divided doses may be necessary in pregnant women treated with METHADOSE. Pregnant women appear to have significantly lower trough plasma methadone concentrations, increased plasma methadone clearance, and shorter methadone half-life than after delivery (see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY). Withdrawal signs and symptoms should be closely monitored and the dose adjusted as necessary.

 

Fetal/Neonatal Adverse Reactions

Neonatal opioid withdrawal syndrome may occur in newborn infants of mothers who are receiving treatment with METHADOSE.

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 (see WARNINGS).

Labor or Delivery

Opioid-dependent women on methadone maintenance therapy may require additional analgesia during labor.

Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Data

Human Data

The majority of available data from clinical trials, observational studies, case series, and case reports on methadone use in pregnancy do not indicate an increased risk of major malformations specifically due to methadone. Findings regarding specific major malformations, decreased fetal growth, premature birth and Sudden Infant Death Syndrome have been inconsistent. Children prenatally exposed  to  methadone  have been reported to demonstrate mild but persistent deficits in performance  on psychometric and behavioral tests and visual abnormalities.

In a multicenter, double-blind, randomized, controlled trial [Maternal Opioid Treatment: Human Experimental Research (MOTHER)] designed primarily to assess neonatal opioid withdrawal effects, opioid-dependent pregnant women were randomized to buprenorphine (n=86) or methadone (n=89) treatment, with enrollment at an average gestational age of 18.7 weeks in both groups. A total of 28 of the 86 women in the buprenorphine group (33%) and 16 of the 89 women in the methadone group (18%) discontinued treatment before the end of pregnancy.

Among women who remained in treatment until delivery, there was no difference between methadone-treated and buprenorphine-treated groups in the number  of neonates requiring NOWS treatment or in the peak severity of NOWS. Buprenorphine- exposed neonates required less morphine (mean total dose, 1.1 mg vs. 10.4 mg), had shorter hospital stays (10.0 days vs. 17.5 days), and shorter duration of treatment for NOWS (4.1 days vs. 9.9 days) compared to the methadone-exposed group. There were no differences between groups in other primary outcomes (neonatal head circumference), or secondary outcomes (weight and length at birth, preterm birth, gestational age at delivery, and 1-minute and 5-minute Apgar scores), or in the rates of maternal or neonatal adverse events. The outcomes among mothers who discontinued treatment before delivery and may have relapsed to illicit opioid use are not known. Because of the imbalance in discontinuation rates between the methadone and buprenorphine groups, the study findings are difficult to interpret.

In a study in pregnant JBT/Jd 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.

10/07/2019 (SUPPL-38)

Approved Drug Label (PDF)

5 Warnings and Precautions

PRECAUTIONS

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).

WARNINGS

Life-Threatening Respiratory Depression

Newly added to the end of this titled 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.

Serotonin Syndrome with Concomitant Use of Serotonergic Drugs

Additions and/or revisions underlined:

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of METHADOSE 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).

02/01/2018 (SUPPL-32)

Approved Drug Label (PDF)

Boxed Warning

(additions underlined)

…

Risks From Concomitant Use With Benzodiazepines or Other CNS Depressants

Concomitant use with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, is a risk factor for respiratory depression and death.

• Reserve concomitant prescribing of benzodiazepines or other CNS depressants in patients in methadone treatment to those for whom alternatives to benzodiazepines or other CNS depressants are inadequate.

• 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 daily methadone dosing.

  …

5 Warnings and Precautions

PRECAUTIONS

Information for Patients

(additions underlined)

…

Interactions with Benzodiazepines and Other CNS Depressants

Inform patients and caregivers that potentially fatal additive effects may occur if METHADOSE is used with benzodiazepines or other CNS depressants, including alcohol. Counsel patients that such medications should not be used concomitantly unless supervised by a healthcare provider.

…

WARNINGS

(additions underlined)

…

Risks from Concomitant Use of Benzodiazepines or Other CNS Depressants with Methadone

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.

…

12/16/2016 (SUPPL-29)

Approved Drug Label (PDF)

Boxed Warning

PLR; Newly added section:

WARNING: LIFE-THREATENING RESPIRATORY DEPRESSION, LIFE­ THREATENING QT PROLONGATION, ACCIDENTAL INGESTION, ABUSE POTENTIAL INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES and TREATMENT FOR OPIOID ADDICTION

Life-threatening Respiratory Depression

Respiratory depression, including fatal cases, have been reported during initiation and conversion of patients to methadone, and even when the drug has been used as recommended and not misused or abused. Proper dosing and titration are essential and METHADOSE should only prescribed by healthcare professionals who are knowledgeable in the use of methadone for detoxification and maintenance treatment of opioid addiction. Monitor for respiratory depression, especially during initiation METHADOSE or following a dose increase. The peak respiratory depressant effect of methadone occurs later, and persists longer than the peak pharmacologic effect, especially during the initial dosing period.

Life-Threatening QT Prolongation

QT Interval prolongation and serious arrhythmia (torsades de pointes) have occurred during treatment with methadone. 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 METHADOSE.

Accidental Ingestion

Accidental ingestion of METHADOSE, especially by children, can result in fatal overdose of methadone.

Misuse, Abuse, and Diversion of Opioids

METHADOSE contains methadone, an opioid agonist and Schedule II controlled substance with an abuse liability similar to other opioid agonists, legal or illicit.

Interactions with Drugs Affecting Cytochrome P450 Isoenzymes

The concomitant use of METHADOSE 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.

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

For detoxification and maintenance of opioid dependence, methadone should be administered in accordance with the treatment standards cited in 42 CFR Section 8, including limitations on unsupervised administration.

4 Contraindications

Revised as below:

METHADOSE is 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 or any other ingredient in METHADOSE

5 Warnings and Precautions

WARNINGS

This section has undergone extensive changes; please refer to the label. Contents now include:

• Life-Threatening Respiratory Depression

• Life-Threatening QT Prolongation

• Accidental Ingestion

• Misuse, Abuse, and Diversion of Opioids

• Neonatal Opioid Withdrawal Syndrome

• Risks of Concomitant Use of Cytochrome P450 3A4, 2B6, 2C19, 2C9, or 2D6 Inhibitors or Discontinuation of P450 3A4, 2B6, 2C19, or 2C9 Inducers

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

• Risks Due to Concomitant Use with CNS Depressants and Illicit Drugs

• Serotonin Syndrome with Concomitant Use of Serotonergic Drugs

• Adrenal Insufficiency

• Severe Hypotension

• Use in Patients with Head Injury, or Increased Intracranial Pressure

• Risks of Use in Patients with Gastrointestinal Conditions

• Increased Risks of Seizure in Patients with Seizure Disorders

• Withdrawal

• Laboratory Test Interactions

  PRECAUTIONS

  This section has undergone extensive changes; please refer to the label. Contents now include:

  Information for Patients

• Life-Threatening Respiratory Depression

• Symptoms of Arrhythmia

• Accidental Ingestion

• Abuse Potential

• Risks from Concomitant Use of Alcohol and other CNS Depressants

• Important Administration Instructions

• Serotonin Syndrome

• MAOI Interaction

• Adrenal Insufficiency

• Anaphylaxis

• Neonatal Opioid Withdrawal

• Lactation

• Constipation

  Drug Interactions

  Information has undergone a conversion to a table format; please refer to label. In addition, the following

  underlined information is added or revised:

  Paradoxical Effects of Antiretroviral Agents on Methadone

  Concurrent use of certain protease inhibitors with CYP3A4 inhibitory activity, alone and in combination, such as abacavir, amprenavir, darunavir+ritonavir, efavirenz, nelfinavir, nevirapine, ritonavir, telaprevir, lopinavir+ritonavir, saquinavir+ritonavir, and tipranvir+ritonavir, has resulted in increased clearance or decreased plasma levels of methadone. This may result in reduced efficacy of METHADOSE and could precipitate a withdrawal syndrome. Monitor patients receiving METHADOSE and any of these anti­ retroviral   therapies   closely   for   evidence   of   withdrawal   effects   and   adjust   the METHADOSE dose accordingly.

  Effects of Methadone on Antiretroviral Agents

  Didanosine and Stavudine – Experimental evidence demonstrated that methadone decreased the area under the concentration-time curve (AUC) and peak levels for didanosine and stavudine, with a more significant decrease for didanosine. Methadone disposition was not substantially altered.

  Zidovudine – Experimental evidence demonstrated that methadone increased the AUC of zidovudine which could result in toxic effects.

  Desipramine   –   Plasma   levels   of   desipramine   have   increased   with   concurrent methadone administration.

  Impairment of Fertility

  Published animal studies provide additional data indicating that methadone treatment of males can alter reproductive function. Methadone produces decreased sexual activity (mating) of male rats at 10 mg/kg/day (corresponding to 0.3 times the human daily oral dose of 120 mg/day based on body surface area). Methadone also produces  a significant regression of sex accessory organs and testes of male mice and rats at 0.2 and 0.8 times the HDD, respectively. Methadone treatment of pregnant rats from Gestation Day 14 to 19 reduced fetal blood testosterone and androstenedione in male. Decreased serum levels of testosterone were observed in male rats that were treated with methadone (1.3 to 3.3 mg/kg/day for 14 days, corresponding to 0.1 to 0.3 times the HDD) or 10 to 15 mg/kg/day for 10 days (0.8 to 1.2 times the HDD).

8 Use in Specific Populations

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 …

Geriatric Use

Additions and/or revisions underlined:

Clinical studies of methadone did not include sufficient numbers …

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.

Hepatic Impairment

Additions and/or revisions underlined:

The use of methadone has not been extensively evaluated … Start these patients on lower doses and titrate slowly while carefully monitoring for signs of respiratory and central nervous system depression.

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, were lower than maternal serum drug concentrations at steady state.

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 of 150 mL/kg/day, an infant would consume approximately 17.4 mcg/kg/day, which is approximately 2 to 3% of the oral maternal dose. Methadone has been detected in very low plasma concentrations in some infants whose mothers were taking methadone.

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

Pregnancy

Pregnancy Category C.

Extensive changes; please refer to label.

Sex

Sex replaces gender in all instances in this section.