Methadone

If you take too much methadone or overdose, call 911 or your local emergency number right away.

Deaths, cardiac and respiratory, have been reported during initiation and conversion of pain patients to methadone treatment from treatment with other opioid agonists. It is critical to understand the pharmacokinetics of methadone when converting patients from other opioids. Particular vigilance is necessary during treatment initiation, during conversion from one opioid to another, and during dose titration.

Respiratory depression is the chief hazard associated with methadone hydrochloride administration. Methadone's peak respiratory depressant effects typically occur later, and persist longer than its peak analgesic effects, particularly in the early dosing period. These characteristics can contribute to cases of iatrogenic overdose, particularly during treatment initiation and dose titration.

In addition, cases of QT interval prolongation and serious arrhythmia (torsades de pointes) have been observed during treatment with methadone. 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.

Methadone treatment for analgesic therapy in patients with acute or chronic pain should only be initiated if the potential analgesic or palliative care benefit of treatment with methadone is considered and outweighs the risks.

Conditions for Distribution and Use of Methadone Products for the Treatment of Opioid Addiction

Code of Federal Regulations, Title 42, Sec 8

Methadone products when used for the treatment of opioid addiction in detoxification or maintenance programs, shall be dispensed only by opioid treatment programs (and agencies, practitioners or institutions by formal agreement with the program sponsor) certified by the Substance Abuse and Mental Health Services Administration and approved by the designated state authority. Certified treatment programs shall dispense and use methadone in oral form only and according to the treatment requirements stipulated in the Federal Opioid Treatment Standards (42 CFR 8.12). See below for important regulatory exceptions to the general requirement for certification to provide opioid agonist treatment.

Failure to abide by the requirements in these regulations may result in criminal prosecution, seizure of the drug supply, revocation of the program approval, and injunction precluding operation of the program.

Regulatory Exceptions to the General Requirement for Certification to Provide Opioid Agonist Treatment:

1. During inpatient care, when the patient was admitted for any condition other than concurrent opioid addiction (pursuant to 21 CFR 1306.07(c)), to facilitate the treatment of the primary admitting diagnosis.
2. During an emergency period of no longer than 3 days while definitive care for the addiction is being sought in an appropriately licensed facility (pursuant to 21 CFR 1306.07(b)).

5 mg Tablets: 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.

10 mg Tablets: 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.

Addiction, Abuse, and Misuse

Methadone hydrochloride tablets contain Methadone, a Schedule II controlled substance. As an opioid, Methadone hydrochloride tablets expose users to the risks of addiction, abuse, and misuse. As long-acting opioids such as Methadone hydrochloride tablets have pharmacological effects over an extended period of time, there is a greater risk for overdose and death [see Drug Abuse and Dependence (9)].

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Methadone hydrochloride tablets. 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 and 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 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 [see Overdosage (10)].

Opioids 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 Counseling Information (17)]. 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 Methadone, even when used as recommended. The peak respiratory depressant effect of Methadone occurs later, and persists longer than the peak analgesic effect. 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 (10)]. 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 dosage increase. The peak respiratory depressant effect of Methadone occurs later, and persists longer than the peak analgesic effect, especially during the initial dosing period. Monitor patients closely 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 (2.2, 2.3)]. Overestimating the Methadone hydrochloride tablets dosage 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 an 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 of Methadone.

The use of Methadone in patients already known to have a prolonged QT interval has not been systematically studied.

Neonatal Opioid Withdrawal Syndrome

Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy, whether that use is medically-authorized or illicit. Unlike opioid withdrawal syndrome in adults, NOWS may be life-threatening if not recognized and treated in the neonate. Advise the patient of the risk of NOWS so that appropriate planning for management of the neonate can occur. Healthcare professionals should observe newborns for signs of NOWS and manage accordingly [see Specific Populations (8.1)].

The balance between the risks of NOWS and the benefits of maternal Methadone hydrochloride tablets use may differ based on the risks associated with the mother’s underlying condition, pain or addiction, and the risks of the alternative treatments.

• For management of pain, prescribers should discuss all available treatment options with females of reproductive potential, including non-opioid and non-pharmacologic options.
• Untreated opioid addiction often results in continued or relapsing illicit opioid use and is associated with poor pregnancy outcomes. NOWS can result from in utero exposure to opioids regardless of the source. Therefore, prescribers should discuss the importance and benefits of management of opioid addiction throughout pregnancy.

Risks of Concomitant Use of Cytochrome P450 3A4, 2B6, 2C19, 2C9, or 2D6 Inhibitors or Discontinuation of P450 3A4, 2B6, 2C19, or 2C9 Inducers

Concomitant use of Methadone hydrochloride tablets with CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors, may increase plasma concentrations of Methadone, prolong opioid adverse reactions, and may cause potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dosage of Methadone hydrochloride tablets is achieved. Similarly, discontinuation of concomitant CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers in Methadone hydrochloride tablets-treated patients may increase Methadone plasma concentrations resulting in fatal respiratory depression. Consider dosage reduction of Methadone hydrochloride tablets when using concomitant CYP3A4, CYP2B6, CYP2C19, CYP2C9 or CYP2D6 inhibitors or discontinuing CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers in Methadone-treated patients, and follow patients closely at frequent intervals for signs and symptoms of respiratory depression and sedation [see Drug Interactions (7)].

Addition of CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers or discontinuation of CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors in patients treated with Methadone hydrochloride tablets may decrease Methadone plasma concentrations, reducing efficacy and may lead to opioid withdrawal symptoms in patients physically dependent on Methadone. When using Methadone hydrochloride tablets with CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers or discontinuing CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors, follow patients for signs or symptoms of opioid withdrawal and consider increasing the Methadone hydrochloride tablets dosage as needed [see Drug Interactions (7)].

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Methadone hydrochloride tablets with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7)].

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.

Advise both patients and caregivers about the risks of respiratory depression and sedation when Methadone hydrochloride tablets are used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions (7) and Patient Counseling Information (17)].

Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

The use of Methadone hydrochloride tablets in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Patients with Chronic Pulmonary Disease

Methadone hydrochloride tablets-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of Methadone hydrochloride tablets [see Warnings and Precautions (5.2)].

Elderly, Cachectic, or Debilitated Patients

Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see Warnings and Precautions (5.2)].

Monitor such patients closely, particularly when initiating and titrating Methadone hydrochloride tablets and when Methadone hydrochloride tablets are given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2, 5.6)]. Alternatively, consider the use of non-opioid analgesics in these patients.

Serotonin Syndrome with Concomitant Use of Serotonergic Drugs

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of Methadone hydrochloride tablets with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) [see Drug Interactions (7)]. This may occur within the recommended dosage range.

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue Methadone hydrochloride tablets if serotonin syndrome is suspected.

Adrenal Insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

Severe Hypotension

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 (7)]. Monitor these patients for signs of hypotension after initiating or titrating the dosage of Methadone hydrochloride tablets. In patients with circulatory shock, Methadone hydrochloride tablets may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Methadone hydrochloride tablets in patients with circulatory shock.

Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness

In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors) Methadone hydrochloride tablets may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with Methadone hydrochloride tablets.

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.

Risks of Use in Patients with Gastrointestinal Conditions

Methadone hydrochloride tablets are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The Methadone in Methadone hydrochloride tablets may cause spasm of the sphincter of Oddi. Opioids may cause increases in the serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

Increased Risk of Seizures in Patients with Seizure Disorders

The Methadone in Methadone hydrochloride tablets may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during Methadone hydrochloride tablets therapy.

 Withdrawal

Avoid the use of mixed agonist/antagonist (i.e., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist, including 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 Interactions (7)].

When discontinuing Methadone hydrochloride tablets, gradually taper the dosage [see Dosage and Administration (2.4)]. Do not abruptly discontinue Methadone hydrochloride tablets [see Drug Abuse and Dependence (9.3)].

Risks 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 [see Patient Counseling Information (17)].

 Laboratory Test Interactions

False positive urine drug screens for Methadone have been reported for several drugs including diphenhydramine, doxylamine, clomipramaine, chlorpromazine, thioridazine, quetiapine, and verapamil.

Mechanism of Action

Methadone hydrochloride is a mu-agonist; a synthetic opioid 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.

Pharmacodynamics

Effects on the Central Nervous System

Methadone produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.

Methadone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

Some NMDA receptor antagonists have been shown to produce neurotoxic effects in animals.

Effects on the Gastrointestinal Tract and Other Smooth Muscle

Methadone causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone is increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

Effects on the Cardiovascular System

Methadone produces peripheral vasodilation, which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.

Effects on the Endocrine System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions (6)]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6)].

Effects on the Immune System

Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

Concentration-Efficacy Relationships

The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids. The minimum effective analgesic concentration of Methadone for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see Dosage and Administration (2.1), (2.3)].

Concentration-Adverse Reaction Relationships

There is a relationship between increasing Methadone plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression.  In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration (2.1), (2.2), (2.3)].

Pharmacokinetics

Absorption

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.

Distribution

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.

Elimination

Metabolism: 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, CYP2C19, 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. 

Excretion: 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.

Drug Interaction Studies

Cytochrome P450 Interactions: Methadone undergoes hepatic N-demethylation by cytochrome P450 (CYP) isoforms, principally CYP3A4, CYP2B6, CYP2C19, CYP2C9 and CYP2D6. Co-administration 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)].

Cytochrome P450 Inducers: The following drug interactions were reported following co-administration 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:

Voriconazole: Voriconazole can inhibit the activity of CYP3A4, CYP2C9, and CYP2C19. 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 co-administration. Dose reduction of Methadone may be needed [see Drug Interactions (7)].

Antiretroviral Drugs: 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: Co-administration of these anti-retroviral agents resulted in increased clearance or decreased plasma levels of Methadone [see Drug Interactions (7)].

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)].

Zidovudine: Methadone increased the AUC of zidovudine which could result in toxic effects [see Drug Interactions (7)].

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 dosage is increased, and that it can occur even at recommended dosages [see Warnings and Precautions (5.2)]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.

Accidental Ingestion

Inform patients that accidental ingestion, especially by 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 [see Warnings and Precautions (5.3)].

Interactions with Benzodiazepines and Other CNS Depressants

Inform patients and caregivers that potentially fatal additive effects may occur if Methadone hydrochloride tablets are used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider [see Warnings and Precautions (5.6), Drug Interactions (7)].

Serotonin Syndrome

Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications [see Warnings and Precautions (5.8), Drug Interactions (7)].

MAOI Interaction

Inform patients to avoid taking Methadone hydrochloride tablets while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking Methadone hydrochloride tablets [see Warnings and Precautions (5.8), Drug Interactions (7)].

Adrenal Insufficiency

Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions (5.9)].

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) [see Dosage and Administration (2), Warnings and Precautions (5.2)].

• Do not discontinue Methadone hydrochloride tablets without first discussing the need for a tapering regimen with the prescriber [see Warnings and Precautions (5.14)].

Hypotension

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) [see Warnings and Precautions (5.10)].

Anaphylaxis

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 [see Contraindications (4), Adverse Reactions (6)].

Pregnancy

Neonatal Opioid Withdrawal Syndrome: Advise women that if they are pregnant while being treated with Methadone hydrochloride tablets, the baby may have signs of withdrawal at birth and that withdrawal is treatable [see Warnings and Precautions (5.4), Specific Populations (8.1)].

Embryo-Fetal Toxicity: Inform female patients of reproductive potential that Methadone hydrochloride tablets can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1)].

Lactation

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) [see Use in Specific Populations (8.2)].

Infertility

Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Populations (8.3)].

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 [see Warnings and Precautions (5.15)].

Constipation

Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions (6), Clinical Pharmacology (12.2)].

Disposal of Unused Methadone Hydrochloride Tablets

Advise patients to flush the unused tablets down the toilet when Methadone hydrochloride tablets are no longer needed.

Mallinckrodt, the “M” brand mark, the Mallinckrodt Pharmaceuticals logo and M are trademarks of a Mallinckrodt company.

© 2017 Mallinckrodt.

Mallinckrodt Inc.
Hazelwood, MO 63042 USA

Issued: 01/2017

Mallinckrodt™
Pharmaceuticals 

An electronic copy of this medication guide can be obtained from www.mallinckrodt.com/Medguide/L20M28.pdf or by calling 1-800-778-7898 for alternate delivery options.

Methadone Hydrochloride Tablets USP, CII
(METH a done HYE droe KLOR ide)

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 than 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.
• Taking Methadone hydrochloride tablets with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.
• 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 plan to become pregnant. If you take Methadone hydrochloride tablets while pregnant, your baby may have symptoms of opioid withdrawal or respiratory depression at birth. Talk to your doctor if you are pregnant or plan to become pregnant.
• breastfeeding. Methadone hydrochloride tablets 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. Use the lowest dose possible for the shortest time needed.
• 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 tablets 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 affects 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, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.

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

Manufactured by: Mallinckrodt Inc., Hazelwood, MO 63042 USA, www.Mallinckrodt.com or call 1-800-778-7898 

Mallinckrodt™

This Medication Guide has been approved by the U.S. Food and Drug Administration.                                 
Revised: January 2017

L20M28

• Analgesic, Opioid

Binds to opiate receptors in the CNS, causing inhibition of ascending pain pathways, altering the perception of and response to pain; produces generalized CNS depression. Methadone has also been shown to have N-methyl-D-aspartate (NMDA) receptor antagonism.

Distribution

Lipophilic

Vd: (Mean ± SD): Children: 7.1 ± 2.5 L/kg; Adults: 6.1 ± 2.4 L/kg

Vdss: Adults: 1 to 8 L/kg

Metabolism

Hepatic; N-demethylation primarily via CYP3A4, CYP2B6, CYP2C19, CYP2C9, and CYP2D6 to inactive metabolites

Excretion

Urine (<10% as unchanged drug); increased with urine pH <6; Note: Methadone may persist in the liver and other tissues; slow release from tissues may prolong the pharmacologic effect despite low serum concentrations

Hypersensitivity (eg, anaphylaxis) to methadone or any component of the formulation; significant respiratory depression (in the absence of resuscitative equipment or in unmonitored settings); acute or severe bronchial asthma (in the absence of resuscitative equipment or in an unmonitored setting); hypercarbia; GI obstruction, including paralytic ileus (known or suspected)

Documentation of allergenic cross-reactivity for opioids is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Canadian labeling: Additional contraindications (not in US labeling): Diarrhea associated with pseudomembranous colitis or caused by poisoning until toxic material has been eliminated from the GI tract; concurrent use or use within 14 days of a monoamine oxidase inhibitor (Methadose product labeling)

There are no dosage adjustments provided in the manufacturer's labeling; initiate at lower doses and titrate slowly; monitor closely for respiratory and CNS depression.

The following dosage adjustments have been recommended (Aronoff 2007): Adults:

CrCl ≥10 mL/minute: No dosage adjustment necessary.

CrCl <10 mL/minute: Administer 50% to 75% of normal dose

Hemodialysis and peritoneal dialysis do not increase elimination of methadone.