Methadone Hydrochloride

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Methadone Hydrochloride Prescribing Information

WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF METHADONE HYDROCHLORIDE TABLETS

Addiction, Abuse, and Misuse

Because the use of Methadone Hydrochloride Tablets exposes patients and other users to the

risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient’s risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.1)].

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression may occur with use of Methadone Hydrochloride Tablets, especially during initiation or following a dose increase. To reduce the risk of respiratory depression, proper dosage and titration of Methadone Hydrochloride Tablets are essential [see Warnings and Precautions (5.6)].

Accidental Ingestion

Accidental ingestion of even one dose of Methadone Hydrochloride Tablets, especially by children, can result in a fatal overdose of methadone [see Warnings and Precautions (5.1)].

Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of Methadone Hydrochloride Tablets and benzodiazepines or other CNS depressants for use in patients for whom alternatives to benzodiazepines or other CNS depressants are inadequate. [see Warnings and Precautions (5.2), Drug Interactions (7)].

Neonatal Opioid Withdrawal Syndrome (NOWS)

If Opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of NOWS, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery [see Warnings and Precautions (5.5)].

Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

Healthcare providers are strongly encouraged to complete a REMS-compliant education program, and to counsel patients and their caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription [See Warnings and Precautions (5.6)].

Life-Threatening QT Prolongation

QT interval prolongation and serious arrhythmia (torsades de pointes) have occurred 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. Closely monitor patients with risk factors for development of prolonged QT interval, a history of cardiac conduction abnormalities, and those taking medications affecting cardiac conduction for changes in cardiac rhythm during initiation and titration of Methadone Hydrochloride Tablets [see Warnings and Precautions (5.4)].

Cytochrome P450 Interaction

The concomitant use of Methadone Hydrochloride Tablets with all cytochrome P450 3A4, 2B6, 2C19, 2C9 or 2D6 inhibitors may result in an increase in methadone plasma concentrations, which could cause potentially fatal respiratory depression. In addition, discontinuation of concomitantly used cytochrome P450 3A4 2B6, 2C19, or 2C9 inducers may also result in an increase in methadone plasma concentration. Follow patients closely for respiratory depression and sedation and consider dosage reduction with any changes of concomitant medications that can result in an increase in methadone levels [see Warnings and Precautions (5.7), Drug interactions (7)].

Conditions For Distribution And Use Of Methadone Products For The Treatment Of Opioid Addiction

For detoxification and maintenance of opioid dependence, methadone should be administered in accordance with the treatment standards cited in 42 CFR Section 8, including limitations on unsupervised administration [see Indications and Usage (1), Dosage And Administration (2.1)].

Methadone Hydrochloride Tablets are indicated for the:

1. Management of severe and persistent pain that requires an extended treatment period with a daily opioid analgesic and for which alternative treatment options are inadequate.

Limitations of Use

Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration [See Warnings and Precautions (5.1)], reserve Methadone Hydrochloride Tablets for use in patients for whom alternative analgesic treatment options (e.g., non-opioid analgesics or immediate-release opioid analgesics) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.
Methadone Hydrochloride Tablets are not indicated as an as-needed (prn) analgesic.

2. Detoxification treatment of opioid addiction (heroin or other morphine-like drugs).

3.Maintenance treatment of opioid addiction (heroin or other morphine-like drugs), in conjunction with appropriate social and medical services.

Limitations of Use

Methadone products used for the treatment of opioid addiction in detoxification or maintenance programs are subject to the conditions for distribution and use required under 42 CFR 8.12

2 DOSAGE AND ADMINISTRATION

Consider prescribing naloxone based on the patient’s risk factors for overdose [2.3, 5.1, 5.2, 5.7].

Management of Pain

• Methadone Hydrochloride Tablets should be prescribed only by healthcare professionals who are knowledgeable in use of extended release/long-acting opioids and how to mitigate the associated risks. (2.1)

• Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. reserve titration to higher doses of Methadone Hydrochloride Tablets for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. (2.1, 5)

• Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse (2.4,5.1)

• Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Methadone Hydrochloride Consider this risk when selecting an initial dose and when making dose adjustments (2.1, 5.10)

• For opioid naïve patients, initiate Methadone Hydrochloride Tablets treatment with 2.5 mg every 8 to 12 hours. (2.4)

• To convert to Methadone Hydrochloride Tablets from another opioid, use available conversion factors to obtain estimated dose. (2.4)

• Titrate slowly with dose increases no more frequent than every 3 to 5 days. (2.5)

• Do not abruptly discontinue Methadone Hydrochloride Tablets in a physically dependent patient. because rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. (2.6, 5.16)

Initiation of Detoxification and Maintenance Treatment

• A single dose of 20 to 30 mg may be sufficient to suppress withdrawal syndrome. (2.7)

2.1 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:

During inpatient care, when the patient was admitted for any condition other than concurrent opioid addiction (pursuant to 21CFR 1306.07(c)), to facilitate the treatment of the primary admitting diagnosis).
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 21CFR 1306.07(b)).

2.2 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.

2.3 Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with Methadone Hydrochloride Tablets [see Warnings and Precautions (5.2), Overdosage (10)].

For Patients Being Treated for Pain

Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient.

For Patients Being Treated for Opioid Addiction

Because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose, strongly consider prescribing naloxone for the emergency treatment of opioid overdose. Advise patients and caregivers that naloxone may also be administered for a known or suspected overdose with Methadone Hydrochloride Tablets itself.

Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone. [see Warnings and Precautions (5.2), Patient Counseling Information (17)].

Inform patients and caregivers of their options for obtaining naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program) [see Patient Counseling Information (17)].

2.4 Methadone Hydrochloride Tablets for Management of Pain

Important Dosage and Administration Information

Methadone Hydrochloride Tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.

Consider the following important factors that differentiate methadone from other opioid analgesics:

There is high interpatient variability in absorption, metabolism, and relative analgesic potency of methadone. Population-based equianalgesic conversion ratios between methadone and other opioids are not accurate when applied to individuals.
The duration of analgesic action of methadone is 4 to 8 hours (based on single-dose studies) but the plasma elimination half-life is 8 to 59 hours.
With repeated dosing, the potency of methadone increases due to systemic accumulation.
Steady-state plasma concentrations and full analgesic effects are not attained until at least 3 to 5 days on a dose, and may take longer in some patient Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see Warnings and Precautions (5)]. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of Methadone Hydrochloride Tablets for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)]. Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Methadone Hydrochloride Tablets. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions (5)].

Use of Methadone Hydrochloride Tablets as the First Opioid Analgesic:

Initiate treatment with Methadone Hydrochloride Tablets with 2.5 mg orally every 8 to 12 hours as needed for pain.

Conversion from OtherOral Opioids to Methadone Hydrochloride Tablets:

When Methadone Hydrochloride Tablets therapy is initiated, discontinue all other opioid analgesics other than those used on an as needed basis for breakthrough pain when appropriate. Deaths have occurred in opioid-tolerant patients during conversion to methadone.

Thepotency of methadone relative to other opioid analgesics is nonlinearandincreases with increasing dose.Table 1 provides anestimated conversionfactorforusewhen convertingpatientsfromanother opioid to methadone.Because of the high inter-patient variability in absorption,metabolism,and relative potency, it is critical to avoid overestimating the methadonedosewhichcanlead to fatal respiratory depression.It is safer to underestimate a patients 24-hour methadonedosageand provide rescuemedication (e.g.,immediate-release opioid) than to overestimate the 24-hour methadonedosageandmanageanadversereaction due to anoverdose.

Consider the following whenusing the information in Table 1:

This is
not
a table of equianalgesicdoses.
Theconversion factors in this table are only for the conversion
from
another oral opioid analgesic
to
Methadone Hydrochloride Tablets.
Thetable
cannot
be used to convert
from
Methadone Hydrochloride Tablets
to
another opioid. Doingso will result in anoverestimation of the dose of the new opioid andmayresult in fatal overdose.

Table 1: Conversion Factors to Methadone Hydrochloride Tablets
Total Daily Baseline Oral EstimatedDaily Oral Methadone Requirement as Percent Morphine Equivalent Dose of Total Daily Morphine Equivalent Dose < 100 mg 20% to 30% 100 to 300 mg 10% to 20% 300 to 600 mg 8% to 12% 600 mg to 1,000 mg 5% to 10% > 1,000 mg < 5 %

Tocalculate the estimated Methadone Hydrochloride Tablets doseusing Table 1:

Forpatients on a single opioid, sum the current total dailydose of the opioid, convert it to a Morphine Equivalent Doseaccording to specificconversionfactorforthatspecific opioid, then multiply the MorphineEquivalentDose by the correspondingpercentage in the abovetable to calculate the approximate oral methadonedailydose. Divide the totaldailymethadonedosederivedfrom the tableabove to reflect the intended dosing schedule(i.e.,foradministrationevery 8 hours, divide totaldailymethadonedose by 3).
Forpatients on a regimen of morethan one opioid, calculate the approximate oral methadonedoseforeach opioid and sum the totals to obtain the approximate totalmethadonedaily dose. Divide the totaldailymethadonedosederivedfrom the tableabove to reflect the intended dosing schedule(i.e.,foradministrationevery 8 hours,dividetotal dailymethadonedose by 3).
Forpatients on a regimen of fixed-ratio opioid/non-opioid analgesicproducts,use only the opioid component of these products in the conversion.

Always round the dose down, if necessary, to the appropriate Methadone Hydrochloride Tablets strength(s) available.

Example conversion from a single opioid to Methadone Hydrochloride Tablets:

Step 1:

Sum the total dailydose of the opioid (in this case,Morphine Extended ReleaseTablets 50 mg twicedaily) 50 mg Morphine Extended-ReleaseTablets 2 timesdaily = 100 mg total dailydose of Morphine 50 mg Morphine Extended Release Tablets 2 times daily = 100 mg total daily dose of Morphine

Step 2:

Calculate the approximate equivalent dose of Methadone Hydrochloride Tablets based on the total daily dose of Morphine using Table 1.

100 mg totaldailydose of Morphine x 15% (10% to 20% perTable 1) = 15 mg Methadone Hydrochloride Tablets daily

Step 3:

Calculate the approximate startingdose of Methadone Hydrochloride Tablets to be givenevery 12 hours.Rounddown, if necessary, to the appropriate Methadone Hydrochloride Tablets strengthsavailable.

15 mg daily / 2 = 7.5 mg Methadone Hydrochloride Tablets every 12 hours

Then7.5 mg is rounded down to 5 mg Methadone Hydrochloride Tablets every 12 hours

Closeobservation and frequent titration are warranted until painmanagement is stable on the new opioid. Monitorpatientsforsignsandsymptoms of opioid withdrawal or forsigns of over-sedation/toxicityafterconverting patientstoMethadone Hydrochloride Tablets.

Conversionfrom ParenteralMethadone to Methadone Hydrochloride Tablets:

Use a conversion ratio of 1:2 mg forparenteral to oral methadone(e.g., 5 mg parenteralmethadone to 10 mg oral methadone).

2.5 Titration and Maintenance of Therapy for Pain

Individually titrate Methadone Hydrochloride Tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Methadone Hydrochloride Tablets to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as reassessing for the development of addiction, abuse, or misuse

[see Warnings and Precautions (5.1,5.16)].

Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. caregiver/family during periods of changing analgesic requirements, including initial titration. During use of opioid therapy for an extended period of time, periodically reassess the continued need for the use of opioid analgesics.

Patients who experience breakthrough pain may require a dose increase of Methadone Hydrochloride Tablets or may need rescue medication with an appropriate dose of an immediate-release analgesic. If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the Methadone Hydrochloride Tablets dosage.

Because of individual variability in the pharmacokinetic profile (i.e., terminal half-life (T1/2) from 8 to 59 hours in different studies

[see Clinical Pharmacology (12.3)]

, titrate Methadone Hydrochloride Tablets slowly, with dose increases no more frequent than every 3 to 5 days. However, because of this high variability, some patients may require substantially longer periods between dose increases (up to 12 days). Monitor patients closely for the development of potentially life- threatening adverse reactions (e.g., CNS and respiratory depression).

If after increasing the dosage, unacceptable opioid-related adverse reactions are observed, (including an increase in pain after dosage increase), consider reducing the dosage [see Warnings and Precautions (5)]. Adjust the dose to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

2.6 Safe Reduction and Discontinuation of Methadone Hydrochloride Tablets for Pain

Do not abruptly discontinue Methadone Hydrochloride Tablets in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances.

When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking Methadone Hydrochloride Tablets , there are a variety of factors that should be considered, including the total daily dose of opioid (including Methadone Hydrochloride Tablets) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow- up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with co-morbid pain and substance use disorders may benefit from referral to a specialist.

There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient- specific plan to taper the dose of the opioid gradually. For patients on Methadone Hydrochloride Tablets who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper.

It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include 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. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances.

When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic

[see Warnings and Precautions (5.16),

Drug Abuse and Dependence (9.3)].

2.7 Induction/Initial Dosing for Detoxification and Maintenance Treatment of Opioid Addiction

Fordetoxification andmaintenance of opioid dependence,methadoneshould be administered in accordance with the treatmentstandardscited in 42 CFRSection 8.12,including limitations on unsupervisedadministration.

Administer the initial methadone dose under supervision, when there are no signs of sedation or intoxication, and the patient shows symptoms of withdrawal. An initial single dose of 20 to 30 mg of Methadone Hydrochloride Tablets will often be sufficient to suppress withdrawal symptoms. The initial dose should not exceed 30 mg.

To make same-day dosing adjustments, have the patient wait 2 to 4 hours for further evaluation, when peak levels have been reached. Provide an additional 5 to 10 mg of Methadone Hydrochloride Tablets if withdrawal symptoms have not been suppressed or if symptoms reappear.

The total daily dose of Methadone Hydrochloride Tablets on the first day of treatment should not ordinarily exceed 40 mg. Adjust the dose over the first week of treatment based on control of withdrawal symptoms at the time of expected peak activity (e.g., 2 to 4 hours after dosing). When adjusting the dose, keep in mind that methadone levels will accumulate over the first several days of dosing; deaths have occurred in early treatment due to the cumulative effects. Instruct patients that the dose will “hold” for a longer period of time as tissue stores of methadone accumulate.

Use lower initial doses for patients whose tolerance is expected to be low at treatment entry. Any patient who has not taken opioids for more than 5 days may no longer be tolerant. Do not determine initial doses based on previous treatment episodes or dollars spent per day on illicit drug use.

During the induction phase of methadone maintenance treatment, patients are being withdrawn from opioids and may have opioid withdrawal symptoms. Monitor patients for signs and symptoms of opioid withdrawal 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.

Short-term Detoxification

For a brief course of stabilization followed by a period of medically supervised withdrawal, titrate the patient to a total daily dose of about 40 mg in divided doses to achieve an adequate stabilizing level. After 2 to 3 days of stabilization, gradually decrease the dose of Methadone Hydrochloride Tablets . Decrease the dose of Methadone Hydrochloride Tablets on a daily basis or at 2-day intervals, keeping the amount of Methadone Hydrochloride Tablets sufficient to keep withdrawal symptoms at a tolerable level. Hospitalized patients may tolerate a daily reduction of 20% of the total daily dose. Ambulatory patients may need a slower schedule.

2.8 Titration and Maintenance Treatment of Opioid Dependence

Titrate patients in maintenance treatment to a dose that prevents opioid withdrawal symptoms for 24 hours, reduces drug hunger or craving, and blocks or attenuates the euphoric effects of self-administered opioids, ensuring that the patient is tolerant to the sedative effects of methadone. Most commonly, clinical stability is achieved at doses between 80 to 120 mg/day. During prolonged administration of methadone, monitor patients for persistent constipation and manage accordingly.

2.9 Medically Supervised Withdrawal after a Period of Maintenance Treatment for Opioid Addiction

There is considerable variability in the appropriate rate of methadone taper in patients choosing medically supervised withdrawal from methadone treatment. Dose reductions should generally be less than 10% of the established tolerance or maintenance dose, and 10 to 14-day intervals should elapse between dose reductions. Apprise patients of the high risk of relapse to illicit drug use associated with discontinuation of methadone maintenance treatment.

2.10 Risk of Relapse in Patients on Methadone Maintenance Treatment of Opioid Addiction

Abrupt opioid discontinuation can lead to development of opioid withdrawal symptoms

[see Drug Abuse and Dependence (9.3)].

Opioid withdrawal symptoms have been associated with an increased risk of relapse to illicit drug use in susceptible patients.

2.11 Considerations for Management of Acute Pain during Methadone Maintenance Treatment

Patients in methadone maintenance treatment for opioid dependence who experience physical trauma, postoperative pain or other acute pain cannot be expected to derive analgesia from their existing dose of methadone. Such patients should be administered analgesics, including opioids, in doses that would otherwise be indicated for non-methadone-treated patients with similar painful conditions. When opioids are required for management of acute pain in methadone maintenance patients, somewhat higher and/or more frequent doses will often be required than would be the case for non-tolerant patients due to the opioid tolerance induced by methadone.

2.12 Dosage Adjustment During Pregnancy

Methadone clearance may be increased during pregnancy. During pregnancy, a woman's methadone dose may need to be increased or the dosing interval decreased

[see Use in Specific Populations (8.1)].