Included as part of the PRECAUTIONS section.
Addiction, Abuse And Misuse
Methadone hydrochloride tablets, USP contains methadone,
a Schedule II controlled substance. As an opioid, methadone exposes users to
the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence].
As long-acting opioids such as methadone have pharmacological effects over an extended
period of time, there is a greater risk for overdose and death.
Although the risk of addiction in any individual is
unknown, it can occur in patients appropriately prescribed methadone
hydrochloride tablets and in those who obtain the drug illicitly. Addiction can
occur at recommended doses and if the drug is misused or abused.
Assess each patient's risk for opioid addiction, abuse,
or misuse prior to prescribing methadone hydrochloride tablets, and monitor all
patients receiving methadone hydrochloride tablets for the development of these
behaviors or conditions. Risks are increased in patients with a personal or
family history of substance abuse (including drug or alcohol addiction or
abuse) or mental illness (e.g., major depression). The potential for these
risks should not, however, prevent the prescribing of methadone hydrochloride
tablets for the proper management of pain in any given patient. Patients at
increased risk may be prescribed long-acting opioids such as methadone
hydrochloride tablets, but use in such patients necessitates intensive
counseling about the risks and proper use of methadone hydrochloride tablets along
with the intensive monitoring for signs of addiction, abuse, and misuse.
Abuse or misuse of methadone hydrochloride tablets by
crushing, chewing, snorting, or injecting the dissolved product will result in
the uncontrolled delivery of the methadone and can result in overdose and death
Opioid agonists such as methadone hydrochloride tablets
are sought by drug abusers and people with addiction disorders and are subject
to criminal diversion. Consider these risks when prescribing or dispensing
methadone hydrochloride tablets. Strategies to reduce these risks include
prescribing the drug in the smallest appropriate quantity and advising the
patient on the proper disposal of unused drug [see PATIENT INFORMATION)]. 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
Serious, life-threatening, or fatal respiratory
depression has been reported with the use of long-acting opioids, even when
used as recommended. Respiratory depression from opioid use, if not immediately
recognized and treated, may lead to respiratory arrest and death. Management of
respiratory depression may include close observation, supportive measures, and
use of opioid antagonists, depending on the patient's clinical status [see OVERDOSAGE].
Carbon dioxide (CO2) retention from opioid-induced respiratory
depression can exacerbate the sedating effects of opioids.
While serious, life-threatening, or fatal respiratory
depression can occur at any time during the use of methadone hydrochloride
tablets, the risk is greatest during the initiation of therapy or following a
dose increase. The peak respiratory depress ant 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 methadone hydrochloride tablets and
following dose increases.
To reduce the risk of respiratory depression, proper
dosing and titration of methadone hydrochloride tablets are essential [see DOSAGE
AND ADMINISTRATION]. Overestimating the methadone hydrochloride tablets
dose when converting patients from another opioid product can result in fatal overdose
with the first dose.
Accidental ingestion of even one dose of methadone
hydrochloride tablets, especially by children, can result in respiratory
depression and death due to overdose of methadone.
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 methadone hydrochloride tablets 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
The use of methadone in patients already known to have a
prolonged QT interval has not been systematically studied.
Neonatal Opioid Withdrawal Syndrome
Prolonged use of methadone hydrochloride tablets during
pregnancy can result in withdrawal signs in the neonate. Neonatal opioid
withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening
if not recognized and treated, and requires management according to protocols developed
by neonatology experts. If opioid use is required for a prolonged period in a
pregnant woman, advise the patient of the risk of neonatal opioid withdrawal
syndrome and ensure that appropriate treatment will be available.
Neonatal opioid 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 opioid withdrawal syndrome vary based on the specific
opioid used, duration of use, timing and amount of last maternal use, and rate
of elimination of the drug by the newborn [see Use in Special Populations].
Interactions With Central Nervous System Depressants
Hypotension, profound sedation, coma, respiratory
depression, and death may result if methadone hydrochloride tablet is used
concomitantly with alcohol or other central nervous system (CNS) depressants
(e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). When
considering the use of methadone hydrochloride tablets 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, evaluate the patient's use of alcohol or illicit
drugs that cause CNS depression. If the decision to begin methadone
hydrochloride tablets is made, start with methadone hydrochloride tablets 2.5
mg every 12 hours, monitor patients for signs of sedation and respiratory
depression, and consider using a lower dose of the concomitant CNS depressant [see
Use In Elderly, Cachectic, And Debilitated Patients
Life-threatening respiratory depression is more likely to
occur in elderly, cachectic, or debilitated patients as they may have altered
pharmacokinetics or altered clearance compared to younger, healthier patients.
Monitor such patients closely, particularly when initiating and titrating
methadone hydrochloride tablets and when methadone hydrochloride tablets is
given concomitantly with other drugs that depress respiration [see Life-threatening Respiratory Depression].
Use In Patients With Chronic Pulmonary Disease
Monitor patients with significant chronic obstructive
pulmonary disease or corpulmonale, 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 methadone hydrochloride tablets, as in these
patients, even usual therapeutic doses of methadone hydrochloride tablets may
decrease respiratory drive to the point of apnea [see Life-threatening Respiratory Depression].
Consider the use of alternative non-opioid analgesics in
these patients if possible.
Methadone hydrochloride tablets 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 methadone hydrochloride
Use In Patients With Head Injury Or Increased
Monitor patients taking methadone hydrochloride tablets
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 methadone hydrochloride tablets. Methadone hydrochloride tablets
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 methadone hydrochloride tablets in
patients with impaired consciousness or coma.
Use In Patients With Gastrointestinal Conditions
Methadone hydrochloride tablets are contraindicated in
patients with paralyticileus. Avoid the use of methadone hydrochloride tablets
in patients with other gastrointestinal obstruction.
The methadone in methadone hydrochloride tablets 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 methadone hydrochloride tablets 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 methadone
hydrochloride tablets therapy.
Avoidance Of Withdrawal
Avoid the use of mixed agonist/antagonist (i.e.,
pentazocine, nalbuphine, and butorphanol) and partial agonist (buprenorphine)
analgesics in patients who have received or are receiving a course of therapy with
a full opioid agonist analgesic, including methadone hydrochloride tablets. In
these patients, mixed agonists/antagonist and partial agonist analgesics may
reduce the analgesic effect and/or may precipitate withdrawal symptoms [see DRUG
When discontinuing methadone hydrochloride tablets,
gradually taper the dose [see DOSAGE AND ADMINISTRATION]. Do not
abruptly discontinue methadone hydrochloride tablets.
Driving And Operating Machinery
Methadone hydrochloride tablets 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 methadone
hydrochloride tablets and know how they will react to the medication.
Patient Counseling Information
Advise the patient to read the FDA-approved patient
labeling (Medication Guide)
Addiction, Abuse, And Misuse
Inform patients that the use of methadone hydrochloride
tablets, even when taken as recommended, can result in addiction, abuse, and
misuse, which can lead to overdose or death [see WARNINGS AND PRECAUTIONS].
Instruct patients not to share methadone hydrochloride tablets with others and
to take steps to protect methadone hydrochloride tablets from theft or misuse.
Life-threatening Respiratory Depression
Inform patients of the risk of life-threatening
respiratory depression, including information that the risk is greatest when
starting methadone hydrochloride tablets or when the dose is increased, and
that it can occur even at recommended doses [see WARNINGS AND PRECAUTIONS].
Advise patients how to recognize respiratory depression and to seek medical
attention if breathing difficulties develop.
Inform patients that accidental ingestion, especially in
children, may result in respiratory depression or death [see WARNINGS AND
PRECAUTIONS]. Instruct patients to take steps to store methadone hydrochloride
tablets securely and to dispose of unused methadone hydrochloride tablets by
flushing the tablets down the toilet.
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.
Neonatal Opioid Withdrawal Syndrome
Inform female patients of reproductive potential that
prolonged use of methadone hydrochloride tablets during pregnancy can result in
neonatal opioid withdrawal syndrome, which may be life-threatening if not
recognized and treated [see WARNINGS AND PRECAUTIONS].
Interactions With Alcohol And Other CNS Depressants
Inform patients that potentially serious additive effects
may occur if methadone hydrochloride tablets is used with alcohol or other CNS
depressants, and not to use such drugs unless supervised by a health care
Important Administration Instructions
Instruct patients how to properly take methadone
hydrochloride tablets, including the following:
- Use methadone hydrochloride tablets exactly as prescribed
to reduce the risk of life-threatening adverse reactions (e.g., respiratory
- Do not discontinue methadone hydrochloride tablets
without first discussing the need for a tapering regimen with the prescriber
Inform patients that methadone hydrochloride tablets 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 methadone hydrochloride tablets 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 methadone hydrochloride tablets. Advise patients how
to recognize such a reaction and when to seek medical attention.
Instruct nursing mothers using methadone hydrochloride
tablets 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).
Disposal Of Unused Methadone Hydrochloride Tablets
Advise patients to flush the unused tablets down the
toilet when methadone hydrochloride tablets are no longer needed.
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
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
Fetal/neonatal adverse reactions Prolonged use of opioid
analgesics during pregnancy for medical or nonmedical purposes can result in physical
dependence in the neonate and neonatal opioid withdrawal syndrome shortly after
birth. Observe newborns for symptoms of neonatal opioid withdrawal syndrome,
such as poor feeding, diarrhea, irritability, tremor, rigidity, and seizures,
and manage accordingly [see WARNINGS AND PRECAUTIONS].
Pregnancy Category C
There are no adequate and well controlled studies in
pregnant women. Methadone hydrochloride tablets should be used during pregnancy
only if the potential benefit justifies the potential risk to the fetus.
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.
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 AND ADMINISTRATION].
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: poor feeding, irritability, excessive
crying, tremors, rigidity, hyper-active reflexes, increased respiratory rate, diarrhea,
sneezing, yawning, vomiting, fever, and seizures. 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 WARNINGS AND PRECAUTIONS].
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/m 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 methadonetreated 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. Â
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 post-meiotic states.
Labor And Delivery
Opioids cross the placenta and may produce respiratory
depression in neonates. Methadone hydrochloride tablets is not for use in women
during and immediately prior to labor, when shorter acting analgesics or other
analgesic techniques are more appropriate. Opioid analgesics can prolong labor
through actions that temporarily reduce the strength, duration, and frequency
of uterine contractions. However this effect is not consistent and may be
offset by an increased rate of cervical dilatation, which tends to shorten
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
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 depression.
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.