METHADONE HYDROCHLORIDE tablet
|Category||DEA Schedule||Marketing Status|
|HUMAN PRESCRIPTION DRUG LABEL||CII||Abbreviated New Drug Application|
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use Methadone Hydrochloride Tablets USP safely and effectively. See full prescribing information for Methadone Hydrochloride Tablets USP.
Methadone Hydrochloride Tablets USP, for oral use, CII
Initial U.S. Approval: 1947
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; LIFE-THREATENING QT PROLONGATION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and TREATMENT FOR OPIOID ADDICTION
See full prescribing information for complete boxed warning
RECENT MAJOR CHANGES
INDICATIONS AND USAGE
Methadone hydrochloride tablets are an opioid agonist indicated for the:
Limitations of Use
DOSAGE AND ADMINISTRATION
DOSAGE FORMS AND STRENGTHS
Tablets: 5 mg and 10 mg (3)
WARNINGS AND PRECAUTIONS
Most common adverse reactions are: lightheadedness, dizziness, sedation, nausea, vomiting, and sweating. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Mallinckrodt at 1-800-778-7898 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
USE IN SPECIFIC POPULATIONS
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
FULL PRESCRIBING INFORMATION
2 DOSAGE AND ADMINISTRATION
2.1 Important General Information
- The peak respiratory depressant effect of methadone occurs later and persists longer than its peak therapeutic effect.
- A high degree of opioid tolerance does not eliminate the possibility of methadone overdose, iatrogenic or otherwise. Deaths have been reported during conversion to methadone from chronic, high-dose treatment with other opioid agonists and during initiation of methadone treatment of addiction in subjects previously abusing high doses of other agonists.
- With repeated dosing, methadone is retained in the liver and then slowly released, prolonging the duration of potential toxicity.
- Methadone has a narrow therapeutic index, especially when combined with other drugs.
3 DOSAGE FORMS AND STRENGTHS
Methadone hydrochloride tablets are available in 5 mg and 10 mg dosage strengths. The 5 mg tablets are white to off-white, modified rectangle shaped convex tablets and are debossed with a score between “57” and “55” on one side and on the other side. The 10 mg tablets are white to off-white, modified rectangle shaped convex tablets and are debossed with a score between “57” and “71” on one side and on the other side.
Methadone hydrochloride tablets are 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 paralytic ileus
- Hypersensitivity (e.g., anaphylaxis) to methadone [see Adverse Reactions (6)]
5 WARNINGS AND PRECAUTIONS
6 ADVERSE REACTIONS
The following serious adverse reactions are discussed elsewhere in the labeling:
- Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)]
- Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2)]
- QT Prolongation [see Warnings and Precautions (5.3)]
- Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.4)]
- Interactions with Other CNS Depressants [see Warnings and Precautions (5.5)]
- Hypotensive Effect [see Warnings and Precautions (5.8)]
- Gastrointestinal Effects [see Warnings and Precautions (5.10)]
- Seizures [see Warnings and Precautions (5.11)]
The major hazards of methadone are respiratory depression and, to a lesser degree, systemic hypotension. Respiratory arrest, shock, cardiac arrest, and death have occurred.
The most frequently observed adverse reactions include lightheadedness, dizziness, sedation, nausea, vomiting, and sweating. These effects seem to be more prominent in ambulatory patients and in those who are not suffering severe pain. In such individuals, lower doses are advisable.
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, torsades de pointes, ventricular fibrillation, ventricular tachycardia
Central Nervous System: agitation, confusion, disorientation, dysphoria, euphoria, insomnia, hallucinations, seizures, visual disturbances
Gastrointestinal: abdominal pain, anorexia, biliary tract spasm, constipation, dry mouth, glossitis
Hematologic: reversible thrombocytopenia has been described in opioid addicts with chronic hepatitis
Metabolic: hypokalemia, hypomagnesemia, weight gain
Renal: antidiuretic effect, urinary retention or hesitancy
Reproductive: amenorrhea, reduced libido and/or potency, reduced ejaculate volume, reduced seminal vesicle and prostate secretions, decreased sperm motility, abnormalities in sperm morphology
Respiratory: pulmonary edema, respiratory depression
Skin and Subcutaneous Tissue: pruritus, urticaria, other skin rashes, and rarely, hemorrhagic urticaria
Hypersensitivity: 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.
Maintenance on a Stabilized Dose: During prolonged administration of methadone, as in a methadone maintenance treatment program, constipation and sweating often persist and hypogonadism, decreased serum testosterone and reproductive effects are thought to be related to chronic opioid use.
Methadone Hydrochloride Tablets for the Detoxification and Maintenance Treatment of Opioid Dependence
During the induction phase of methadone maintenance treatment, patients are being withdrawn from illicit opioids and may have opioid withdrawal symptoms. Monitor patients for signs and symptoms including: lacrimation, rhinorrhea, sneezing, yawning, excessive perspiration, goose-flesh, fever, chilling alternating with flushing, restlessness, irritability, weakness, anxiety, depression, dilated pupils, tremors, tachycardia, abdominal cramps, body aches, involuntary twitching and kicking movements, anorexia, nausea, vomiting, diarrhea, intestinal spasms, and weight loss and consider dose adjustment as indicated.
7 DRUG INTERACTIONS
7.1 CNS Depressants
The concomitant use of methadone hydrochloride tablets with other CNS depressants including sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, and alcohol can increase the risk of respiratory depression, profound sedation, coma and death. Monitor patients receiving CNS depressants and methadone hydrochloride tablets for signs of respiratory depression, sedation and hypotension.
When combined therapy with any of the above medications is considered, the dose of one or both agents should be reduced [see Warnings and Precautions (5.5)].
7.2 Drugs Affecting Cytochrome P450 Isoenzymes
Methadone undergoes hepatic N-demethylation by cytochrome P450 (CYP) isoforms, principally CYP3A4, CYP2B6, CYP2C19, and to a lesser extent by CYP2C9 and CYP2D6 [see Clinical Pharmacology (12.3)].
Inhibitors of CYP3A4 and 2C9
Because the CYP3A4 isoenzyme plays a major role in the metabolism of methadone, drugs that inhibit CYP3A4 activity may cause decreased clearance of methadone which could lead to an increase in methadone plasma concentrations and result in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of CYP 2C9 and 3A4 inhibitors. If co-administration with methadone hydrochloride tablets is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved [see Clinical Pharmacology (12.3)].
Inducers of CYP3A4
CYP450 3A4 inducers may induce the metabolism of methadone and, therefore, may cause increased clearance of the drug which could lead to a decrease in methadone plasma concentrations, lack of efficacy or, possibly, development of a withdrawal syndrome in a patient who had developed physical dependence to methadone. If co-administration with methadone hydrochloride tablets is necessary, monitor for signs of opioid withdrawal and consider dose adjustments until stable drug effects are achieved [see Clinical Pharmacology (12.3)].
After stopping the treatment of a CYP3A4 inducer, as the effects of the inducer decline, methadone plasma concentration will increase which could increase or prolong both the therapeutic and adverse effects, and may cause serious respiratory depression. If co-administration or discontinuation of a CYP3A4 inducer with methadone hydrochloride tablets is necessary, monitor for signs of opioid withdrawal and consider dose adjustments until stable drug effects are achieved [see Clinical Pharmacology (12.3)].
Paradoxical Effects of Antiretroviral Agents on Methadone Hydrochloride Tablets
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 tablets and could precipitate a withdrawal syndrome. Monitor methadone-maintained patients receiving any of these antiretroviral therapies closely for evidence of withdrawal effects and adjust the methadone dose accordingly.
Effects of Methadone Hydrochloride Tablets 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.
7.3 Potentially Arrhythmogenic Agents
Monitor patients closely for cardiac conduction changes when any drug known to have the potential to prolong the QT interval is prescribed in conjunction with methadone. Pharmacodynamic interactions may occur with concomitant use of methadone and potentially arrhythmogenic agents such as class I and III antiarrhythmics, some neuroleptics and tricyclic antidepressants, and calcium channel blockers.
Similarly, monitor patients closely when prescribing methadone concomitantly with drugs capable of inducing electrolyte disturbances (hypomagnesemia, hypokalemia) that may prolong the QT interval, including diuretics, laxatives, and, in rare cases, mineralocorticoid hormones.
7.4 Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Mixed agonist/antagonist (i.e., pentazocine, nalbuphine and butorphanol) and partial agonist (buprenorphine) analgesics may reduce the analgesic effect of methadone hydrochloride tablets or precipitate withdrawal symptoms. Avoid the use of mixed agonist/antagonist and partial agonist analgesics in patients receiving methadone hydrochloride tablets.
Monoamine Oxidase (MAO) Inhibitors: Therapeutic doses of meperidine have precipitated severe reactions in patients concurrently receiving monoamine oxidase inhibitors or those who have received such agents within 14 days. Similar reactions thus far have not been reported with methadone. However, if the use of methadone is necessary in such patients, a sensitivity test should be performed in which repeated small, incremental doses of methadone are administered over the course of several hours while the patient’s condition and vital signs are carefully observed.
Desipramine: Blood levels of desipramine have increased with concurrent methadone administration.
Anticholinergics or other drugs with anticholinergic activity when used concurrently with opioids may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Monitor patients for signs of urinary retention or reduced gastric motility when methadone hydrochloride tablets are used concurrently with anticholinergic drugs.
8 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 (5.4)].
Teratogenic Effects - 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 opioid-dependent 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 (2.10)].
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 (5.4)].
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
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-naïve 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-naïve 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-naïve 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.
8.2 Labor and Delivery
Opioids cross the placenta and may produce respiratory depression in neonates. Methadone hydrochloride tablets are 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 labor.
8.3 Nursing Mothers
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.
8.4 Pediatric Use
The safety, effectiveness, and pharmacokinetics of methadone in pediatric patients below the age of 18 years have not been established.
8.5 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, 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.
8.6 Renal Impairment
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 depression.
8.7 Hepatic Impairment
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.
9 DRUG ABUSE AND DEPENDENCE
9.1 Controlled Substance
Methadone is a mu-agonist opioid with an abuse liability similar to other opioid agonists and is a Schedule II controlled substance. Methadone can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.1)].
All patients treated with opioids for pain management require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use.
Drug abuse is the intentional non-therapeutic use of an over-the-counter or prescription drug, even once, for its rewarding psychological or physiological effects. Drug abuse includes, but is not limited to the following examples: the use of a prescription or over-the-counter drug to get “high”, or the use of steroids for performance enhancement and muscle build up.
Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and include: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.
“Drug-seeking” behavior is very common in addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated claims of lost prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” (visiting multiple prescribers) to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.
Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.
Methadone hydrochloride tablets, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state law, is strongly advised.
Risks Specific to Abuse of Methadone Hydrochloride Tablets
Abuse of methadone hydrochloride tablets poses a risk of overdose and death. This risk is increased with concurrent abuse of methadone and alcohol or other substances. Methadone hydrochloride tablets are for oral use only and must not be injected. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.
Proper assessment and selection of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.
Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.
Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity, e.g., naloxone, mixed agonist/antagonist analgesics (pentazocine, butorphanol, nalbuphine), or partial agonists (buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.
Methadone hydrochloride tablets should not be abruptly discontinued [see Dosage and Administration (2.4)]. If methadone hydrochloride tablets are abruptly discontinued in a physically dependent patient, an abstinence syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.
Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms [see Use in Specific Populations (8.1) and Warnings and Precautions (5.4)].
Acute overdosage of methadone is manifested by respiratory depression, somnolence progressing to stupor or coma, maximally constricted pupils, skeletal-muscle flaccidity, cold and clammy skin, and sometimes, bradycardia and hypotension. In severe overdosage, particularly by the intravenous route, apnea, circulatory collapse, cardiac arrest, and death may occur.
Treatment of Overdose
In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation if needed. Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques.
The opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to methadone overdose. Such agents should be administered cautiously to patients who are known, or suspected to be, physically dependent on methadone hydrochloride tablets. In such cases, an abrupt or complete reversal of opioid effects may precipitate an acute withdrawal syndrome.
Because the duration of reversal would be expected to be less than the duration of action of methadone in methadone hydrochloride tablets, carefully monitor the patient until spontaneous respiration is reliably re-established. If the response to opioid antagonists is suboptimal or not sustained, additional antagonist should be given as directed in the product’s prescribing information.
In an individual physically dependent on opioids, administration of an opioid receptor antagonist may precipitate an acute withdrawal. The severity of the withdrawal produced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist.
Methadone hydrochloride is chemically described as 6-(dimethylamino)-4,4-diphenyl-3-hepatanone hydrochloride. Methadone hydrochloride is a white, crystalline material that is water-soluble. Methadone hydrochloride has a melting point of 235°C, and a pKa of 8.25 in water at 20°C. Its octanol/water partition coefficient at pH 7.4 is 117. A solution (1:100) in water has a pH between 4.5 and 6.5.
It has the following structural formula:
Each Methadone Hydrochloride Tablet contains 5 or 10 mg of methadone hydrochloride, USP and the following inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose and silicon dioxide.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Methadone hydrochloride is a mu-agonist; a synthetic opioid analgesic with multiple actions qualitatively similar to those of morphine, the most prominent of which involves the central nervous system and organs composed of smooth muscle. The principal therapeutic uses for methadone are for analgesia and for detoxification or maintenance in opioid addiction. The methadone withdrawal syndrome, although qualitatively similar to that of morphine, differs in that the onset is slower, the course is more prolonged, and the symptoms are less severe.
Some data also indicate that methadone acts as an antagonist at the N-methyl-D-aspartate (NMDA) receptor. The contribution of NMDA receptor antagonism to methadone’s efficacy is unknown. Other NMDA receptor antagonists have been shown to produce neurotoxic effects in animals.
Following oral administration the bioavailability of methadone ranges between 36 to 100% and peak plasma concentrations are achieved between 1 to 7.5 hours. Dose proportionality of methadone pharmacokinetics is not known. However, after administration of daily oral doses ranging from 10 to 225 mg, the steady-state plasma concentrations ranged between 65 to 630 ng/mL and the peak concentrations ranged between 124 to 1255 ng/mL. Effect of food on the bioavailability of methadone has not been evaluated.
Methadone is a lipophilic drug and the steady-state volume of distribution ranges between 1.0 to 8.0 L/kg. In plasma, methadone is predominantly bound to α1-acid glycoprotein (85% to 90%). Methadone is secreted in saliva, breast milk, amniotic fluid and umbilical cord plasma.
Methadone is primarily metabolized by N-demethylation to an inactive metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidene (EDDP). Cytochrome P450 enzymes, primarily CYP3A4, CYP2B6, and CYP2C19 and to a lesser extent CYP2C9 and CYP2D6, are responsible for conversion of methadone to EDDP and other inactive metabolites, which are excreted mainly in the urine. Methadone appears to be a substrate for P-glycoprotein but its pharmacokinetics do not appear to be significantly altered in case of P-glycoprotein polymorphism or inhibition.
The elimination of methadone is mediated by extensive biotransformation, followed by renal and fecal excretion. Published reports indicate that after multiple dose administration the apparent plasma clearance of methadone ranged between 1.4 and 126 L/h, and the terminal half-life (T1/2) was highly variable and ranged between 8 to 59 hours in different studies. Methadone is a basic (pKa=9.2) compound and the pH of the urinary tract can alter its disposition in plasma. Also, since methadone is lipophilic, it has been known to persist in the liver and other tissues. The slow release from the liver and other tissues may prolong the duration of methadone action despite low plasma concentrations.
Cytochrome P450 Interactions
Methadone undergoes hepatic N-demethylation by cytochrome P450 (CYP) isoforms, principally CYP3A4, CYP2B6, CYP2C19, and to a lesser extent by CYP2C9 and CYP2D6. Coadministration of methadone with CYP inducers may result in more rapid metabolism and potential for decreased effects of methadone, whereas administration with CYP inhibitors may reduce metabolism and potentiate methadone’s effects. Although antiretroviral drugs such as efavirenz, nelfinavir, nevirapine, ritonavir, lopinavir+ritonavir combination are known to inhibit some CYPs, they are shown to reduce the plasma levels of methadone, possibly due to CYP induction activity [see Drug Interactions (7.2)]. Therefore, drugs administered concomitantly with methadone should be evaluated for interaction potential; clinicians are advised to evaluate individual response to drug therapy.
Cytochrome P450 Inducers
The following drug interactions were reported following coadministration of methadone with known inducers of cytochrome P450 enzymes:
Rifampin: In patients well-stabilized on methadone, concomitant administration of rifampin resulted in a marked reduction in serum methadone levels and a concurrent appearance of withdrawal symptoms.
Phenytoin: In a pharmacokinetic study with patients on methadone maintenance therapy, phenytoin administration (250 mg twice daily initially for 1 day followed by 300 mg daily for 3 to 4 days) resulted in an approximately 50% reduction in methadone exposure and withdrawal symptoms occurred concurrently. Upon discontinuation of phenytoin, the incidence of withdrawal symptoms decreased and methadone exposure increased to a level comparable to that prior to phenytoin administration.
St. John’s Wort, Phenobarbital, Carbamazepine: Administration of methadone with other CYP3A4 inducers may result in withdrawal symptoms.
Cytochrome P450 Inhibitors
Since the metabolism of methadone is mediated primarily by CYP3A4 isozyme, coadministration of drugs that inhibit CYP3A4 activity may cause decreased clearance of methadone.
Voriconazole: Repeat dose administration of oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 4 days) increased the peak plasma concentration (Cmax) and AUC of (R)-methadone by 31% and 47%, respectively, in subjects receiving a methadone maintenance dose (30 to 100 mg daily). The Cmax and AUC of (S)-methadone increased by 65% and 103%, respectively. Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed [see Drug Interactions (7.2)].
Although antiretroviral drugs such as efavirenz, nelfinavir, nevirapine, ritonavir, telaprevir, lopinavir+ritonavir combination are known to inhibit some CYPs, they are shown to reduce the plasma levels of methadone, possibly due to CYP induction activity.
Abacavir, amprenavir, darunavir+ritonavir, efavirenz, nelfinavir, nevirapine, ritonavir, telaprevir, lopinavir+ritonavir, saquinavir+ritonavir, tipranvir+ritonavir combination: Coadministration of these antiretroviral agents resulted in increased clearance or decreased plasma levels of methadone [see Drug Interactions (7.2)].
Didanosine and Stavudine: Methadone decreased the AUC and peak levels for didanosine and stavudine, with a more significant decrease for didanosine. Methadone disposition was not substantially altered [see Drug Interactions (7.2)].
Zidovudine: Methadone increased the AUC of zidovudine which could result in toxic effects [see Drug Interactions (7.2)].
13 NONCLINICAL TOXICOLOGY
13.1 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.
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 Storage and Handling
Methadone hydrochloride tablets contain methadone which is a controlled substance. Like fentanyl, morphine, oxycodone, hydromorphone, and oxymorphone, methadone is controlled under Schedule II of the Federal Controlled Substances Act. Methadone hydrochloride tablets may be targeted for theft and diversion by criminals [see Warnings and Precautions (5.1)].
Dispense in a tight, light-resistant container (as defined in USP) with a child-resistant closure.
Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].
16.2 How Supplied
Each 5 mg Methadone Hydrochloride Tablet USP contains 5 mg methadone hydrochloride USP. It is available as a white to off-white, modified rectangle shaped convex tablet, one side debossed with a score between “57” and “55”; on the other side.
Bottles of 100 ...................NDC 0406-5755-01
Unit Dose (10 x 10)...........NDC 0406-5755-62
Each 10 mg Methadone Hydrochloride Tablet USP contains 10 mg methadone hydrochloride USP. It is available as a white to off-white, modified rectangle shaped convex tablet, one side debossed with a score between “57” and “71”; on the other side.
Bottles of 100 ...................NDC 0406-5771-01
Unit Dose (10 x 10)...........NDC 0406-5771-62
DEA order form required.
17 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 (5.1)]. 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 (5.2)]. 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 (5.2)]. 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 (5.4)].
Interactions with Alcohol and other CNS Depressants
Inform patients that potentially serious additive effects may occur if methadone hydrochloride tablets are used with alcohol or other CNS depressants, and not to use such drugs unless supervised by a healthcare provider.
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 depression)
- 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.
Methadone Hydrochloride Tablets USP, CII
Methadone hydrochloride tablets are:
- A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage pain severe enough to require daily around-the-clock, long-term treatment with an opioid, when other pain treatments such as non-opioid pain medicines or immediate-release opioid medicines do not treat your pain well enough or you cannot tolerate them.
- A long-acting opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.
- Not for use to treat pain that is not around-the-clock.
- Also used to manage drug addiction.
Important information about methadone hydrochloride tablets:
- Get emergency help right away if you take too much methadone hydrochloride tablets (overdose). When you first start taking methadone hydrochloride tablets, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur.
- Never give anyone your methadone hydrochloride tablets. They could die from taking it. Store methadone hydrochloride tablets away from children and in a safe place to prevent stealing or abuse. Selling or giving away methadone hydrochloride tablets is against the law.
Do not take methadone hydrochloride tablets if you have:
- severe asthma, trouble breathing, or other lung problems.
- a bowel blockage or have narrowing of the stomach or intestines.
Before taking methadone hydrochloride tablets, tell your healthcare provider if you have a history of:
- head injury, seizures
- problems urinating
- heart rhythm problems (Long QT syndrome)
- abuse of street or prescription drugs, alcohol addiction, or mental health problems.
- liver, kidney, thyroid problems
- pancreas or gallbladder problems
Tell your healthcare provider if you are:
- pregnant or planning to become pregnant. Prolonged use of methadone hydrochloride tablets during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.
- breastfeeding. Methadone hydrochloride passes into breast milk and may harm your baby.
- taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking methadone hydrochloride tablets with certain other medicines may cause serious side effects.
When taking methadone hydrochloride tablets:
- Do not change your dose. Take methadone hydrochloride tablets exactly as prescribed by your healthcare provider.
- Do not take more than your prescribed dose in 24 hours. If you take methadone hydrochloride tablets for pain and miss a dose, take methadone hydrochloride tablets as soon as possible and then take your next dose 8 or 12 hours later as directed by your healthcare provider. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule.
- If you take methadone hydrochloride tablets for opioid addiction and miss a dose, take your next dose the following day as scheduled. Do not take extra doses. Taking more than the prescribed dose may cause you to overdose because methadone hydrochloride builds up in your body over time.
- Do not crush, dissolve, snort or inject methadone hydrochloride tablets because this may cause you to overdose and die.
- Call your healthcare provider if the dose you are taking does not control your pain.
- Do not stop taking methadone hydrochloride tablets without talking to your healthcare provider.
- After you stop taking methadone hydrochloride tablets, flush any unused tablets down the toilet.
While taking methadone hydrochloride tablets DO NOT:
- Drive or operate heavy machinery, until you know how methadone hydrochloride tablets affect you. Methadone hydrochloride tablets can make you sleepy, dizzy, or lightheaded.
- Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with methadone hydrochloride tablets may cause you to overdose and die.
The possible side effects of methadone hydrochloride tablets are:
- constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe.
Get emergency medical help if you have:
- trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue or throat, extreme drowsiness, light-headedness when changing positions, or you are feeling faint.
These are not all the possible side effects of methadone hydrochloride tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov
This Medication Guide has been approved by the U.S. Food and Drug Administration.
is a trademark of Mallinckrodt LLC.
Hazelwood, MO 63042 USA
Issued 04/2014 Mallinckrodt
PRINCIPAL DISPLAY PANEL
Each tablet contains:
Methadone Hydrochloride USP. . . . . 5 mg
PHARMACIST: PLEASE DISPENSE WITH MEDICATION GUIDE PROVIDED WITH PRODUCT
methadone hydrochloride tablet
methadone hydrochloride tablet
|Labeler - Mallinckrodt, Inc. (047021092)|
|MALLINCKRODT INC||957414238||ANALYSIS(0406-5755, 0406-5771), MANUFACTURE(0406-5755, 0406-5771)|