Drug Safety-related Labeling Changes (SrLC)

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METHADONE HYDROCHLORIDE (NDA-017058)

(METHADONE HYDROCHLORIDE)

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

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12/22/2025 (SUPPL-29)

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), Drug Interactions (7)].

• 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 DISKETS Dispersible Tablets. 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 DISKETS Dispersible Tablets 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 with Benzodiazepines or Other CNS Depressants with Methadone

Subsection title revised.

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 DISKETS Dispersible Tablets, gradually taper the dosage [see Dosage and Administration (2.7, 2.8)]. Do not rapidly reduce or abruptly discontinue DISKETS Dispersible Tablets [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:

Table 1: Clinically Significant Drug Interactions with DISKETS Dispersible Tablets

. . .

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:

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

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

Monitor patients receiving muscle relaxants and DISKETS Dispersible Tablets for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of 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 DISKETS 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 Pharmacology (13.1)]. 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 DISKETS Dispersible Tablets [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 easily 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 DISKETS Dispersible Tablets are 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)].

. . .

Infertility:

Advise patients that use of opioids, such as DISKETS Dispersible Tablets, 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-28)

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 (5.17)]

. . .

Hypoglycemia: Cases of hypoglycemia have been reported in patients taking methadone [see Warnings and Precautions (5.17)].

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 that symptoms of low blood glucose and to contact their healthcare provider if these symptoms occur [see Warnings and Precautions (5.17)].

06/02/2021 (SUPPL-27)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Life-Threatening Respiratory Depression

(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 Patient Counseling Information (17)].

Patient Access to Naloxone for the Emergency 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 DISKETS Dispersible Tablets. 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 (2.3)].

Advise patients and caregivers that naloxone may also be administered for a known or suspected overdose with DISKETS Dispersible Tablets itself [see Overdosage (10)].

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 Patient Counseling Information (17)].

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

(Section title updated)

(Newly added information)

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 and Precautions (5.1)].

6 Adverse Reactions

(Additions and/or revisions underlined)

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

7 Drug Interactions

(Newly added information)

If concomitant use is warranted, strongly consider prescribing naloxone for the emergency

treatment of opioid overdose, as is recommended for all patients in treatment for opioid use

disorder [see Warnings and Precautions (5.1)].

Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and

opioids, strongly consider prescribing naloxone for the emergency treatment of opioid

overdose [see Dosage and Administration (2.3), Warnings and Precautions (5.1, 5.2)].

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions underlined)

Risk Summary

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 and Precautions (5.6)].

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 DISKETS. 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 (2.10) and Clinical Pharmacology (12.3)]. 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 DISKETS. 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 and Precautions (5.6)].

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.

8.2 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 DISKETS 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

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.

8.3 Females and Males of Reproductive Potential

(Newly added information)

The effect of DISKETS on fertility is unknown.

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

Patient Counseling Information

(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 and Precautions (5.1)].

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 there are 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 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 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. Repeat administration may be necessary, particularly for overdose involving DISKETS Dispersible Tablets, because naloxone is often not effective at the doses available for patient access [Dosage and Administration (2.3), Warnings and Precautions (5.1), Overdosage (10)].

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 easily 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.

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

Infertility:

Advise patients that chronic use of opioids, such as DISKETS Dispersible Tablets, may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Populations (8.3)].

10/07/2019 (SUPPL-26)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Life-Threatening Respiratory Depression

Newly added information to the end of the 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.

5.7 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 DISKETS 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).

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).

02/01/2018 (SUPPL-25)

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

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

(new subsection added)

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 health care 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.

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

PATIENT COUNSELING INFORMATION

(additions underlined)

…

Interactions with Benzodiazepines and Other CNS Depressants

Inform patients and caregivers that potentially fatal additive effects may occur if DISKETS Dispersible Tablets are 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.

…

12/16/2016 (SUPPL-22)

Approved Drug Label (PDF)

Boxed Warning

Additions and/or revisions underlined:

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 DISKETS Dispersible Tablets should only be 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 of DISKETS Dispersible Tablets 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 DISKETS Dispersible Tablets.

Accidental Ingestion

Accidental ingestion of DISKETS Dispersible Tablets …

Misuse, Abuse, and Diversion of Opioids

ISKETS Dispersible Tablets contain 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 DISKETS 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.

4 Contraindications

Additions and/or revisions in the one bullet underlined:

DISKETS Dispersible Tablets are contraindicated in patients with:

• known or suspected gastrointestinal obstruction, including paralytic ileus

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 …

To reduce the risk of respiratory depression, proper dosing and titration of methadone are essential. Overestimating the methadone dosage when initiating treatment can result in fatal overdose with the first dose.

To further reduce the risk of respiratory depression, consider the following:

• … Deaths have been reported during conversion from chronic, high-dose treatment with other opioid agonists. Follow induction directions closely to avoid inadvertent overdose.

• Proper dosing and titration are essential and methadone should be overseen only by healthcare professionals …

5.10 Adrenal Insufficiency

Newly added subsection:

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

5.11 Severe Hypotension

Additions and/or revisions underlined

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

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

Additions and/or revisions underlined, unless otherwise noted

… DISKETS 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 methadone.  Opioids may also obscure the clinical course in a patient with a head injury ...

5.13 Risks of Use in Patients with Gastrointestinal Conditions

Additions and/or revisions underlined, unless otherwise noted

DISKETS Dispersible Tablets are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The methadone in DISKETS 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.

5.14 Increased Risks of Seizure in Patients with Seizure Disorders

Additions and/or revisions underlined

Methadone may increase frequency of seizures in patients with seizure disorders, and increase the risks of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders …

5.15 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 DISKETS Dispersible Tablets. In these patients, mixed agonists/ antagonist and partial agonist analgesics may precipitate withdrawal symptoms.

5.3 Accidental Ingestion

Additions and/or revisions underlined

Accidental ingestion of even one dose of DISKETS Dispersible Tablets, especially by children, can result in respiratory depression and death due to an overdose. Keep DISKETS Dispersible Tablets out of reach of children to prevent accidental ingestion.

5.4 Misuse, Abuse, and Diversion of Opioids

DISKETS Dispersible Tablets contain methadone, an opioid agonist …

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

Newly added subsection:

Concomitant use of DISKETS 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 dose of DISKETS is achieved. Similarly, discontinuation of concomitant CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers in DISKETS-treated patients may increase methadone plasma concentrations resulting in fatal respiratory depression. Consider dosage reduction of DISKETS 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 DISKETS may decrease methadone plasma concentrations, reducing efficacy and may lead to opioid withdrawal symptoms in patients physically dependent on methadone. When using DISKETS 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 DISKETS dosage as needed.

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 DISKETS 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

DISKETS-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 DISKETS.

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 DISKETS and when DISKETS is given concomitantly with other drugs that depress respiration.

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

Additions and/or revisions underlined

Profound sedation, respiratory depression, coma, and death may result if methadone is used concomitantly with other CNS depressants  …

5.9 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs

Newly added subsection:

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of DISKETS 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 DISKETS if serotonin syndrome is suspected.

6 Adverse Reactions

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

Additions underlined:

• Respiratory Depression

• QT Prolongation

• Interactions with CNS Depressants

• Severe Hypotension …

• Serotonin Syndrome

• Adrenal Insufficiency …

• Gastrointestinal Adverse Reactions

• Seizures

• Withdrawal

  Anaphylaxis: Anaphylaxis has been reported with ingredients contained in DISKETS.

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

  Other adverse reactions include the following:

  Addition of the following:

  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.

7 Drug Interactions

Addition of the following:

7.5 Serotonergic Drugs

The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system, has resulted in serotonin syndrome.

If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue DISKETS if serotonin syndrome is suspected.

AND

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

8 Use in Specific Populations

8.1 Pregnancy

Extensive changes due to PLLR conversion; please refer to label.

8.2 Lactation

PLLR conversion:

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.

8.3 Females and Males of Reproductive Potential

PLLR conversion:

Infertility

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

Clinical studies of methadone did not include sufficient numbers of subjects aged 65 and over to determine whether … Closely monitor elderly patients for signs of respiratory and central nervous system 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)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Accidental Ingestion

Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death.  Instruct patients to take steps to store DISKETS Dispersible Tablets …

Serotonin Syndrome

Inform patients that DISKETS 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.

Adrenal Insufficiency:

Inform patients that DISKETS 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.

MAOI Interaction

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

12/16/2016 (SUPPL-23)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Neonatal Opioid Withdrawal Syndrome

Newly added subsection:

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. Healthcare professionals should observe newborns for signs of NOWS and manage accordingly

Advise pregnant women receiving opioid addiction treatment with DISKETS of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. This risk must be balanced against the risk of untreated opioid addiction which often results in continued or relapsing illicit opioid use and is associated with poor pregnancy outcomes. Therefore, prescribers should discuss the importance and benefits of management of opioid addiction throughout pregnancy.

8 Use in Specific Populations

8.1 Pregnancy

Addition of the following:

Risk Summary …

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.

Fetal/neonatal adverse reactions

Neonatal opioid withdrawal syndrome may occur in newborn infants of mothers who are

receiving treatment with DISKETS.

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 …

Dosage Adjustment During Pregnancy …

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

PATIENT COUNSELING INFORMATION

Addition of the following:

Neonatal Opioid Withdrawal

Advise women that if they are pregnant while being treated with DISKETS, the baby

may have signs of withdrawal at birth and that withdrawal is treatable.