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.
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.