Drug Safety-related Labeling Changes (SrLC)

Get Email Alerts | Guide

Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

METHADONE HYDROCHLORIDE (NDA-006383)

(METHADONE HYDROCHLORIDE)

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

Download Data

Expand all

02/01/2018 (SUPPL-18)

Approved Drug Label (PDF)

Boxed Warning

(Additions and/or revisions are 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

WARNINGS

(Additions and/or revisions are 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 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.

7 Drug Interactions

(Table has been revised; please refer to label)

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

Information for Patients

(Additions and/or revisions are underlined)

Interactions with Benzodiazepines and Other CNS Depressants

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

12/16/2016 (SUPPL-17)

Approved Drug Label (PDF)

Boxed Warning

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 (see WARNINGS). Proper dosing and titration are essential and Methadone Hydrochloride 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 Methadone Hydrochloride 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 (see WARNINGS). 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 Methadone Hydrochloride.

Accidental Ingestion

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

Misuse, Abuse, and Diversion of Opioids

Methadone Hydrochloride 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 Methadone Hydrochloride 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

Additions and/or revisions underlined:

Methadone Hydrochloride Powder 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 Methadone Hydrochloride Powder

5 Warnings and Precautions

PRECAUTIONS

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

Hypotension

Anaphylaxis

Neonatal Opioid Withdrawal

Lactation

Driving or Operating Heavy Machinery

Constipation

WARNINGS

Extensive changes; please refer to label:

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 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

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

Risks of Use in Patients with Gastrointestinal Conditions

Increased Risks of Seizure in Patients with Seizure Disorders

Withdrawal

Risks of Driving or Operating Heavy Machinery

Laboratory Test Interactions

6 Adverse Reactions

Additions and/or revisions underlined:

The major hazards of methadone, are respiratory depression and, to a lesser degree, systemic hypotension, circulatory depression. Respiratory arrest, shock, cardiac arrest, and death have occurred.

The most frequently observed adverse reactions ….

Other adverse reactions include the following:

Body as a Whole – asthenia (weakness), edema, headache

Cardiovascular – arrhythmias, bigeminal rhythms, bradycardia, cardiomyopathy, ECG abnormalities, extrasystoles, flushing, heart failure, hypotension, palpitations, phlebitis, QT interval prolongation, syncope, T-wave inversion, tachycardia, torsade de pointes, ventricular fibrillation, ventricular tachycardia

Central Nervous System – Euphoria, dysphoria, weakness, headache, insomnia, agitation, disorientation, and visual disturbances.

Gastro-Intestinal – Dry mouth, anorexia, constipation, and biliary tract spasm.

Skin and Appendages – Pruritus, urticarial, other skin rashes, edema, and, rarely, hemorrhagic urticarial.

Urogenital – Urinary retention or hesitancy, antidiuretic effect, and reduced libido and/or potency.

Postmarketing Experience

Newly added:

The following adverse reactions have been identified during post approval use of methadone.

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

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

Anaphylaxis: Anaphylactic reaction has been reported with ingredients contained in

Methadone Hydrochloride Powder.

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

7 Drug Interactions

Table created; please refer to label. Additional text information below:

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 Methadone Hydrochloride Powder and could precipitate a withdrawal syndrome. Monitor patients receiving Methadone Hydrochloride Powder and any of these anti-retroviral therapies closely for evidence of withdrawal effects and adjust the Methadone Hydrochloride Powder 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.

8 Use in Specific Populations

Females and Males of Reproductive Potential

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.

Geriatric Use

Clinical studies of methadone did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently compared to younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for elderly patients should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

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

The use of methadone has not been extensively evaluated in patients with hepatic insufficiency. Methadone is metabolized in the liver and patients with liver impairment may be at risk of accumulating methadone after multiple dosing. Start these patients on lower doses and titrate slowly while carefully monitoring for signs of respiratory and central nervous system depression.

Lactation

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.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 18 years have not been established.

Accidental or deliberate ingestion by a child may cause respiratory depression that can result in death. Patients and caregivers should be instructed to keep Methadone Hydrochloride Powder in a secure place out of the reach of children and to discard unused methadone in such a way that individuals other than the patient for whom it was originally prescribed will not come in contact with the drug.

Pregnancy

Extensive changes; please refer to label.

Renal Impairment

The use of methadone has not been extensively evaluated in patients with renal insufficiency. Since unmetabolized methadone and its metabolites are excreted in urine to a variable degree, start these patients on lower doses and with longer dosing intervals and titrate slowly while carefully monitoring for signs of respiratory and central nervous system depression.