METHADOSE and METHADOSE Sugar-Free are for oral administration only. The
preparation must not be injected. METHADOSE and METHADOSE Sugar-Free, if
dispensed, should be packaged in child-resistant containers and kept out of reach of
children to prevent accidental ingestion.
Life-Threatening Respiratory Depression
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 antagonists, depending on the patient’s clinical
status (see OVERDOSE).
While serious, life-threatening, or fatal respiratory depression can occur at any time
during the use of METHADOSE, the risk is greatest during the initiation of therapy 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. Monitor patients closely for respiratory depression, when initiating
therapy with METHADOSE and following dose increases.
Instruct patients against use by individuals other than the patient for whom methadone
was prescribed and to keep methadone out of the reach of children, as such
inappropriate use may result in fatal respiratory depression.
To reduce the risk of respiratory depression, proper dosing and titration of methadone
are essential (see DOSAGE AND ADMINISTRATION). 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:
- Patients tolerant to other opioids may be incompletely tolerant to methadone.
Incomplete cross-tolerance is of particular concern for patients tolerant to other
mu-opioid agonists. Deaths have been reported during conversion from chronic,
high-dose treatment with other opioid agonists. Follow induction directions
closely to avoid inadvertent overdose (see DOSAGE AND ADMINISTRATION).
- Proper dosing and titration are essential and methadone should be overseen
only by healthcare professionals who are knowledgeable in the pharmacokinetics
and pharmacodynamics of methadone.
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 (see DOSAGE AND ADMINISTRATION).
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. Medicationassisted
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
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 (see PRECAUTIONS, DRUG INTERACTIONS).
Life-Threatening QT Prolongation
Cases of QT interval prolongation and serious arrhythmia (torsades de pointes) have
been observed during treatment with methadone. These cases appear to be more
commonly associated with, but not limited to, higher dose treatment (> 200 mg/day).
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. In most patients on the lower doses
typically used for maintenance, concomitant medications and/or clinical conditions such
as hypokalemia were noted as contributing factors. However, the evidence strongly
suggests that methadone possesses the potential for adverse cardiac conduction
effects in some patients. The effects of methadone on the QT interval have been
confirmed in in vivo laboratory studies, and methadone has been shown to inhibit
cardiac potassium channels in in vitro studies.
Closely monitor patients with risk factors for development of prolonged QT interval (e.g.,
cardiac hypertrophy, concomitant diuretic use, hypokalemia, hypomagnesemia), a
history of cardiac conduction abnormalities, and those taking medications affecting
cardiac conduction. QT prolongation has also been reported in patients with no prior
cardiac history who have received high doses of methadone.
Evaluate patients developing QT prolongation while on METHADOSE treatment for the
presence of modifiable risk factors, such as concomitant medications with cardiac
effects, drugs which might cause electrolyte abnormalities, and drugs which might act
as inhibitors of methadone metabolism.
Only initiate therapy with METHADOSE in patients for whom the anticipated benefit
outweighs the risk of QT prolongation and development of dysrhythmias that have been
reported with high doses of methadone. The use of methadone in patients already
known to have a prolonged QT interval has not been systematically studied.
Accidental ingestion of even one dose of METHADOSE, especially by children, can
result in respiratory depression and death due to an overdose. Keep METHADOSE out
of reach of children to prevent accidental ingestion.
Misuse, Abuse, And Diversion Of Opioids
METHADOSE contain methadone, an opioid agonist and a Schedule II controlled
substance. Methadone can be abused in a manner similar to other opioid agonists, legal
or illicit. Opioid agonists are sought by drug abusers and people with addiction disorders
and are subject to criminal diversion.
Contact local state professional licensing board or state controlled substances authority
for information on how to prevent and detect abuse or diversion of this product.
Neonatal Opioid Withdrawal Syndrome
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 (see PRECAUTIONS,
Advise pregnant women receiving opioid addiction treatment with METHADOSE 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.
Risks Of Concomitant Use Of Cytochrome P450 3A4, 2B6, 2C19, 2C9, Or 2D6
Inhibitors Or Discontinuation P450 3A4, 2B6, 2C19, Or 2C9 Inducers
Concomitant use of METHADOSE 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 METHADOSE is achieved. Similarly,
discontinuation of concomitant CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers in
METHADOSE-treated patients may increase methadone plasma concentrations
resulting in fatal respiratory depression. Consider dosage reduction of METHADOSE
when using concomitant CYP3A4, CYP2B6, CYP2C19, CYP2C9 or CYP2D6 inhibitors
or discontinuing CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers in methadonetreated
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 a
CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors in patients treated with
METHADOSE may decrease methadone plasma concentrations, reducing efficacy or,
and may, lead to a withdrawal symptoms in patients physically dependent on
methadone. When using METHADOSE 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 METHADOSE dosage as needed.
Life-Threatening Respiratory Depression In Patients With Chronic Pulmonary
Disease Or In Elderly, Cachectic, Or Debilitated Patients
The use of METHADOSE 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
METHADOSE-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 METHADOSE (see WARNINGS, Life-
Threatening Respiratory Depression).
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
(see WARNINGS, Life-Threatening Respiratory Depression).
Monitor such patients closely, particularly when initiating and titrating METHADOSE and
when METHADOSE is given concomitantly with other drugs that depress respiration.
Serotonin Syndrome With Concomitant Use Of Serotonergic Drugs
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) (see DRUG INTERACTIONS). 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 METHADOSE if serotonin syndrome is
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 nonspecific
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.
Methadone may cause severe hypotension including orthostatic hypotension and
syncope in ambulatory patients. There is an increased risk in patients whose ability to
maintain normal blood pressure is compromised by a reduced blood volume or
concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or
general anesthetics) (see DRUG INTERACTIONS). Monitor these patients
for signs of hypotension after initiating or titrating the dosage of METHADOSE. In
patients with circulatory shock, METHADOSE may cause vasodilation that can further
reduce cardiac output and blood pressure. Avoid the use of METHADOSE in patients
with circulatory shock.
Use In Patients With Head Injury Or Increased Intracranial Pressure
In patients who may be susceptible to the intracranial effects of CO2 retention (e.g.,
those with evidence of increased intracranial pressure or brain tumors), METHADOSE
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.
Avoid the use of methadone in patients with impaired consciousness or coma.
Risks Of Use In Patients With Gastrointestinal Conditions
METHADOSE is contraindicated in patients with known or suspected gastrointestinal
obstruction, including paralytic ileus. The methadone in METHADOSE 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
Increased Risks Of Seizure In Patients With Seizure Disorders
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 for worsened seizure
control during METHADOSE therapy.
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 METHADOSE. In these patients, mixed
agonists/antagonist and partial agonist analgesics may precipitate withdrawal symptoms
(see DRUG INTERACTIONS).
When discontinuing METHADOSE, gradually taper the dosage (see DOSAGE AND ADMINISTRATION). Do not abruptly discontinue METHADOSE.
Use In Ambulatory Patients
Driving Or Operating Heavy Machinery
Inform patients that METHADOSE may impair the ability to perform potentially
hazardous activities such as driving or operating heavy machinery. Advise patients not
to perform such tasks until they know how they will react to the medication (see PATIENT INFORMATION).
Laboratory Test Interactions
False positive urine drug screens for methadone have been reported for several drugs
including diphenhydramine, doxylamine, clomipramaine, chlorpromazine, thioridazine,
quetiapine, and verapamil.