Label: METHADONE HYDROCHLORIDE - methadone hydrochloride tablet
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- Packager: Aurolife Pharma, LLC
- Category: HUMAN PRESCRIPTION DRUG LABEL
- DEA Schedule: CII
- Marketing Status: Abbreviated New Drug Application
Updated July 15, 2015
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- BOXED WARNING(What is this?)
WARNING: ADDICTION, ABUSE AND MISUSE; LIFE-THREATENING RESPIRATORYDEPRESSION; ACCIDENTAL INGESTION; LIFE-THREATENING QT PROLONGATION; NEONATALOPIOID WITHDRAWAL SYNDROME; and TREATMENT FOR OPIOID ADDICTION
Addiction, Abuse, and Misuse
Methadone hydrochloride tablets exposes patients and other users to therisks of opioid addiction, abuse, and misuse, which can lead to overdose anddeath. Assess each patient's risk prior to prescribing methadone hydrochloridetablets, and monitor all patients regularly for the development of thesebehaviors or conditions [see Warnings and Precautions (5.1)].
Life-threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression may occurwith use of methadone hydrochloride tablets. Monitor for respiratorydepression, especially during initiation of methadone hydrochloride tablets orfollowing a dose increase [see Warnings and Precautions (5.2)].
Accidental ingestion of even one dose of methadone hydrochloridetablets, especially by children, can result in a fatal overdose of methadone [see Warnings and Precautions (5.2)].
Life-threatening QT Prolongation
QTinterval prolongation and serious arrhythmia (torsades de pointes) haveoccurred during treatment with methadone. Most cases involve patients beingtreated for pain with large, multiple daily doses of methadone, although caseshave been reported in patients receiving doses commonly used for maintenancetreatment of opioid addiction. Closely monitor patients for changes in cardiacrhythm during initiation and titration of methadone hydrochloride tablets [see Warnings and Precautions (5.3)].
Neonatal Opioid Withdrawal Syndrome
Prolonged use of methadone hydrochloride tablets during pregnancy canresult in neonatal opioid withdrawal syndrome, which may be life-threatening ifnot recognized and treated, and requires management according to protocolsdeveloped by neonatology experts. If opioid use is required for a prolongedperiod in a pregnant woman, advise the patient of the risk of neonatal opioidwithdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.4)].
Conditions For Distribution And Use Of Methadone Products For TheTreatment Of Opioid Addiction
Fordetoxification and maintenance of opioid dependence, methadone should beadministered in accordance with the treatment standards cited in 42 CFR Section8, including limitations on unsupervised administration [see Indications and Usage (1)].Close
- HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use methadone hydrochloride tablets safely and effectively. See full prescribing information for methadone hydrochloride tablets.
METHADONE Hydrochloride Tablets USP, for oral use, CII
Initial U.S. Approval: 1947
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFETHREATENING 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
- Methadone hydrochloride tablets exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk before prescribing, and monitor regularly for development of these behaviors or conditions. (5.1, 9)
- Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. (5.2)
- Accidental ingestion of methadone hydrochloride tablets, especially in children, can result in fatal overdose of methadone. (5.2)
- QT interval prolongation and serious arrhythmia (torsades de pointes) have occurred during treatment with methadone (5.3).
- 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. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available (5.4).
- Methadone products, when used for the treatment of opioid addiction in detoxification or maintenance programs, shall be dispensed only by certified opioid treatment programs as stipulated in 42 CFR 8.12. (1)
RECENT MAJOR CHANGES
Boxed Warning 04/2014
Indications and Usage (1) 04/2014
Dosage and Administration (2) 04/2015
Warnings and Precautions (5) 04/2014
INDICATIONS AND USAGE
Methadone hydrochloride tablets is an opioid agonist indicated for the: (1)
- Management of pain severe enough to require daily, around-theclock, long-term opioid treatment and for which alternative treatment options are inadequate. Limitations of Use
- Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with long-acting opioids, reserve methadone hydrochloride tablets for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.
- Methadone hydrochloride tablets is not indicated as an as-needed (prn) analgesic.
- Detoxification treatment of opioid addiction (heroin or other morphine-like drugs).
- Maintenance treatment of opioid addiction (heroin or other morphine-like drugs), in conjunction with appropriate social and medical services. (1)
DOSAGE AND ADMINISTRATION
- Management of Pain:
- For opioid naïve patients, initiate methadone hydrochloride tablets treatment with 2.5 mg every 8 to 12 hours. (2.2)
- Titrate slowly with dose increases no more frequent than every 3 to 5 days. (2.3)
- To convert to methadone hydrochloride tablets from another opioid, use available conversion factors to obtain estimated dose. (2.2)
- Initiation of Detoxification and Maintenance Treatment: A single dose of 20 to 30 mg may be sufficient to suppress withdrawal syndrome. (2.5)
- Do not abruptly discontinue methadone hydrochloride tablets in a physically dependent patient. (2.4, 5.12)
DOSAGE FORMS AND STRENGTHS
Tablets: 5 mg and 10 mg. (3) (3)
- Significant respiratory depression (4)
- Acute or severe bronchial asthma (4)
- Known or suspected paralytic ileus (4)
- Hypersensitivity to methadone (4)
WARNINGS AND PRECAUTIONS
- Respiratory Depression: The peak respiratory depressant effect typically occurs later, and persists longer than the peak analgesic effect. (5.2)
- May cause QT interval prolongation and serious arrhythmia. (5.3)
- Interactions with CNS depressants: Concomitant use may cause profound sedation, respiratory depression, and death. If coadministration is required, consider dose reduction of one or both drugs because of additive pharmacological effects. (5.5, 7.1)
- Elderly, cachectic, debilitated patients, and those with chronic pulmonary disease: Monitor closely because of increased risk for life-threatening respiratory depression. (5.6, 5.7)
- Hypotensive effect: Monitor during dose initiation and titration (5.8)
- Patients with head injury or increased intracranial pressure: Monitor for sedation and respiratory depression. Avoid use of methadone hydrochloride tablets in patients with impaired consciousness or coma susceptible to intracranial effects of CO2 retention. (5.9)
- CYP3A4 Inducers: Increased risk of more rapid metabolism and decreased effects of methadone. (7.2)
- CYP3A4 Inhibitors: Increased risk of reduced metabolism and methadone toxicity. (7.2)
- Anti-retroviral Agents: May result in increased clearance and decreased plasma levels of methadone or in certain cases, increased plasma levels and risk of toxicity. (7.2)
- Potentially Arrhythmogenic Agents: Extreme caution is necessary when any drug known to have the potential to prolong the QT interval is prescribed in conjunction with methadone. (7.3)
- Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid use with methadone hydrochloride tablets because they may reduce analgesic effect of methadone hydrochloride tablets or precipitate withdrawal symptoms. (5.12, 7.4)
USE IN SPECIFIC POPULATIONS
- Pregnancy: Based on animal data, may cause fetal harm. (8.1).
- Nursing mothers: Methadone has been detected in human milk. Closely monitor infants of nursing women receiving methadone hydrochloride tablets. (8.3 )
See 17 for PATIENT COUNSELING INFORMATION.
- FULL PRESCRIBING INFORMATION: CONTENTS*
- Sections or subsections omitted from the full prescribing information are not listed.
- 1 INDICATIONS & USAGE
Methadone hydrochloride tabletsUSP is indicated for the:
• Management of pain severe enough to require daily,around-the-clock, long-term opioid treatmentand for which alternative treatment options are inadequate.
Limitations of Use
• Because of the risks of addiction, abuse, and misusewith opioids, even at recommended doses, and because of the greater risks ofoverdose and death with long-acting opioids, reserve methadone hydrochloridetablets for use in patients for whom alternative analgesic treatment options(e.g., non-opioid analgesics or immediate-release opioid analgesics) areineffective, not tolerated, or would be otherwise inadequate to providesufficient management of pain.
• Methadone hydrochloride tablets is not indicated as anas-needed (prn) analgesic.
• Detoxification treatment of opioid addiction (heroin orother morphine-like drugs).
• Maintenance treatment of opioid addiction (heroin orother morphine-like drugs), in conjunction with appropriate social and medicalservices.
Conditions for Distribution and Use of Methadone Products for theTreatment of Opioid Addiction
Code of Federal Regulations,Title 42, Sec 8
Methadone products when used forthe 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 andapproved by the designated state authority. Certified treatment programs shalldispense and use methadone in oral form only and according to the treatmentrequirements stipulated in the Federal Opioid Treatment Standards (42 CFR8.12). See below for important regulatory exceptions to the general requirementfor certification to provide opioid agonist treatment.
Failure to abide by therequirements in these regulations may result in criminal prosecution, seizureof the drug supply, revocation of the program approval, and injunctionprecluding operation of the program.
Regulatory Exceptions To TheGeneral Requirement For Certification To Provide Opioid Agonist Treatment:During inpatient care, when the patient was admitted for any condition otherthan concurrent opioid addiction (pursuant to 21CFR 1306.07(c)), to facilitatethe treatment of the primary admitting diagnosis).
During an emergency period of no longer than 3 dayswhile definitive care for the addiction is being sought in an appropriatelylicensed facility (pursuant to 21CFR 1306.07(b)).Close
- 2 DOSAGE & 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.
2.2 Initial Dosing for Management of Pain
Methadone hydrochloride tablets should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.
Consider the following important factors that differentiate methadone from other opioid analgesics:
- There is high interpatient variability in absorption, metabolism, and relative analgesic potency. 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.
- 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 patients.
Initiate the dosing regimen for each patient individually, taking into account the patient's prior analgesic treatment experience and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)]. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with methadone hydrochloride tablets [see Warnings and Precautions (5.2)].
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.
Conversion from Other Oral Opioids to methadone hydrochloride tablets: Discontinue all other around-the-clock opioid drugs when methadone hydrochloride tablets therapy is initiated. Deaths have occurred in opioid-tolerant patients during conversion to methadone.
While there are useful tables of opioid equivalents readily available, there is substantial inter-patient variability in the relative potency of different opioid drugs and products. As such, it is safer to underestimate a patient's 24-hour oral methadone requirements and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour oral methadone requirements which could result in adverse reactions. With repeated dosing, the potency of methadone increases due to systemic accumulation.
Consider the following when using the information in Table 1:
- This is not a table of equinalgesic doses.
- The conversion factors in this table are only for the conversion from another oral opioid analgesic to methadone hydrochloride tablets.
- The table cannot be used to convert from methadone hydrochloride tablets to another opioid. Doing so will result in an overestimation of the dose of the new opioid and may result in fatal overdose.
Table 1: Conversion Factors to Methadone hydrochloride tablets
Total Daily Baseline Oral Morphine Equivalent Dose
Estimated Daily Oral Methadone Requirement as Percent of Total Daily Morphine Equivalent Dose
< 100 mg
100 to 300 mg
300 to 600 mg
600 mg to 1000 mg
> 1000 mg
20% to 30%
10% to 20%
8% to 12%
5% to 10%
< 5 %
To calculate the estimated methadone hydrochloride tablets dose using Table 1:
- For patients on a single opioid, sum the current total daily dose of the opioid, convert it to a Morphine Equivalent Dose according to specific conversion factor for that specific opioid, then multiply the Morphine Equivalent Dose by the corresponding percentage in the above table to calculate the approximate oral methadone daily dose. Divide the total daily methadone dose derived from the table above to reflect the intended dosing schedule (i.e., for administration every 8 hours, divide total daily methadone dose by 3).
- For patients on a regimen of more than one opioid, calculate the approximate oral methadone dose for each opioid and sum the totals to obtain the approximate total methadone daily dose. Divide the total daily methadone dose derived from the table above to reflect the intended dosing schedule (i.e., for administration every 8 hours, divide total daily methadone dose by 3).
- For patients on a regimen of fixed-ratio opioid/non-opioid analgesic products, 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 daily dose of the opioid (in this case, Morphine Extended Release Tablets 50 mg twice daily)
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 total daily dose of Morphine x 15% (10% to 20% per Table 1) = 15 mg methadone hydrochloride tablets daily
Step 3: Calculate the approximate starting dose of methadone hydrochloride tablets to be given every 12 hours. Round down, if necessary, to the appropriate methadone hydrochloride tablets strengths available.
15 mg daily / 2 = 7.5 mg methadone hydrochloride tablets every 12 hours
Then 7.5 mg is rounded down to 5 mg methadone hydrochloride tablets every 12 hours
Close observation and frequent titration are warranted until pain management is stable on the new opioid. Monitor patients for signs and symptoms of opioid withdrawal or for signs of over-sedation/toxicity after converting patients to methadone hydrochloride tablets.
Conversion from Parenteral Methadone to methadone hydrochloride tablets: Use a conversion ratio of 1:2 mg for parenteral to oral methadone (e.g., 5 mg parenteral methadone to 10 mg oral methadone).
2.3 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 and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse. 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. During chronic therapy, periodically reassess the continued need for the use of opioid analgesics.
Because of individual variability in the pharmacokinetic profile (i.e., terminal half-life (T 1/2) 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). 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 medication. If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the methadone hydrochloride tablets dose.
If unacceptable opioid-related adverse reactions are observed, the subsequent doses may be reduced and/or the dosing interval adjusted (i.e., every 8 hours or every 12 hours). Adjust the dose to obtain an appropriate balance between management of pain and opioid-related adverse reactions
2.4 Discontinuation of methadone hydrochloride tablets for Pain
When a patient no longer requires therapy with methadone hydrochloride tablets for pain, use a gradual downward titration, of the dose every two to four days, to prevent signs and symptoms of withdrawal in the physically-dependent patient. Do not abruptly discontinue methadone hydrochloride tablets.
2.5 Induction/Initial Dosing for Detoxification and Maintenance 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 8.12, including limitations on unsupervised administration.
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.
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.
2.6 Titration and Maintenance Treatment of Opioid Dependence Detoxification
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.
2.7 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.
2.8 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.
2.9 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.
2.10 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. Methadone should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.1)].
- 3 DOSAGE FORMS & STRENGTHS
Methadone Hydrochloride Tablets are available in 5mg and 10 mg dosage strengths. The 5 mg tablets are White to off white, round tablets debossed with 'U41' on one side and break line on the other side .The 10 mg tablets are White to off white, round tablets debossed with 'U42' on one side and break line on the other side.Close
- 4 CONTRAINDICATIONS
Methadone hydrochloride tablets is contraindicated inpatients with:
• Significant respiratory depression
• Acute or severe bronchial asthma in an unmonitoredsetting or in the absence of resuscitative equipment
• Known or suspected paralytic ileus
• Hypersensitivity (e.g., anaphylaxis) to methadone [see Adverse Reactions (6)].Close
- 5 WARNINGS AND PRECAUTIONS
5.1 Addiction, Abuse and Misuse
Methadone hydrochloride tablets contains methadone, a Schedule II controlled substance. As an opioid, methadone hydrochloride tablets exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9)]. 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.
Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed methadone hydrochloride tablets and in those who obtain the drug illicitly. Addiction can occur at recommended doses and if the drug is misused or abused.
Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing methadone hydrochloride tablets, and monitor all patients receiving methadone hydrochloride tablets for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol addiction or abuse) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the prescribing of methadone hydrochloride tablets for the proper management of pain in any given patient. Patients at increased risk may be prescribed long-acting opioids such as methadone hydrochloride tablets, but use in such patients necessitates intensive counseling about the risks and proper use of methadone hydrochloride tablets along with the intensive monitoring for signs of addiction, abuse, and misuse.
Abuse or misuse of methadone hydrochloride tablets by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of the methadone and can result in overdose and death [see Overdose (10)].
Opioid agonists such as methadone hydrochloride tablets are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing methadone hydrochloride tablets. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see Patient 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.
5.2 Life Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression has been reported with the use of long-acting opioids, even when used as recommended. Respiratory depression from opioid use, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status [see Overdosage (10)]. Carbon dioxide (CO 2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of methadone hydrochloride tablets, the risk is greatest during the initiation of therapy or following a dose increase. The peak respiratory depressant effect of methadone occurs later, and persists longer than the peak analgesic effect, especially during the initial dosing period. Closely monitor patients for respiratory depression when initiating therapy with 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 dose when converting patients from another opioid product can result in fatal overdose with the first dose.
Accidental ingestion of even one dose of methadone hydrochloride tablets, especially by children, can result in respiratory depression and death due to overdose of methadone.
5.3 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.
5.4 Neonatal Opioid Withdrawal Syndrome
Prolonged use of methadone hydrochloride tablets during pregnancy can result in withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.
Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn [see Use in Special Populations (8.1)].
5.5 Interactions with Central Nervous System Depressants
Hypotension, profound sedation, coma, respiratory depression, and death may result if methadone hydrochloride tablets is used concomitantly with alcohol or other central nervous system (CNS) depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids).
When considering the use of methadone hydrochloride tablets in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient's response, including the degree of tolerance that has developed to CNS depression. Additionally, evaluate the patient's use of alcohol or illicit drugs that cause CNS depression. If the decision to begin methadone hydrochloride tablets is made, start with methadone hydrochloride tablets 2.5 mg every 12 hours, monitor patients for signs of sedation and respiratory depression, and consider using a lower dose of the concomitant CNS depressant [see Drug Interactions (7.1)].
5.6 Use in Elderly, Cachectic, and Debilitated Patients
Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. Monitor such patients closely, particularly when initiating and titrating methadone hydrochloride tablets and when methadone hydrochloride tablets is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2)].
5.7 Use in Patients with Chronic Pulmonary Disease
Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression for respiratory depression, particularly when initiating therapy and titrating with methadone hydrochloride tablets, as in these patients, even usual therapeutic doses of methadone hydrochloride tablets may decrease respiratory drive to the point of apnea [see Warnings and Precautions (5.2)]. Consider the use of alternative non-opioid analgesics in these patients if possible.
5.8 Hypotensive Effect
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 (7.1)]. Monitor these patients for signs of hypotension after initiating or titrating the dose of methadone hydrochloride tablets.
5.9 Use in Patients with Head Injury or Increased Intracranial Pressure
Monitor patients taking methadone hydrochloride tablets who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors) for signs of sedation and respiratory depression, particularly when initiating therapy with methadone hydrochloride tablets. Methadone hydrochloride tablets may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Opioids may also obscure the clinical course in a patient with a head injury.
Avoid the use of methadone hydrochloride tablets in patients with impaired consciousness or coma.
5.10 Use in Patients with Gastrointestinal Conditions
Methadone hydrochloride tablets is contraindicated in patients with paralytic ileus. Avoid the use of Methadone hydrochloride tablets in patients with other gastrointestinal obstruction.
The methadone in methadone hydrochloride tablets may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. Opioids may cause increases in the serum amylase.
5.11 Use in Patients with Convulsive or Seizure Disorders
The methadone in methadone hydrochloride tablets may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings. Monitor patients with a history of seizure disorders for worsened seizure control during methadone hydrochloride tablets therapy.
5.12 Avoidance of Withdrawal
Avoid the use of mixed agonist/antagonist (i.e., pentazocine, nalbuphine, and butorphanol) and partial agonist (buprenorphine) analgesics in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including methadone hydrochloride tablets. In these patients, mixed agonists/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms [see Drug Interactions (7.4)].
When discontinuing methadone hydrochloride tablets, gradually taper the dose [see Dosage and Administration (2.4)]. Do not abruptly discontinue methadone hydrochloride tablets.
5.13 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.
- 6 ADVERSE REACTIONS
The following serious adversereactions 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[seeWarnings 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 [seeWarnings and Precautions (5.8)]
• Gastrointestinal Effects [see Warnings and Precautions (5.10)]
• Seizures [seeWarnings and Precautions (5.11)]
The major hazards of methadone are respiratory depression and, to alesser degree, systemic hypotension. Respiratory arrest, shock, cardiac arrest,and death have occurred.
The most frequently observedadverse reactions include lightheadedness, dizziness, sedation, nausea,vomiting, and sweating. These effects seem to be more prominent in ambulatorypatients and in those who are not suffering severe pain. In such individuals,lower doses are advisable.
Other adverse reactions includethe 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-waveinversion, 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 inopioid addicts with chronic hepatitis
Metabolic: hypokalemia, hypomagnesemia, weight gain
Renal: antidiuretic effect, urinary retention or hesitancy
Reproductive: amenorrhea, reduced libido and/or potency, reducedejaculate volume, reduced seminal vesicle and prostate secretions, decreasedsperm motility, abnormalities in sperm morphology
Respiratory: pulmonary edema, respiratory depression
Skin and Subcutaneous Tissue:pruritus, urticaria, other skin rashes, and rarely, hemorrhagic urticarial
Hypersensitivity: Anaphylaxis has been reported with ingredientscontained in methadone hydrochloride tablets. Advise patients how to recognizesuch a reaction and when to seek medical attention.
Maintenance on a Stabilized Dose: During prolonged administrationof methadone, as in a methadone maintenance treatment program, constipation andsweating often persist and hypogonadism, decreased serum testosterone andreproductive effects are thought to be related to chronic opioid use.
Methadone hydrochloride tabletsfor the Detoxification and Maintenance Treatment of Opioid Dependence: Duringthe induction phase of methadone maintenance treatment, patients are beingwithdrawn from illicit opioids and may have opioid withdrawal symptoms. Monitorpatients for signs and symptoms including: lacrimation, rhinorrhea, sneezing,yawning, excessive perspiration, goose-flesh, fever, chilling alternating withflushing, restlessness, irritability, weakness, anxiety, depression, dilatedpupils, tremors, tachycardia, abdominal cramps, body aches, involuntarytwitching and kicking movements, anorexia, nausea, vomiting, diarrhea,intestinal spasms, and weight loss and consider dose adjustment as indicated.Close
- 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 [Warnings and Precautions (5.5)].
Deaths have been reported when methadone has been abused in conjunction with benzodiazepines.
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 antiretroviral agents 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 is used concurrently with anticholinergic drugs.
7.7 Laboratory Test Interactions
False positive urine drug screens for methadone have been reported for several drugs including diphenhydramine, doxylamine, clomipramine, chlorpromazine, thioridazine, quetiapine, and verapamil.
- 8 USE IN SPECIFIC POPULATIONS
Clinical Considerations:Fetal/neonatal adverse reactions:Prolonged use of opioid analgesics during pregnancy for medical or nonmedicalpurposes can result in physical dependence in the neonate and neonatal opioidwithdrawal syndrome shortly after birth. Observe newborns for symptoms ofneonatal 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 noadequate and well controlled studies in pregnant women. Methadone hydrochloridetablets should be used during pregnancy only if the potential benefit justifiesthe potential risk to the fetus.
Methadone has been shown to beteratogenic in the hamster at doses 2 times the human daily oral dose (120mg/day on a mg/m2 basis) and in mice at doses equivalent to the human dailyoral dose (120 mg/day on a mg/m2 basis). Increased neonatal mortality andsignificant differences in behavioral tests have been reported in the offspringof male rodents that were treated with methadone prior to mating when comparedto control animals. Methadone has been detected in human amniotic fluid and cordplasma at concentrations proportional to maternal plasma and in newborn urineat lower concentrations than corresponding maternal urine.
Dosage Adjustment during Pregnancy: The disposition of oralmethadone has been studied in approximately 30 pregnant patients in 2nd and 3rdtrimesters. Total body clearance of methadone was increased in pregnantpatients compared to the same patients postpartum or to non-pregnantopioid-dependent women. The terminal half-life of methadone is decreased during2nd and 3rd trimesters. The decrease in plasma half-life and increasedclearance of methadone resulting in lower methadone trough levels duringpregnancy can lead to withdrawal symptoms in some pregnant patients. The dosagemay need to be increased or the dosing interval decreased in pregnant patientsreceiving methadone to achieve therapeutic effect [see Dosage and Administration (2.10)].
Effects on the Neonate: Babies born to mothers who have been takingopioids regularly prior to delivery may be physically dependent. Onset ofwithdrawal 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, andseizures. The intensity of the neonatal withdrawal syndrome does not alwayscorrelate with the maternal dose or the duration of maternal exposure. Theduration of the withdrawal signs may vary from a few days to weeks or evenmonths. There is no consensus on the appropriate management of infantwithdrawal [see Warnings andPrecautions (5.4)].
Human Data: Reported studies have generally compared the benefit ofmethadone to the risk of untreated addiction to illicit drugs; the relevance ofthese findings to pain patients prescribed methadone during pregnancy isunclear. Pregnant women involved in methadone maintenance programs have beenreported to have significantly improved prenatal care leading to significantlyreduced incidence of obstetric and fetal complications and neonatal morbidityand mortality when compared to women using illicit drugs. Several factors,including maternal use of illicit drugs, nutrition, infection and psychosocialcircumstances, complicate the interpretation of investigations of the childrenof women who take methadone during pregnancy. Information is limited regardingdose and duration of methadone use during pregnancy, and most maternal exposureappears to occur after the first trimester of pregnancy.
A review of published data onexperiences with methadone use during pregnancy by the Teratogen InformationSystem (TERIS) concluded that maternal use of methadone during pregnancy aspart of a supervised, therapeutic regimen is unlikely to pose a substantialteratogenic risk (quantity and quality of data assessed as “limited to fair”).However, the data are insufficient to state that there is no risk (TERIS, lastreviewed October, 2002). A retrospective case series of 101 pregnant,opioid-dependent women who underwent inpatient opioid detoxification withmethadone did not demonstrate any increased risk of miscarriage in the 2ndtrimester or premature delivery in the 3rd trimester. Recent studies suggest anincreased risk of premature delivery in opioid-dependent women exposed tomethadone during pregnancy, although the presence of confounding factors makesit difficult to determine a causal relationship. Several studies have suggestedthat infants born to narcotic-addicted women treated with methadone during allor part of pregnancy have been found to have decreased fetal growth withreduced birth weight, length, and/or head circumference compared to controls.This growth deficit does not appear to persist into later childhood. Childrenprenatally exposed to methadone have been reported to demonstrate mild butpersistent deficits in performance on psychometric and behavioral tests. Inaddition, several studies suggest that children born to opioid-dependent womenexposed to methadone during pregnancy may have an increased risk of visualdevelopment anomalies; however, a causal relationship has not been assigned.
There are conflicting reports onwhether Sudden Infant Death Syndrome occurs with an increased incidence ininfants born to women treated with methadone during pregnancy. Abnormal fetalnon-stress tests have been reported to occur more frequently when the test isperformed 1 to 2 hours after a maintenance dose of methadone in late pregnancycompared to controls.
Animal Data: Methadone did not produce teratogenic effects in rator rabbit models. Methadone produced teratogenic effects following large doses,in the guinea pig, hamster and mouse. One published study in pregnant hamstersindicated that a single subcutaneous dose of methadone ranging from 31 to 185mg/kg (the 31 mg/kg dose is approximately
2 times a human daily oral doseof 120 mg/day on a mg/m2 basis) on day 8 of gestation resulted in a decrease inthe number of fetuses per litter and an increase in the percentage of fetusesexhibiting congenital malformations described as exencephaly, cranioschisis,and “various other lesions.” The majority of the doses tested also resulted inmaternal death. In another study, a single subcutaneous dose of 22 to 24 mg/kgmethadone (estimated exposure was approximately equivalent to a human dailyoral dose of 120 mg/day on a mg/m2 basis) administered on day 9 of gestation inmice also produced exencephaly in 11% of the embryos. However, no effects werereported in rats and rabbits at oral doses up to
40 mg/kg (estimated exposure wasapproximately 3 and 6 times, respectively, a human daily oral dose of 120mg/day on a mg/m2 basis) administered during days 6 to 15 and 6 to 18,respectively.
Published animal data havereported increased neonatal mortality in the offspring of male rodents thatwere treated with methadone prior to mating. In these studies, the femalerodents were not treated with methadone, indicating paternally-mediateddevelopmental toxicity. Specifically, methadone administered to the male ratprior to mating with methadone-naïve females resulted in decreased weight gainin progeny after weaning. The male progeny demonstrated reduced thymus weights,whereas the female progeny demonstrated increased adrenal weights. Behavioraltesting of these male and female progeny revealed significant differences inbehavioral tests compared to control animals, suggesting that paternalmethadone exposure can produce physiological and behavioral changes in progenyin this model. Other animal studies have reported that perinatal exposure toopioids including methadone alters neuronal development and behavior in theoffspring. Perinatal methadone exposure in rats has been linked to alterationsin learning ability, motor activity, thermal regulation, nociceptive responsesand sensitivity to drugs.
Additional animal datademonstrates evidence for neurochemical changes in the brains ofmethadone-treated offspring, including changes to the cholinergic,dopaminergic, noradrenergic and serotonergic systems. Studies demonstrated thatmethadone treatment of male rats for 21 to 32 days prior to mating withmethadone-naïve females did not produce any adverse effects, suggesting thatprolonged methadone treatment of the male rat resulted in tolerance to thedevelopmental toxicities noted in the progeny. Mechanistic studies in this ratmodel suggest that the developmental effects of “paternal” methadone on theprogeny appear to be due to decreased testosterone production. These animaldata mirror the reported clinical findings of decreased testosterone levels inhuman males on methadone maintenance therapy for opioid addiction and in malesreceiving chronic intraspinal opioids.
Additional data have beenpublished indicating that methadone treatment of male rats (once a day forthree consecutive days) increased embryolethality and neonatal mortality.Examination of uterine contents of methadone-naïve female mice bred tomethadone-treated mice indicated that methadone treatment produced an increasein the rate of preimplantation deaths in all post-meiotic states.
8.2 Labor & Delivery
Opioids cross the placenta andmay produce respiratory depression in neonates. methadone hydrochloride tabletsis not for use in women during and immediately prior to labor, when shorteracting analgesics or other analgesic techniques are more appropriate. Opioidanalgesics can prolong labor through actions that temporarily reduce thestrength, duration, and frequency of uterine contractions. However this effectis not consistent and may be offset by an increased rate of cervicaldilatation, which tends to shorten labor.
8.3 Nursing Mothers
Methadone is secreted into humanmilk. At maternal oral doses of 10 to 80 mg/day, methadone concentrations from50 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. Peakmethadone 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 consumeapproximately 17.4 mcg/kg/day which is approximately 2 to 3% of the oralmaternal dose. Methadone has been detected in very low plasma concentrations insome infants whose mothers were taking methadone. Cases of sedation andrespiratory depression in infants exposed to methadone through breast milk havebeen reported. Caution should be exercised when methadone is administered to anursing woman.
Advise women who are beingtreated with methadone and who are breastfeeding or express a desire tobreastfeed of the presence of methadone in human milk. Instruct breastfeedingmothers how to identify respiratory depression and sedation in their babies andwhen it may be necessary to contact their healthcare provider or seek immediatemedical care. Breastfed infants of mothers using methadone should be weanedgradually to prevent development of withdrawal symptoms in the infant.
8.4 Pediatric Use
The safety, effectiveness, andpharmacokinetics of methadone in pediatric patients below the age of 18 yearshave not been established.
8.5 Geriatric Use
Clinical studies of methadone didnot include sufficient numbers of subjects aged 65 and over to determinewhether they respond differently compared to younger subjects. Other reportedclinical experience has not identified differences in responses between elderlyand younger patients. In general, start elderly patients at the low end of thedosing range, taking into account the greater frequency of decreased hepatic,renal, or cardiac function and of concomitant disease or other drug therapy ingeriatric patients. Closely monitor elderly patients for signs of respiratoryand central nervous system depression.
8.6 Renal Impairment
Methadone pharmacokinetics havenot been extensively evaluated in patients with renal insufficiency. Sinceunmetabolized methadone and its metabolites are excreted in urine to a variabledegree, start these patients on lower doses and with longer dosing intervalsand titrate slowly while carefully monitoring for signs of respiratory andcentral nervous system depression.
8.7 Hepatic Impairment
Methadone has not beenextensively evaluated in patients with hepatic insufficiency. Methadone ismetabolized by hepatic pathways; therefore, patients with liver impairment maybe at risk of increased systemic exposure to methadone after multiple dosing.Start these patients on lower doses and titrate slowly while carefullymonitoring for signs of respiratory and central nervous system depression.
- 9 DRUG ABUSE AND DEPENDENCE
9.1 Controlled Substance
Methadone is a mu-agonist opioidwith an abuse liability similar to other opioid agonists and is a Schedule IIcontrolled substance. Methadone can be abused and is subject to misuse,addiction, and criminal diversion [seeWarnings and Precautions (5.1)].
All patients treated with opioidsfor pain management require careful monitoring for signs of abuse andaddiction, since use of opioid analgesic products carries the risk of addictioneven under appropriate medical use.
Drug abuse is the intentionalnon-therapeutic use of an over-the-counter or prescription drug, even once, forits rewarding psychological or physiological effects. Drug abuse includes, butis not limited to the following examples: the use of a prescription or over-thecounter drug to get “high”, or the use of steroids for performance enhancementand muscle build up.
Drug addiction is a cluster ofbehavioral, cognitive, and physiological phenomena that develop after repeatedsubstance use and include: a strong desire to take the drug, difficulties incontrolling its use, persisting in its use despite harmful consequences, ahigher priority given to drug use than to other activities and obligations,increased tolerance, and sometimes a physical withdrawal.
“Drug-seeking” behavior is verycommon in addicts and drug abusers. Drug-seeking tactics include emergencycalls or visits near the end of office hours, refusal to undergo appropriateexamination, testing or referral, repeated claims of lost prescriptions,tampering with prescriptions and reluctance to provide prior medical records orcontact information for other treating physician(s). “Doctor shopping”(visiting multiple prescribers) to obtain additional prescriptions is commonamong drug abusers and people suffering from untreated addiction. Preoccupationwith achieving adequate pain relief can be appropriate behavior in a patientwith poor pain control.
Abuse and addiction are separateand distinct from physical dependence and tolerance. Physicians should be awarethat addiction may not be accompanied by concurrent tolerance and symptoms ofphysical dependence in all addicts. In addition, abuse of opioids can occur inthe absence of true addiction.
Methadone hydrochloride tablets,like other opioids, can be diverted for non-medical use into illicit channelsof distribution. Careful record-keeping of prescribing information, includingquantity, frequency, and renewal requests, as required by state law, isstrongly advised.
Risks Specific to Abuse of methadone hydrochloride tablets: Abuseof methadone hydrochloride tablets poses a risk of overdose and death. Thisrisk is increased with concurrent abuse of methadone and alcohol or othersubstances. methadone hydrochloride tablets is for oral use only and must notbe injected. Parenteral drug abuse is commonly associated with transmission ofinfectious diseases such as hepatitis and HIV.
Proper assessment and selectionof the patient, proper prescribing practices, periodic re-evaluation oftherapy, and proper dispensing and storage are appropriate measures that helpto limit abuse of opioid drugs.
Both tolerance and physicaldependence can develop during chronic opioid therapy. Tolerance is the need forincreasing doses of opioids to maintain a defined effect such as analgesia (inthe absence of disease progression or other external factors). Tolerance mayoccur to both the desired and undesired effects of drugs, and may develop atdifferent rates for different effects.
Physical dependence results inwithdrawal symptoms after abrupt discontinuation or a significant dosereduction of a drug. Withdrawal also may be precipitated through theadministration of drugs with opioid antagonist activity, e.g., naloxone, mixedagonist/ antagonist analgesics (pentazocine, butorphanol, nalbuphine), orpartial agonists (buprenorphine). Physical dependence may not occur to aclinically significant degree until after several days to weeks of continuedopioid usage.
Methadone hydrochloride tabletsshould not be abruptly discontinued [seeDosage and Administration (2.4)]. If methadone hydrochloride tablets isabruptly discontinued in a physically dependent patient, an abstinence syndromemay 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, includingirritability, 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)].
- 10 OVERDOSAGE
Acute overdosage of methadone ismanifested 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, particularlyby the intravenous route, apnea, circulatory collapse, cardiac arrest, anddeath may occur.
Treatment of Overdose
In case of overdose, prioritiesare the re-establishment of a patent and protected airway and institution ofassisted or controlled ventilation if needed. Employ other supportive measures(including oxygen, vasopressors) in the management of circulatory shock andpulmonary edema as indicated. Cardiac arrest or arrhythmias will requireadvanced life support techniques.
The opioid antagonists, such asnaloxone, are specific antidotes to respiratory depression resulting fromopioid overdose. Opioid antagonists should not be administered in the absenceof clinically significant respiratory or circulatory depression secondary tomethadone overdose. Such agents should be administered cautiously to patientswho are known, or suspected to be, physically dependent on methadonehydrochloride tablets. In such cases, an abrupt or complete reversal of opioideffects may precipitate an acute withdrawal syndrome.
Because the duration of reversalwould be expected to be less than the duration of action of methadone inmethadone hydrochloride tablets, carefully monitor the patient untilspontaneous respiration is reliably re-established. If the response to opioidantagonists is suboptimal or not sustained, additional antagonist should begiven as directed in the product's prescribing information.
In an individual physicallydependent on opioids, administration of an opioid receptor antagonist mayprecipitate an acute withdrawal. The severity of the withdrawal produced willdepend on the degree of physical dependence and the dose of the antagonistadministered. If a decision is made to treat serious respiratory depression inthe physically dependent patient, administration of the antagonist should bebegun with care and by titration with smaller than usual doses of theantagonist.Close
- 11 DESCRIPTION
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. Its molecular formula is C21H27NO• HCl and it has a molecular weight of 345.91. 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 Tablets tablet contains 5 or 10 mg of methadone hydrochloride, USP and the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, pregelatinized starch (physically modified corn (maize) starch), colloidal silicon dioxide and magnesium stearate.Close
- 12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Methadone hydrochloride is amu-agonist; a synthetic opioid analgesic with multiple actions qualitativelysimilar to those of morphine, the most prominent of which involves the centralnervous system and organs composed of smooth muscle. The principal therapeuticuses for methadone are for analgesia and for detoxification or maintenance inopioid addiction. The methadone withdrawal syndrome, although qualitativelysimilar to that of morphine, differs in that the onset is slower, the course ismore prolonged, and the symptoms are less severe.
Some data also indicate thatmethadone acts as an antagonist at the N-methyl-D-aspartate (NMDA) receptor.The contribution of NMDA receptor antagonism to methadone's efficacy isunknown. Other NMDA receptor antagonists have been shown to produce neurotoxiceffects in animals.
Absorption: Following oral administration the bioavailability ofmethadone ranges between 36 to 100% and peak plasma concentrations are achievedbetween 1 to 7.5 hours. Dose proportionality of methadone pharmacokinetics isnot known. However, after administration of daily oral doses ranging from 10 to225 mg, the steady-state plasma concentrations ranged between 65 to 630 ng/mLand the peak concentrations ranged between 124 to 1255 ng/mL. Effect of food onthe bioavailability of methadone has not been evaluated.
Distribution: Methadone is a lipophilic drug and the steady-statevolume of distribution ranges between 1.0 to 8.0 L/kg. In plasma, methadone ispredominantly bound to α1-acid glycoprotein (85% to 90%). Methadone is secretedin saliva, breast milk, amniotic fluid and umbilical cord plasma.
Metabolism: Methadone is primarily metabolized by N-demethylationto an inactive metabolite, 2-ethylidene-1,5dimethyl-3,3-diphenylpyrrolidene(EDDP). Cytochrome P450 enzymes, primarily CYP3A4, CYP2B6, and CYP2C19 and to alesser extent CYP2C9 and CYP2D6, are responsible for conversion of methadone toEDDP and other inactive metabolites, which are excreted mainly in the urine.Methadone appears to be a substrate for P-glycoprotein but its pharmacokineticsdo not appear to be significantly altered in case of P-glycoproteinpolymorphism or inhibition.
Excretion: The elimination of methadone is mediated by extensivebiotransformation, followed by renal and fecal excretion. Published reportsindicate that after multiple dose administration the apparent plasma clearanceof methadone ranged between 1.4 and
126 L/h, and the terminalhalf-life (T 1/2) was highly variable and ranged between 8 to 59 hours indifferent studies. Methadone is a basic (pKa=9.2) compound and the pH of the urinarytract 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 releasefrom the liver and other tissues may prolong the duration of methadone actiondespite low plasma concentrations.
Drug Interactions: Cytochrome P450 Interactions: Methadoneundergoes hepatic
N-demethylation by cytochromeP450 (CYP) isoforms, principally CYP3A4, CYP2B6, CYP2C19, and to a lesserextent by CYP2C9 and CYP2D6. Coadministration of methadone with CYP inducersmay result in more rapid metabolism and potential for decreased effects ofmethadone, whereas administration with CYP inhibitors may reduce metabolism andpotentiate methadone's effects. Although antiretroviral drugs such as efavirenz,nelfinavir, nevirapine, ritonavir, lopinavir+ritonavir combination are known toinhibit some CYPs, they are shown to reduce the plasma levels of methadone,possibly due to CYP induction activity [seeDrug Interactions (7.2)]. Therefore, drugs administered concomitantlywith methadone should be evaluated for interaction potential; clinicians areadvised to evaluate individual response to drug therapy.
Cytochrome P450 Inducers:The following drug interactions were reported following coadministration ofmethadone with known inducers of cytochrome P450 enzymes:
Rifampin: In patients well-stabilized on methadone, concomitantadministration of rifampin resulted in a marked reduction in serum methadonelevels and a concurrent appearance of withdrawal symptoms.
Phenytoin: In a pharmacokinetic study with patients on methadonemaintenance therapy, phenytoin administration (250 mg twice daily initially for1 day followed by 300 mg daily for 3 to 4 days) resulted in an approximately50% reduction in methadone exposure and withdrawal symptoms occurredconcurrently. Upon discontinuation of phenytoin, the incidence of withdrawalsymptoms decreased and methadone exposure increased to a level comparable tothat prior to phenytoin administration.
St. John's Wort, Phenobarbital,Carbamazepine: Administration of methadone with other CYP3A4 inducers mayresult 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 decreasedclearance of methadone.
Voriconazole: Repeat dose administration of oral voriconazole (400mg every 12 hours for
1 day, then 200 mg every 12 hoursfor 4 days) increased the peak plasma concentration
(C max) and AUC of (R)-methadoneby 31% and 47%, respectively, in subjects receiving a methadone maintenancedose (30 to 100 mg daily. The C max and AUC of (S) methadone increased by 65%and 103%, respectively. Increased plasma concentrations of methadone have beenassociated with toxicity including QT prolongation. Frequent monitoring foradverse events and toxicity related to methadone is recommended duringcoadministration. Dose reduction of methadone may be needed [see Drug Interactions (7.2)].
Antiretroviral drugs: Although antiretroviral drugs such asefavirenz, nelfinavir, nevirapine, ritonavir, telaprevir, lopinavir+ritonavircombination are known to inhibit some CYPs, they are shown to reduce the plasmalevels 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 anti-retroviral agents resulted in increasedclearance or decreased plasma levels of methadone [see Drug Interactions (7.2)].
Didanosine and Stavudine: Methadone decreased the AUC and peaklevels for didanosine and stavudine, with a more significant decrease fordidanosine. Methadone disposition was not substantially altered [see Drug Interactions (7.2)].
Zidovudine: Methadone increased the AUC of zidovudine which couldresult in toxic effects [see DrugInteractions (7.2)].
- 13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility
Carcinogenesis: The results of carcinogenicity assessment in B6C2F1mice and Fischer
344 rats following dietaryadministration of two doses of methadone HCl have been published. Mice consumed15 mg/kg/day or 60 mg/kg/day methadone for two years. These doses wereapproximately 0.6 and 2.5 times a human daily oral dose of 120 mg/day on a bodysurface area basis (mg/m2). There was a significant increase in pituitaryadenomas 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 atreatment-related increase in the incidence of neoplasms in male rats. Due todecreased food consumption in males at the high dose, male rats consumed 16mg/kg/day and 28 mg/kg/day of methadone for two years. These doses wereapproximately 1.3 and 2.3 times a human daily oral dose of 120 mg/day, based onbody surface area comparison. In contrast, female rats consumed 46 mg/kg/day or88 mg/kg/day for two years. These doses were approximately 3.7 and 7.1 times ahuman 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 atreatment-related increase in the incidence of neoplasms in either male orfemale rats.
Mutagenesis: There are several published reports on the potentialgenetic toxicity of methadone. Methadone tested positive in the in vivo mousedominant lethal assay and the in vivo mammalian spermatogonial chromosomeaberration test. Additionally, methadone tested positive in the E. coli DNArepair system and Neurospora crassa and mouse lymphoma forward mutation assays.In contrast, methadone tested negative in tests for chromosome breakage anddisjunction and sex-linked recessive lethal gene mutations in germ cells ofDrosophila using feeding and injection procedures.
Fertility: Published animal studies show that methadone treatmentof males can alter reproductive function. Methadone produces a significantregression of sex accessory organs and testes of male mice and rats.
- 16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 Storage and Handling
Methadone hydrochloride tabletscontains methadone which is a controlled substance. Like fentanyl, morphine,oxycodone, hydromorphone, and oxymorphone, methadone is controlled underSchedule II of the Federal Controlled Substances Act. Methadone hydrochloridetablets 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 the USP/NF.
Store at 25ºC (77ºF); excursionspermitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].
16. 2 How Supplied
MethadoneHydrochloride Tablets USP, 5 mg are white to off white, round tabletsdebossed with 'U41' on one side and breakline on the other side.
Bottles of 30 NDC 13107-088-30
Bottles of100 NDC 13107-088-01
Bottles of1000 NDC 13107-088-99
MethadoneHydrochloride Tablets USP, 10 mg are white to off white, round tabletsdebossed with 'U42' on one side and breakline on the other side.
Bottles of 30 NDC 13107-089-30
Bottles of100 NDC 13107-089-01
Bottles of1000 NDC 13107-089-99
DEAorder 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 ofmethadone hydrochloride tablets, even when taken as recommended, can result inaddiction, 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 andto take steps to protect methadone hydrochloride tablets from theft or misuse.
Life-threatening Respiratory Depression: Inform patients of therisk of life-threatening respiratory depression, including information that therisk is greatest when starting methadone hydrochloride tablets or when the doseis increased, and that it can occur even at recommended doses [see Warnings and Precautions (5.2)]. Advisepatients how to recognize respiratory depression and to seek medical attentionif breathing difficulties develop.
Accidental Ingestion: 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 tabletssecurely and to dispose of unused methadone hydrochloride tablets by flushingthe tablets down the toilet.
Symptoms of Arrhythmia: Instruct patients to seek medical attentionimmediately if they experience symptoms suggestive of an arrhythmia (such aspalpitations, near syncope, or syncope) when taking methadone.
Neonatal Opioid Withdrawal Syndrome: Inform female patients of reproductivepotential that prolonged use of methadone hydrochloride tablets duringpregnancy can result in neonatal opioid withdrawal syndrome, which may belife-threatening if not recognized and treated [see Warnings and Precautions (5.4)].
Interactions with Alcohol and other CNS Depressants: Informpatients that potentially serious additive effects may occur if methadonehydrochloride tablets is used with alcohol or other CNS depressants, and not touse such drugs unless supervised by a health care provider.
Important Administration Instructions: Instruct patients how toproperly take methadone hydrochloride tablets, including the following:
• Use methadone hydrochloride tablets exactly asprescribed to reduce the risk of life-threatening adverse reactions (e.g.,respiratory depression)
• Do not discontinue methadone hydrochloride tabletswithout first discussing the need for a tapering regimen with the prescriber.
Hypotension: Inform patients thatmethadone hydrochloride tablets may cause orthostatic hypotension and syncope.Instruct patients how to recognize symptoms of low blood pressure and how toreduce the risk of serious consequences should hypotension occur (e.g., sit orlie down, carefully rise from a sitting or lying position).
Driving or Operating Heavy Machinery: Inform patients thatmethadone hydrochloride tablets may impair the ability to perform potentiallyhazardous activities such as driving a car or operating heavy machinery. Advisepatients not to perform such tasks until they know how they will react to themedication.
Constipation: Advise patients of the potential for severeconstipation, including management instructions and when to seek medicalattention.
Anaphylaxis: Inform patients that anaphylaxis has been reportedwith ingredients contained in methadone hydrochloride tablets. Advise patientshow to recognize such a reaction and when to seek medical attention.
Breastfeeding: Instruct nursing mothers using methadonehydrochloride tablets to watch for signs of methadone toxicity in theirinfants, which include increased sleepiness (more than usual), difficultybreastfeeding, breathing difficulties, or limpness. Instruct nursing mothers totalk to the baby's healthcare provider immediately if they notice these signs.If they cannot reach the healthcare provider right away, instruct them to takethe baby to the emergency room or call 911 (or local emergency services).
Disposal of Unused methadone hydrochloride tablets: Advise patientsto flush the unused tablets down the toilet when methadone hydrochloridetablets is no longer needed.
Aurolife Pharma LLC
Dayton, NJ 08810
Aurobindo Pharma USA,Inc.
Dayton, NJ 08810
- Medication guide
Methadone Hydrochloride Tablets USP, CII
Methadone hydrochloride tablets is:
• 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.
• 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
• liver, kidney, thyroid problems
• problems urinating
• heart rhythm problems (Long QT syndrome)
• pancreas or gallbladder problems
• Abuse of street or prescription drugs, alcohol addiction, or mental health 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 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.
• 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.
• 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 or call at 1-866-850-2876
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Aurolife Pharma LLC
Dayton, NJ 08810
Aurobindo Pharma USA, Inc.
Dayton, NJ 08810
- PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 5 mg (30 Tablet Bottle)
Methadone Hydrochloride Tablets, USP CII
Pharmacist: A Medication Guide must be distributed with the medication upon dispensing
Rx only 30 Tablets
- PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 10 mg (30 Tablet Bottle)
Methadone Hydrochloride Tablets, USP CII
Pharmacist: A Medication Guide must be distributed with the medication upon dispensing
Rx only 30 Tablets
- INGREDIENTS AND APPEARANCE
methadone hydrochloride tablet
Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:13107-088 Route of Administration ORAL DEA Schedule CII Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength METHADONE HYDROCHLORIDE (UNII: 229809935B) (METHADONE - UNII:UC6VBE7V1Z) METHADONE HYDROCHLORIDE 5 mg Inactive Ingredients Ingredient Name Strength CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) STARCH, CORN (UNII: O8232NY3SJ) SILICON DIOXIDE (UNII: ETJ7Z6XBU4) MAGNESIUM STEARATE (UNII: 70097M6I30) Product Characteristics Color WHITE (White to off white) Score 2 pieces Shape ROUND Size 6mm Flavor Imprint Code U41 Contains Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:13107-088-30 30 in 1 BOTTLE; Type 0: Not a Combination Product 2 NDC:13107-088-01 100 in 1 BOTTLE; Type 0: Not a Combination Product 3 NDC:13107-088-99 1000 in 1 BOTTLE; Type 0: Not a Combination Product Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA203502 09/15/2015 METHADONE HYDROCHLORIDE
methadone hydrochloride tablet
Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:13107-089 Route of Administration ORAL DEA Schedule CII Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength METHADONE HYDROCHLORIDE (UNII: 229809935B) (METHADONE - UNII:UC6VBE7V1Z) METHADONE HYDROCHLORIDE 10 mg Inactive Ingredients Ingredient Name Strength CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) STARCH, CORN (UNII: O8232NY3SJ) SILICON DIOXIDE (UNII: ETJ7Z6XBU4) MAGNESIUM STEARATE (UNII: 70097M6I30) Product Characteristics Color WHITE (White to off white) Score 2 pieces Shape ROUND Size 8mm Flavor Imprint Code U42 Contains Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:13107-089-30 30 in 1 BOTTLE; Type 0: Not a Combination Product 2 NDC:13107-089-01 100 in 1 BOTTLE; Type 0: Not a Combination Product 3 NDC:13107-089-99 1000 in 1 BOTTLE; Type 0: Not a Combination Product Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA203502 09/15/2015 Labeler - Aurolife Pharma, LLC (829084461) Establishment Name Address ID/FEI Business Operations Aurolife Pharma, LLC 829084461 MANUFACTURE(13107-088, 13107-089)