Included as part of the PRECAUTIONS section.
Methadose contains 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. Consider these risks when prescribing or dispensing Methadose in situations
where there is concern about increased risks of misuse, abuse, or diversion.
Concerns about abuse, addiction, and diversion should not, however, prevent the
proper management of pain.
For each patient prescribed Methadose for pain management,
assess the risk for opioid abuse or addiction prior to prescribing Methadose.
The risk for opioid abuse is increased in patients with a personal or family
history of substance abuse (including drug or alcohol abuse or addiction) or
mental illness (e.g., major depression). Patients at increased risk may still
be appropriately treated with modified-release opioid formulations; however
these patients will require intensive monitoring for signs of misuse, abuse, or
addiction. Routinely monitor all patients receiving opioids for signs of
misuse, abuse, and addiction because these drugs carry a risk for addiction
even under appropriate medical use.
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.
Life-Threatening Respiratory Depression
Respiratory depression is the primary risk of Methadose.
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
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 analgesic effect, especially during the initial dosing
period. Closely monitor patients for respiratory depression when initiating
therapy with Methadose and following dose increases.
Instruct patients against use by individuals other than the
patient for whom Methadose was prescribed and to keep Methadose out of the
reach of children, as such inappropriate use may result in fatal respiratory
To reduce the risk of respiratory depression, proper dosing
and titration of Methadose is essential [see DOSAGE AND ADMINISTRATION].
Overestimating the Methadose dose when converting patients from another opioid
product can result in fatal overdose with the first dose. Respiratory depression
has also been reported with use of methadone when used as recommended and not
misused or abused.
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 who are being converted to treatment with
methadone, thus making determination of dosing during opioid treatment
conversion complex. Deaths have been reported during conversion from chronic,
high-dose treatment with other opioid agonists.
- Proper dosing and titration are essential and Methadose should be prescribed only by healthcare professionals who are knowledgeable
in the pharmacokinetics and pharmacodynamics of methadone, especially when
converting patients from other opioids, and in the use of potent opioids for
the management of chronic pain.
- Methadose is contraindicated in patients with respiratory
depression and in patients with conditions that increase the risk of
lifethreatening respiratory depression [see CONTRAINDICATIONS].
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 methadone
treatment for the presence of modifiable risk factors, such as concomitant
medications with cardiac effects, drugs that might cause electrolyte
abnormalities, and drugs that might act as inhibitors of methadone metabolism.
Only initiate Methadose therapy for pain 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 Methadose, especially in children,
can result in a fatal overdose of methadone. Methadone should be kept out of
the reach of children to prevent accidental ingestion.
Elderly, Cachectic, and Debilitated Patients
Respiratory depression is more likely to occur in elderly,
cachectic, or debilitated patients as they may have altered pharmacokinetics due
to poor fat stores, muscle wasting, or altered clearance compared to younger,
healthier patients. Therefore, monitor such patients closely, particularly when
initiating and titrating Methadose and when Methadose is given concomitantly
with other drugs that depress respiration.
Use in Patients with Chronic Pulmonary Disease
Monitor patients with significant chronic obstructive
pulmonary disease or cor pulmonale, and patients having a substantially decreased
respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory
depression for respiratory depression, particularly when initiating therapy and
titrating with Methadose, as in these patients, even usual therapeutic doses of
Methadose may decrease respiratory drive to the point of apnea. Consider the use of alternative non-opioid analgesics in these
patients if possible.
Interactions with CNS Depressants and Illicit Drugs
Hypotension, profound sedation, coma, or respiratory
depression may result if Methadose is used concomitantly with other CNS depressants
(e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). When
considering the use of Methadose in a patient taking a CNS depressant, assess
the duration of use of the CNS depressant and the patient's response, including
the degree of tolerance that has developed to CNS depression. Additionally,
consider the patient's use, if any, of alcohol or illicit drugs that cause CNS
depression. If Methadose therapy is to be initiated in a patient taking a CNS
depressant, start with a lower Methadose dose than usual and monitor patients
for signs of sedation and respiratory depression and consider using a lower
dose of the concomitant CNS depressant [see DRUG INTERACTIONS].
Deaths associated with illicit use of methadone have
frequently involved concomitant benzodiazepine abuse.
Methadose may cause severe hypotension including orthostatic
hypotension and syncope in ambulatory patients. There is an increased risk in
patients whose ability to maintain blood pressure has already been 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 dose of Methadose.
Use in Patients with Head Injury or Increased Intracranial
Monitor patients taking Methadose who may be susceptible to
the intracranial effects of CO2 retention (e.g., those with evidence of increased
intracranial pressure or brain tumors) for signs of sedation and respiratory
depression, particularly when initiating therapy with Methadose. Methadose may
reduce respiratory drive, and the resultant CO2 retention can further increase
intracranial pressure. Opioids may also obscure the clinical course in a
patient with a head injury. Avoid the use of Methadose in patients with
impaired consciousness or coma.
Use in Patients with Gastrointestinal Conditions
Methadose is contraindicated in patients with paralytic
ileus. Avoid the use of Methadose in patients with other gastrointestinal obstruction.
The methadone in Methadose may cause spasm of the sphincter
of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis,
for worsening symptoms. Opioids may cause increases in the serum amylase.
Use in Patients with Convulsive or Seizure Disorders
The methadone in Methadose may aggravate convulsions in
patients with convulsive disorders, and may induce or aggravate seizures in
some clinical settings. Monitor patients with a history of seizure disorders
for worsened seizure control during Methadose therapy.
Avoidance of Withdrawal
Avoid the use of partial agonists or mixed
agonist/antagonist analgesics (i.e., buprenorphine, pentazocine, nalbuphine,
and butorphanol) in patients who have received or are receiving a course of
therapy with a full opioid agonist analgesic, including Methadose. In these
patients, partial agonists or mixed agonists/antagonists analgesics may reduce
the analgesic effect and/or may precipitate withdrawal symptoms [see DRUG
When discontinuing Methadose, gradually taper the dose [see DOSAGE
AND ADMINISTRATION]. Do not abruptly discontinue Methadose.
Driving and Operating Machinery
Methadose may impair the mental or physical abilities needed
to perform potentially hazardous activities such as driving a car or operating
machinery. Warn patients not to drive or operate dangerous machinery unless
they are tolerant to the effects of Methadose and know how they will react to the
Patient Counseling Information
See FDA-approved patient labeling (Medication Guide)
Inform patients that Methadose contains methadone, a
Schedule II controlled substance that is subject to abuse. Instruct patients not
to share Methadose with others and to take steps to protect Methadose from
theft or misuse.
Life-Threatening Respiratory Depression Discuss the risk of
respiratory depression with patients, explaining that the risk is greatest when
starting Methadose or when the dose is increased. Advise patients how to
recognize respiratory depression and to seek medical attention if they are
experiencing breathing difficulties.
Symptoms of Arrhythmia
Instruct patients to seek medical attention immediately if
they experience symptoms suggestive of an arrhythmia (such as palpitations, near
syncope, or syncope) when taking methadone.
Instruct patients to take steps to store Methadose securely.
Accidental exposure, especially in children, may result in serious harm or death.
Advise patients to dispose of unused Methadose by flushing the tablets down the
Risks from Concomitant Use of Alcohol and other CNS
Inform patients that the concomitant use of alcohol with
Methadose can increase the risk of life-threatening respiratory depression. Instruct
patients not to consume alcoholic beverages, as well as prescription and
over-the-counter drug products that contain alcohol, during treatment with
Inform patients that potentially serious additive effects
may occur if Methadose is used with other CNS depressants, and not to use such
drugs unless supervised by a healthcare provider.
Important Administration Instructions
Instruct patients how to properly take Methadose, including
- Using Methadose exactly as prescribed to reduce the risk of
life-threatening adverse reactions (e.g., respiratory depression)
- Not discontinuing Methadose without first discussing the
need for a tapering regimen with the prescriber
Inform patients that Methadose may cause orthostatic
hypotension and syncope. Instruct patients how to recognize symptoms of low blood
pressure and how to reduce the risk of serious consequences should hypotension
occur (e.g., sit or lie down, carefully rise from a sitting or lying position).
Driving or Operating Heavy Machinery
Inform patients that Methadose may impair the ability to
perform potentially hazardous activities such as driving a car or operating heavy
machinery. Advise patients not to perform such tasks until they know how they
will react to the medication.
Advise patients of the potential for severe constipation,
including management instructions and when to seek medical attention.
Inform patients that anaphylaxis has been reported with
ingredients contained in Methadose. Advise patients how to recognize such a reaction
and when to seek medical attention.
Advise female patients that Methadose can cause fetal harm
and to inform the prescriber if they are pregnant or plan to become pregnant.
Instruct nursing mothers using Methadose to watch for signs
of methadone toxicity in their infants, which include increased sleepiness (more
than usual), difficulty breastfeeding, breathing difficulties, or limpness.
Instruct nursing mothers to talk to the baby's healthcare provider immediately
if they notice these signs. If they cannot reach the healthcare provider right
away, instruct them to take the baby to the emergency room or call 911 (or
local emergency services).
Carcinogenesis, Mutagenesis, Impairment of Fertility
The results of carcinogenicity assessment in B6C2F1 mice and
Fischer 344 rats following dietary administration of two doses of methadone HCl
have been published. Mice consumed 15 mg/kg/day or 60 mg/kg/day methadone for
two years. These doses were approximately 0.6 and 2.5 times a human daily oral
dose of 120 mg/day on a body surface area basis (mg/m²). There was a
significant increase in pituitary adenomas in female mice treated with 15
mg/kg/day but not with 60 mg/kg/day. Under the conditions of the assay, there
was no clear evidence for a treatment-related increase in the incidence of
neoplasms in male rats. Due to decreased food consumption in males at the high
dose, male rats consumed 16 mg/kg/day and 28 mg/kg/day of methadone for two
years. These doses were approximately 1.3 and 2.3 times a human daily oral dose
of 120 mg/day, based on body surface area comparison. In contrast, female rats
consumed 46 mg/kg/day or 88 mg/kg/day for two years. These doses were
approximately 3.7 and 7.1 times a human daily oral dose of 120 mg/day, based on
body surface area comparison. Under the conditions of the assay, there was no
clear evidence for a treatment-related increase in the incidence of neoplasms
in either male or female rats.
There are several published reports on the potential genetic
toxicity of methadone. Methadone tested positive in the in vivo mouse dominant
lethal assay and the in vivo mammalian spermatogonial chromosome aberration
test. Additionally, methadone tested positive in the E. coli DNA repair system
and Neurospora crassa and mouse lymphoma forward mutation assays. In contrast,
methadone tested negative in tests for chromosome breakage and disjunction and
sex-linked recessive lethal gene mutations in germ cells of Drosophila using
feeding and injection procedures.
Published animal studies show that methadone treatment of
males can alter reproductive function. Methadone produces a significant regression
of sex accessory organs and testes of male mice and rats.
Use In Specific Populations
Pregnancy Category C
There are no adequate and well controlled studies of
methadone use in pregnant women. Methadone has been shown to be teratogenic in
the hamster at doses 2 times the human daily oral dose (120 mg/day on a mg/m²
basis) and in mice at doses equivalent to the human daily oral dose (120 mg/day
on a mg/m² basis). Increased neonatal mortality and significant differences in
behavioral tests have been reported in the offspring of male rodents that were
treated with methadone prior to mating when compared to control animals. Methadone
has been detected in human amniotic fluid and cord plasma at concentrations
proportional to maternal plasma and in newborn urine at lower concentrations
than corresponding maternal urine. Methadone should be used during pregnancy
only if the potential benefit justifies the potential risk to the fetus.
Dosage Adjustment during Pregnancy
The disposition of oral methadone has been studied in
approximately 30 pregnant patients in 2nd and 3rd trimesters. Total body clearance
of methadone was increased in pregnant patients compared to the same patients
postpartum or to non-pregnant opioiddependent women. The terminal half-life of
methadone is decreased during 2nd and 3rd trimesters. The decrease in plasma
half-life and increased clearance of methadone resulting in lower methadone
trough levels during pregnancy can lead to withdrawal symptoms in some pregnant
patients. The dosage may need to be increased or the dosing interval decreased
in pregnant patients receiving methadone to achieve therapeutic effect [see DOSAGE
Effects on the Neonate
Babies born to mothers who have been taking opioids
regularly prior to delivery may be physically dependent. Onset of withdrawal symptoms
in infants is usually in the first days after birth. Monitor newborn for
withdrawal signs and symptoms including: irritability and excessive crying,
tremors, hyper-active reflexes, increased respiratory rate, increased stools,
sneezing, yawning, vomiting, and fever. The intensity of the neonatal
withdrawal syndrome does not always correlate with the maternal dose or the
duration of maternal exposure. The duration of the withdrawal signs may vary
from a few days to weeks or even months. There is no consensus on the appropriate
management of infant withdrawal [see Use In Specific Populations].
Reported studies have generally compared the benefit of
methadone to the risk of untreated addiction to illicit drugs; the relevance of
these findings to pain patients prescribed methadone during pregnancy is
unclear. Pregnant women involved in methadone maintenance programs have been
reported to have significantly improved prenatal care leading to significantly
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
appears to occur after the first trimester of pregnancy. A review of published
data on experiences with methadone use during pregnancy by the Teratogen
Information System (TERIS) concluded that maternal use of methadone during
pregnancy as part of a supervised, therapeutic regimen is unlikely to pose a substantial
teratogenic risk (quantity and quality of data assessed as “limited to fair”).
However, the data are insufficient to state that there is no risk (TERIS, last
reviewed October, 2002). A retrospective case series of 101 pregnant,
opioid-dependent women who underwent inpatient opioid detoxification with
methadone did not demonstrate any increased risk of miscarriage in the 2nd
trimester or premature delivery in the 3rd trimester. Recent studies suggest an
increased risk of premature delivery in opioid-dependent women exposed to
methadone during pregnancy, although the presence of confounding factors makes
it difficult to determine a causal relationship. Several studies have suggested
that infants born to narcotic-addicted women treated with methadone during all
or part of pregnancy have been found to have decreased fetal growth with
reduced birth weight, length, and/or head circumference compared to controls.
This growth deficit does not appear to persist into later childhood. Children
prenatally exposed to methadone have been reported to demonstrate mild but
persistent deficits in performance on psychometric and behavioral tests. In
addition, several studies suggest that children born to opioid-dependent women
exposed to methadone during pregnancy may have an increased risk of visual development
anomalies; however, a causal relationship has not been assigned.
There are conflicting reports on whether Sudden Infant Death
Syndrome occurs with an increased incidence in infants born to women treated
with methadone during pregnancy. Abnormal fetal non-stress tests have been
reported to occur more frequently when the test is performed 1 to 2 hours after
a maintenance dose of methadone in late pregnancy compared to controls.
Methadone did not produce teratogenic effects in rat or
rabbit models. Methadone produced teratogenic effects following large doses, in
the guinea pig, hamster and mouse. One published study in pregnant hamsters
indicated that a single subcutaneous dose of methadone ranging from 31 to 185
mg/kg (the 31 mg/kg dose is approximately 2 times a human daily oral dose of
120 mg/day on a mg/m² basis) on day 8 of gestation resulted in a decrease in
the number of fetuses per litter and an increase in the percentage of fetuses exhibiting
congenital malformations described as exencephaly, cranioschisis, and “various
other lesions.” The majority of the doses tested also resulted in maternal
death. In another study, a single subcutaneous dose of 22 to 24 mg/kg methadone
(estimated exposure was approximately equivalent to a human daily oral dose of
120 mg/day on a mg/m² basis) administered on day 9 of gestation in mice also
produced exencephaly in 11% of the embryos. However, no effects were reported
in rats and rabbits at oral doses up to 40 mg/kg (estimated exposure was
approximately 3 and 6 times, respectively, a human daily oral dose of 120
mg/day on a mg/m² basis) administered during days 6 to 15 and 6 to 18,
Published animal data have reported increased neonatal
mortality in the offspring of male rodents that were treated with methadone prior
to mating. In these studies, the female rodents were not treated with
methadone, indicating paternally-mediated developmental toxicity. Specifically,
methadone administered to the male rat prior to mating with methadone-naÃ¯ve
females resulted in decreased weight gain in progeny after weaning. The male
progeny demonstrated reduced thymus weights, whereas the female progeny demonstrated
increased adrenal weights. Behavioral testing of these male and female progeny
revealed significant differences in behavioral tests compared to control
animals, suggesting that paternal methadone exposure can produce physiological
and behavioral changes in progeny in this model. Other animal studies have
reported that perinatal exposure to opioids including methadone alters neuronal
development and behavior in the offspring. Perinatal methadone exposure in rats
has been linked to alterations in learning ability, motor activity, thermal
regulation, nociceptive responses and sensitivity to drugs.
Additional animal data demonstrates evidence for
neurochemical changes in the brains of methadone-treated offspring, including changes
to the cholinergic, dopaminergic, noradrenergic and serotonergic systems.
Studies demonstrated that methadone treatment of male rats for 21 to 32 days
prior to mating with methadone-naÃ¯ve females did not produce any adverse
effects, suggesting that prolonged methadone treatment of the male rat resulted
in tolerance to the developmental toxicities noted in the progeny. Mechanistic studies
in this rat model suggest that the developmental effects of “paternal”
methadone on the progeny appear to be due to decreased testosterone production.
These animal data mirror the reported clinical findings of decreased testosterone
levels in human males on methadone maintenance therapy for opioid addiction and
in males receiving chronic intraspinal opioids.
Additional data have been published indicating that
methadone treatment of male rats (once a day for three consecutive days) increased
embryolethality and neonatal mortality. Examination of uterine contents of
methadone-naÃ¯ve female mice bred to methadone-treated mice indicated that
methadone treatment produced an increase in the rate of preimplantation deaths
in all postmeiotic states.
Labor and Delivery
Methadose is not for use in women during and immediately
prior to labor, where shorter acting analgesics or other analgesic techniques
are more appropriate [see INDICATIONS AND USAGE]. Opioid analgesics may
prolong labor by temporarily reducing the strength, duration and frequency of
uterine contractions. However, these effects are not consistent and may be offset
by an increased rate of cervical dilatation, which tends to shorten labor.
Opioids with mixed agonist-antagonist properties should not
be used for pain control during labor in patients chronically treated with methadone
as they may precipitate acute withdrawal [see DRUG INTERACTIONS].
Opioids cross the placenta and may produce respiratory
depression and psycho-physiologic effects in neonates. Closely observe neonates
whose mothers received opioid analgesics during labor for signs of respiratory depression.
An opioid antagonist, such as naloxone, should be available for reversal of
opioid-induced respiratory depression in the neonate.
Methadone is secreted into human milk. At maternal oral
doses of 10 to 80 mg/day, methadone concentrations from 50 to 570 mcg/L in milk
have been 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. 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. Cases of sedation and respiratory depression in
infants exposed to methadone through breast milk have been reported. Caution
should be exercised when methadone is administered to a nursing woman.
Advise women who are being treated with methadone and who
are breastfeeding or express a desire to breastfeed of the presence of methadone
in human milk. Instruct breastfeeding mothers how to identify respiratory
depression and sedation in their babies and when it may be necessary to contact
their healthcare provider or seek immediate medical care. Breastfed infants of
mothers using methadone should be weaned gradually to prevent development of
withdrawal symptoms in the infant.
The safety, effectiveness, and pharmacokinetics of methadone
in pediatric patients below the age of 18 years have not been established.
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, start elderly patients at the low end of the dosing range, taking into
account the greater frequency of decreased hepatic, renal, or cardiac function
and of concomitant disease or other drug therapy in geriatric patients. Closely
monitor elderly patients for signs of respiratory and central nervous system
Neonatal Opioid Withdrawal Syndrome
Chronic maternal use of methadone during pregnancy can
affect the fetus with subsequent withdrawal signs. Neonatal withdrawal syndrome
presents as irritability, hyperactivity and abnormal sleep pattern, high
pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset,
duration and severity of neonatal withdrawal syndrome vary based on the drug
used, duration of use, the dose of last maternal use, and rate of elimination
drug by the newborn. Neonatal opioid withdrawal syndrome, unlike opioid
withdrawal syndrome in adults, may be life-threatening and should be treated
according to protocols developed by neonatology experts.
Methadone pharmacokinetics have 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
Methadone has not been extensively evaluated in patients
with hepatic insufficiency. Methadone is metabolized by hepatic pathways; therefore,
patients with liver impairment may be at risk of increased systemic exposure to
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.