METHADONE HYDROCHLORIDE- methadone hydrochloride tablet

United States - English - NLM (National Library of Medicine)

Buy It Now

Active ingredient:
METHADONE HYDROCHLORIDE (UNII: 229809935B) (METHADONE - UNII:UC6VBE7V1Z)
Available from:
Direct_Rx
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Methadone hydrochloride tablets are indicated for the: • Management of pain severe enough to require daily, around-the-clock, 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 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 USP are 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 medic
Product summary:
16.1 Storage and Handling Methadone hydrochloride tablets contain methadone which is a controlled substance. Like fentanyl, morphine, oxycodone, hydromorphone, and oxymorphone, methadone is controlled under Schedule II of the Federal Controlled Substances Act. Methadone hydrochloride 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 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] 16.2 How Supplied Methadone Hydrochloride Tablets USP 5 mg tablets supplied as round, white, biconvex tablets debossed with product identification “54” above “210” on one side and scored on the other side. : Bottle of 100 Tablets : 4x25 Unit-Dose Tablets (reverse numbered) 10 mg tablets supplied as round, white, biconvex tablets debossed with product identification “54” above “142” on one side and scored on the other side. : Bottle of 100 Tablets : 4x25 Unit-Dose Tablets (reverse numbered) DEA order form required.
Authorization status:
New Drug Application
Authorization number:
61919-670-90

METHADONE HYDROCHLORIDE- methadone hydrochloride tablet

Direct_Rx

----------

MEDICATION GUIDE

Methadone Hydrochloride Tablets USP CII

(METH a done)

Rx Only

Methadone hydrochloride 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:

Get emergency help right away if you take too much methadone hydrochloride (overdose). When you first

start taking methadone hydrochloride, 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. They could die from taking it. Store methadone

hydrochloride away from children and in a safe place to prevent stealing or abuse. Selling or giving away

methadone hydrochloride is against the law.

Do not take methadone hydrochloride 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, tell your healthcare provider if you have a history of:

head injury, seizures

liver, kidney, thyroid problems

problems urinating

pancreas or gallbladder problems

heart rhythm problems (Long QT syndrome)

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 during pregnancy can

cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and

treated.

breastfeeding. Methadone hydrochloride passes into breast milk and may harm your baby.

taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking methadone

hydrochloride with certain other medicines may cause serious side effects.

When taking methadone hydrochloride:

Do not change your dose. Take methadone hydrochloride exactly as prescribed by your healthcare provider.

Do not take more than your prescribed dose in 24 hours. If you take methadone hydrochloride for pain and

miss a dose, take methadone hydrochloride 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 for opioid addiction and miss a dose, take your next dose the following

day as scheduled. Do not take extra doses. Taking more than the prescribed dose may cause you to overdose

because methadone hydrochloride builds up in your body over time.

Do not crush, dissolve, snort or inject methadone hydrochloride 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 without talking to your healthcare provider.

After you stop taking methadone hydrochloride, flush any unused tablets down the toilet.

While taking methadone hydrochloride Do Not:

Drive or operate heavy machinery, until you know how methadone hydrochloride affects you. Methadone

hydrochloride 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 may cause you to overdose and die.

The possible side effects of methadone hydrochloride are:

constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your

healthcare provider if you have any of these symptoms and they are severe.

Get emergency medical help if you have:

trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue or throat,

extreme drowsiness, light-headedness when changing positions, or you are feeling faint.

These are not all the possible side effects of methadone hydrochloride. Call your doctor for medical advice

about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to

dailymed.nlm.nih.gov.

Distributed by: West-Ward Pharmaceuticals Corp., Eatontown, NJ 07724, 1-800-962-8364

This Medication Guide has been approved by the U.S. Food and Drug Administration. Issue: April 2014

4077442//10

Revised: 7/2019

Document Id: 8e5bc5d9-f8c4-3a34-e053-2995a90a8fb7

34391-3

Set id: 8e5bc5d9-f8c3-3a34-e053-2995a90a8fb7

Version: 1

Effective Time: 20190723

Direct_Rx

METHADONE HYDROCHLORIDE- methadone hydrochloride tablet

Direct_Rx

----------

METHADONE HYDROCHLORIDE

WARNING: ADDICTION, ABUSE AND MISUSE; LIFE-THREATENING RESPIRATORY

DEPRESSION; ACCIDENTAL INGESTION; LIFE-THREATENING QT PROLONGATION;

NEONATAL OPIOID WITHDRAWAL SYNDROME; and TREATMENT FOR OPIOID

ADDICTION

Addiction, Abuse, and Misuse

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 methadone hydrochloride tablets, and monitor all patients regularly for the

development of these behaviors or 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. Monitor for respiratory depression, especially during initiation of

methadone hydrochloride tablets or following a dose increase [see Warnings and Precautions

(5.2)].

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 (5.2)].

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 for

changes in cardiac rhythm 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 can result in neonatal opioid

withdrawal syndrome, which 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 [see Warnings and

Precautions (5.4)].

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)].

Methadone hydrochloride tablets are indicated for the:

Management of pain severe enough to require daily, around-the-clock, 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 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 USP are 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.

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)).

2.1 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 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 [see Warnings and Precautions (5.2)].

Use of Methadone Hydrochloride as the First Opioid Analgesic: Initiate treatment with methadone

hydrochloride with 2.5 mg orally every 8 to 12 hours.

Conversion from Other Oral Opioids to Methadone Hydrochloride: Discontinue all other around-the-

clock opioid drugs when methadone hydrochloride 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.

The table cannot be used to convert from methadone hydrochloride 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

Total Daily Baseline Oral

Morphine Equivalent Dose

Estimated Daily Oral Methadone Requirement as Percent 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 1000 mg

5% to 10%

> 1000 mg

< 5 %

To calculate the estimated methadone hydrochloride 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 strength(s)

available.

Example conversion from a single opioid to methadone hydrochloride:

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 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 daily

Step 3: Calculate the approximate starting dose of methadone hydrochloride 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 every 12 hours

Then 7.5 mg is rounded down to 5 mg methadone hydrochloride 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.

Conversion from Parenteral Methadone to Methadone Hydrochloride: 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 to a dose that provides adequate analgesia and minimizes

adverse reactions. Continually reevaluate patients receiving methadone hydrochloride 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 (T1/2) from 8 to

59 hours in different studies [see Clinical Pharmacology (12.3)], titrate methadone 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, 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 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 for Pain

When a patient no longer requires therapy with methadone hydrochloride 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.

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 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 if

withdrawal symptoms have not been suppressed or if symptoms reappear.

The total daily dose of methadone hydrochloride 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. Decrease the dose of methadone hydrochloride on a daily basis or at 2-day

intervals, keeping the amount of methadone hydrochloride 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.

2.7Medically 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)].

Methadone Hydrochloride Tablets USP are available in 5 mg and 10 mg dosage strengths. The 5 mg

tablets are round, white, biconvex and are debossed with product identification “54” above “210” on

one side and scored on the other side. The 10 mg tablets are round, white, biconvex and are debossed

with product identification “54” above “142” on one side and scored on the other side.

Methadone hydrochloride tablets are contraindicated in patients with:

Significant respiratory depression

Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment

Known or suspected paralytic ileus

Hypersensitivity (e.g., anaphylaxis) to methadone [see Adverse Reactions (6)].

5.1 Addiction, Abuse and Misuse

Methadone hydrochloride tablets contain methadone, a Schedule II controlled substance. As an opioid,

methadone hydrochloride exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse

and Dependence (9)]. As long-acting opioids such as methadone hydrochloride 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 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, and monitor all patients receiving methadone hydrochloride 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 for the proper management of pain in any given patient. Patients at increased risk may be

prescribed long-acting opioids such as methadone hydrochloride, but use in such patients necessitates

intensive counseling about the risks and proper use of methadone hydrochloride along with the

intensive monitoring for signs of addiction, abuse, and misuse.

Abuse or misuse of methadone hydrochloride by crushing, chewing, snorting, or injecting the dissolved

product will result in the uncontrolled delivery of the methadone and can result in overdose and death

[see Overdosage (10)].

Opioid agonists such as methadone hydrochloride 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. 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 (CO2) retention from opioid-induced

respiratory depression can exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of

methadone hydrochloride, 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 and following dose

increases.

To reduce the risk of respiratory depression, proper dosing and titration of methadone hydrochloride

are essential [see Dosage and Administration (2.2, 2.3)]. Overestimating the methadone hydrochloride

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, 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 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 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 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 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 is made, start with

methadone hydrochloride 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 and when methadone hydrochloride 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, as in these patients, even usual therapeutic doses of methadone hydrochloride 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 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.

5.9 Use in Patients with Head Injury or Increased Intracranial Pressure

Monitor patients taking methadone hydrochloride 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.

Methadone hydrochloride 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 in patients with impaired consciousness or coma.

5.10 Use in Patients with Gastrointestinal Conditions

Methadone hydrochloride is contraindicated in patients with paralytic ileus. Avoid the use of methadone

hydrochloride in patients with other gastrointestinal obstruction.

The methadone in methadone hydrochloride 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 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 therapy.

5.12 Avoidance of Withdrawal

Avoid the use of partial agonists or mixed agonist/antagonist (i.e., buprenorphine, pentazocine,

nalbuphine and butorphanol) in patients who have received or are receiving a course of therapy with a

full opioid agonist analgesic, including methadone hydrochloride. 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, gradually taper the dose [see Dosage and Administration

(2.4)]. Do not abruptly discontinue methadone hydrochloride.

5.13 Driving and Operating Machinery

Methadone hydrochloride 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 and know how

they will react to the medication.

The following serious adverse reactions are discussed elsewhere in the labeling:

Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)]

Life Threatening Respiratory Depression [see Warnings and Precautions (5.2)]

QT Prolongation [see Warnings and Precautions (5.3)]

Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.4)]

Interactions with Other CNS Depressants [see Warnings and Precautions (5.5)]

Hypotensive Effect [see Warnings and Precautions (5.8)]

Gastrointestinal Effects [see Warnings and Precautions (5.10)]

Seizures [see Warnings and Precautions (5.11)]

The major hazards of methadone are respiratory depression and, to a lesser degree, systemic

hypotension. Respiratory arrest, shock, cardiac arrest, and death have occurred.

The most frequently observed adverse reactions include lightheadedness, dizziness, sedation, nausea,

vomiting, and sweating. These effects seem to be more prominent in ambulatory patients and in those

who are not suffering severe pain. In such individuals, lower doses are advisable.

Other adverse reactions include the following:

Body as a Whole: asthenia (weakness), edema, headache

Cardiovascular: arrhythmias, bigeminal rhythms, bradycardia, cardiomyopathy, ECG abnormalities,

extrasystoles, flushing, heart failure, hypotension, palpitations, phlebitis, QT interval prolongation,

syncope, T-wave inversion, tachycardia, torsades de pointes, ventricular fibrillation, ventricular

tachycardia

Central Nervous System: agitation, confusion, disorientation, dysphoria, euphoria, insomnia,

hallucinations, seizures, visual disturbances

Endocrine: hypogonadism

Gastrointestinal: abdominal pain, anorexia, biliary tract spasm, constipation, dry mouth, glossitis

Hematologic: reversible thrombocytopenia has been described in opioid addicts with chronic hepatitis

Metabolic: hypokalemia, hypomagnesemia, weight gain

Renal: antidiuretic effect, urinary retention or hesitancy

Reproductive: amenorrhea, reduced libido and/or potency, reduced ejaculate volume, reduced seminal

vesicle and prostate secretions, decreased sperm motility, abnormalities in sperm morphology

Respiratory: pulmonary edema, respiratory depression

Skin and Subcutaneous Tissue: pruritus, urticaria, other skin rashes, and rarely, hemorrhagic urticaria

Hypersensitivity: Anaphylaxis has been reported with ingredients contained in methadone

hydrochloride. Advise patients how to recognize such a reaction and when to seek medical attention.

Maintenance on a Stabilized Dose: During prolonged administration of methadone, as in a methadone

maintenance treatment program, constipation and sweating often persist and hypogonadism, decreased

serum testosterone and reproductive effects are thought to be related to chronic opioid use.

Methadone Hydrochloride for the Detoxification and Maintenance Treatment of Opioid Dependence:

During the induction phase of methadone maintenance treatment, patients are being withdrawn from illicit

opioids and may have opioid withdrawal symptoms. Monitor patients for signs and symptoms including:

lacrimation, rhinorrhea, sneezing, yawning, excessive perspiration, goose-flesh, fever, chilling

alternating with flushing, restlessness, irritability, weakness, anxiety, depression, dilated pupils,

tremors, tachycardia, abdominal cramps, body aches, involuntary twitching and kicking movements,

anorexia, nausea, vomiting, diarrhea, intestinal spasms, and weight loss and consider dose adjustment as

indicated.

7.1 CNS Depressants

The concomitant use of methadone hydrochloride 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 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 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 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 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: 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 and could precipitate a withdrawal syndrome. Monitor methadone-maintained patients

receiving any of these anti-retroviral therapies closely for evidence of withdrawal effects and adjust

the methadone dose accordingly.

Effects of Methadone Hydrochloride 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 or precipitate

withdrawal symptoms. Avoid the use of mixed agonist/antagonist and partial agonist analgesics in

patients receiving methadone hydrochloride.

7.5 Antidepressants

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.

7.6 Anticholinergics

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 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.

8.1 Pregnancy

Clinical Considerations: Fetal/neonatal adverse reactions: Prolonged use of opioid analgesics during

pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and

neonatal opioid withdrawal syndrome shortly after birth. Observe newborns for symptoms of neonatal

opioid withdrawal syndrome, such as poor feeding, diarrhea, irritability, tremor, rigidity, and seizures,

and manage accordingly [see Warnings and Precautions (5.4)].

Teratogenic Effects - Pregnancy Category C: There are no adequate and well controlled studies in

pregnant women. Methadone hydrochloride should be used during pregnancy only if the potential

benefit justifies the potential risk to the fetus.

Methadone has been shown to be teratogenic in the hamster at doses 2 times the human daily oral dose

(120 mg/day on a mg/m2 basis) and in mice at doses equivalent to the human daily oral dose (120 mg/day

on a mg/m2 basis). Increased neonatal mortality and significant differences in behavioral tests have been

reported in the offspring of male rodents that were treated with methadone prior to mating when

compared to control animals. Methadone has been detected in human amniotic fluid and cord plasma at

concentrations proportional to maternal plasma and in newborn urine at lower concentrations than

corresponding maternal urine.

Dosage Adjustment during Pregnancy: The disposition of oral methadone has been studied in

approximately 30 pregnant patients in 2nd and 3rd trimesters. Total body clearance of methadone was

increased in pregnant patients compared to the same patients postpartum or to non-pregnant opioid-

dependent women. The terminal half-life of methadone is decreased during 2nd and 3rd trimesters. The

decrease in plasma half-life and increased clearance of methadone resulting in lower methadone trough

levels during pregnancy can lead to withdrawal symptoms in some pregnant patients. The dosage may

need to be increased or the dosing interval decreased in pregnant patients receiving methadone to

achieve therapeutic effect [see Dosage and Administration (2.10)].

Effects on the Neonate: Babies born to mothers who have been taking opioids regularly prior to

delivery may be physically dependent. Onset of withdrawal symptoms in infants is usually in the first

days after birth. Monitor newborn for withdrawal signs and symptoms including: poor feeding,

irritability, excessive crying, tremors, rigidity, hyper-active reflexes, increased respiratory rate,

diarrhea, sneezing, yawning, vomiting, fever, and seizures. The intensity of the neonatal withdrawal

syndrome does not always correlate with the maternal dose or the duration of maternal exposure. The

duration of the withdrawal signs may vary from a few days to weeks or even months. There is no

consensus on the appropriate management of infant withdrawal [see Warnings and Precautions (5.4)].

Human Data: Reported studies have generally compared the benefit of methadone to the risk of untreated

addiction to illicit drugs; the relevance of these findings to pain patients prescribed methadone during

pregnancy is unclear. Pregnant women involved in methadone maintenance programs have been reported

to have significantly improved prenatal care leading to significantly reduced incidence of obstetric and

fetal complications and neonatal morbidity and mortality when compared to women using illicit drugs.

Several factors, including maternal use of illicit drugs, nutrition, infection and psychosocial

circumstances, complicate the interpretation of investigations of the children of women who take

methadone during pregnancy. Information is limited regarding dose and duration of methadone use

during pregnancy, and most maternal exposure appears to occur after the first trimester of pregnancy.

A review of published data on experiences with methadone use during pregnancy by the Teratogen

Information System (TERIS) concluded that maternal use of methadone during pregnancy as part of a

supervised, therapeutic regimen is unlikely to pose a substantial teratogenic risk (quantity and quality of

data assessed as “limited to fair”). However, the data are insufficient to state that there is no risk

(TERIS, last reviewed October, 2002). A retrospective case series of 101 pregnant, opioid-dependent

women who underwent inpatient opioid detoxification with methadone did not demonstrate any increased

risk of miscarriage in the 2nd trimester or premature delivery in the 3rd trimester. Recent studies

suggest an increased risk of premature delivery in opioid-dependent women exposed to methadone

during pregnancy, although the presence of confounding factors makes it difficult to determine a causal

relationship. Several studies have suggested that infants born to narcotic-addicted women treated with

methadone during all or part of pregnancy have been found to have decreased fetal growth with reduced

birth weight, length, and/or head circumference compared to controls. This growth deficit does not

appear to persist into later childhood. Children prenatally exposed to methadone have been reported to

demonstrate mild but persistent deficits in performance on psychometric and behavioral tests. In

addition, several studies suggest that children born to opioid-dependent women exposed to methadone

during pregnancy may have an increased risk of visual development anomalies; however, a causal

relationship has not been assigned.

There are conflicting reports on whether Sudden Infant Death Syndrome occurs with an increased

incidence in infants born to women treated with methadone during pregnancy. Abnormal fetal non-stress

tests have been reported to occur more frequently when the test is performed 1 to 2 hours after a

maintenance dose of methadone in late pregnancy compared to controls.

Animal Data: Methadone did not produce teratogenic effects in rat or rabbit models. Methadone

produced teratogenic effects following large doses, in the guinea pig, hamster and mouse. One

published study in pregnant hamsters indicated that a single subcutaneous dose of methadone ranging

from 31 to 185 mg/kg (the 31 mg/kg dose is approximately 2 times a human daily oral dose of 120

mg/day on a mg/m2 basis) on day 8 of gestation resulted in a decrease in the number of fetuses per litter

and an increase in the percentage of fetuses exhibiting congenital malformations described as

exencephaly, cranioschisis, and “various other lesions.” The majority of the doses tested also resulted

in maternal death. In another study, a single subcutaneous dose of 22 to 24 mg/kg methadone (estimated

exposure was approximately equivalent to a human daily oral dose of 120 mg/day on a mg/m2 basis)

administered on day 9 of gestation in mice also produced exencephaly in 11% of the embryos.

However, no effects were reported in rats and rabbits at oral doses up to 40 mg/kg (estimated exposure

was approximately 3 and 6 times, respectively, a human daily oral dose of 120 mg/day on a mg/m2 basis)

administered during days 6 to 15 and 6 to 18, respectively.

Published animal data have reported increased neonatal mortality in the offspring of male rodents that

were treated with methadone prior to mating. In these studies, the female rodents were not treated with

methadone, indicating paternally- mediated developmental toxicity. Specifically, methadone

administered to the male rat prior to mating with methadone- nai

ve females resulted in decreased

weight gain in progeny after weaning. The male progeny demonstrated reduced thymus weights,

whereas the female progeny demonstrated increased adrenal weights. Behavioral testing of these male

and female progeny revealed significant differences in behavioral tests compared to control animals,

suggesting that paternal methadone exposure can produce physiological and behavioral changes in

progeny in this model. Other animal studies have reported that perinatal exposure to opioids including

methadone alters neuronal development and behavior in the offspring. Perinatal methadone exposure in

rats has been linked to alterations in learning ability, motor activity, thermal regulation, nociceptive

responses and sensitivity to drugs.

Additional animal data demonstrates evidence for neurochemical changes in the brains of methadone-

treated offspring, including changes to the cholinergic, dopaminergic, noradrenergic and serotonergic

systems. Studies demonstrated that methadone treatment of male rats for 21 to 32 days prior to mating

with methadone-nai

ve females did not produce any adverse effects, suggesting that prolonged

methadone treatment of the male rat resulted in tolerance to the developmental toxicities noted in the

progeny. Mechanistic studies in this rat model suggest that the developmental effects of “paternal”

methadone on the progeny appear to be due to decreased testosterone production. These animal data

mirror the reported clinical findings of decreased testosterone levels in human males on methadone

maintenance therapy for opioid addiction and in males receiving chronic intraspinal opioids.

Additional data have been published indicating that methadone treatment of male rats (once a day for

three consecutive days) increased embryolethality and neonatal mortality. Examination of uterine

contents of methadone-nai

ve female mice bred to methadone-treated mice indicated that methadone

treatment produced an increase in the rate of preimplantation deaths in all post-meiotic states.

8.2 Labor and Delivery

Opioids cross the placenta and may produce respiratory depression in neonates. Methadone

hydrochloride is not for use in women during and immediately prior to labor, when shorter acting

analgesics or other analgesic techniques are more appropriate. Opioid analgesics can prolong labor

through actions that temporarily reduce the strength, duration, and frequency of uterine contractions.

However this effect is not consistent and may be offset by an increased rate of cervical dilatation,

which tends to shorten labor.

8.3 Nursing Mothers

Methadone is secreted into human milk. At maternal oral doses of 10 to 80 mg/day, methadone

concentrations from 50 to 570 mcg/L in milk have been reported, which, in the majority of samples,

were lower than maternal serum drug concentrations at steady state. Peak methadone levels in milk occur

approximately 4 to 5 hours after an oral dose. Based on an average milk consumption of 150 mL/kg/day,

an infant would consume approximately 17.4 mcg/kg/day which is approximately 2 to 3% of the oral

maternal dose. Methadone has been detected in very low plasma concentrations in some infants whose

mothers were taking methadone. Cases of sedation and respiratory depression in infants exposed to

methadone through breast milk have been reported. Caution should be exercised when methadone is

administered to a nursing woman.

Advise women who are being treated with methadone and who are breastfeeding or express a desire to

breastfeed of the presence of methadone in human milk. Instruct breastfeeding mothers how to identify

respiratory depression and sedation in their babies and when it may be necessary to contact their

healthcare provider or seek immediate medical care. Breastfed infants of mothers using methadone

should be weaned gradually to prevent development of withdrawal symptoms in the infant.

8.4 Pediatric Use

The safety, effectiveness, and pharmacokinetics of methadone in pediatric patients below the age of 18

years have not been established.

8.5 Geriatric Use

Clinical studies of methadone did not include sufficient numbers of subjects aged 65 and over to

determine whether they respond differently compared to younger subjects. Other reported clinical

experience has not identified differences in responses between elderly and younger patients. In general,

start elderly patients at the low end of the dosing range, taking into account the greater frequency of

decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in

geriatric patients. Closely monitor elderly patients for signs of respiratory and central nervous system

depression.

8.6 Renal Impairment

Methadone pharmacokinetics have not been extensively evaluated in patients with renal insufficiency.

Since unmetabolized methadone and its metabolites are excreted in urine to a variable degree, start these

patients on lower doses and with longer dosing intervals and titrate slowly while carefully monitoring

for signs of respiratory and central nervous system depression.

8.7 Hepatic Impairment

Methadone has not been extensively evaluated in patients with hepatic insufficiency. Methadone is

metabolized by hepatic pathways; therefore, patients with liver impairment may be at risk of increased

systemic exposure to methadone after multiple dosing. Start these patients on lower doses and titrate

slowly while carefully monitoring for signs of respiratory and central nervous system depression.

9.1 Controlled Substance

Methadone is a mu-agonist opioid with an abuse liability similar to other opioid agonists and is a

Schedule II controlled substance. Methadone can be abused and is subject to misuse, addiction, and

criminal diversion [see Warnings and Precautions (5.1)].

9.2 Abuse

All patients treated with opioids for pain management require careful monitoring for signs of abuse and

addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate

medical use.

Drug abuse is the intentional non-therapeutic use of an over-the-counter or prescription drug, even

once, for its rewarding psychological or physiological effects. Drug abuse includes, but is not limited

to the following examples: the use of a prescription or over-the counter drug to get “high”, or the use

of steroids for performance enhancement and muscle build up.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after

repeated substance use and include: a strong desire to take the drug, difficulties in controlling its use,

persisting in its use despite harmful consequences, a higher priority given to drug use than to other

activities and obligations, increased tolerance, and sometimes a physical withdrawal.

“Drug-seeking” behavior is very common in addicts and drug abusers. Drug-seeking tactics include

emergency calls or visits near the end of office hours, refusal to undergo appropriate examination,

testing or referral, repeated claims of lost prescriptions, tampering with prescriptions and reluctance to

provide prior medical records or contact information for other treating physician(s). “Doctor shopping”

(visiting multiple prescribers) to obtain additional prescriptions is common among drug abusers and

people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be

appropriate behavior in a patient with poor pain control.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians

should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of

physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true

addiction.

Methadone hydrochloride, like other opioids, can be diverted for non-medical use into illicit channels

of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and

renewal requests, as required by state law, is strongly advised.

Risks Specific to Abuse of Methadone Hydrochloride: Abuse of methadone hydrochloride poses a risk

of overdose and death. This risk is increased with concurrent abuse of methadone and alcohol or other

substances. Methadone hydrochloride is for oral use only and must not be injected. Parenteral drug

abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

Proper assessment and selection of the patient, proper prescribing practices, periodic re-evaluation of

therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid

drugs.

9.3 Dependence

Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the

need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of

disease progression or other external factors). Tolerance may occur to both the desired and undesired

effects of drugs, and may develop at different rates for different effects.

Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dose

reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with

opioid antagonist activity, e.g., naloxone, mixed agonist/antagonist analgesics (pentazocine, butorphanol,

nalbuphine), or partial agonists (buprenorphine). Physical dependence may not occur to a clinically

significant degree until after several days to weeks of continued opioid usage.

Methadone hydrochloride should not be abruptly discontinued [see Dosage and Administration (2.4)]. If

methadone hydrochloride is abruptly discontinued in a physically dependent patient, an abstinence

syndrome may occur. Some or all of the following can characterize this syndrome: restlessness,

lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms

also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps,

insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart

rate.

Infants born to mothers physically dependent on opioids will also be physically dependent and may

exhibit respiratory difficulties and withdrawal symptoms [see Use in Specific Populations (8.1) and

Warnings and Precautions (5.4)].

Clinical Presentation

Acute overdosage of methadone is manifested by respiratory depression, somnolence progressing to

stupor or coma, maximally constricted pupils, skeletal-muscle flaccidity, cold and clammy skin, and

sometimes, bradycardia and hypotension. In severe overdosage, particularly by the intravenous route,

apnea, circulatory collapse, cardiac arrest, and death may occur.

Treatment of Overdose

In case of overdose, priorities are the re-establishment of a patent and protected airway and institution

of assisted or controlled ventilation if needed. Employ other supportive measures (including oxygen,

vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest

or arrhythmias will require advanced life support techniques.

The opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting

from opioid overdose. Opioid antagonists should not be administered in the absence of clinically

significant respiratory or circulatory depression secondary to methadone overdose. Such agents should

be administered cautiously to patients who are known, or suspected to be, physically dependent on

methadone hydrochloride. In such cases, an abrupt or complete reversal of opioid effects may

precipitate an acute withdrawal syndrome.

Because the duration of reversal would be expected to be less than the duration of action of methadone

in methadone hydrochloride, carefully monitor the patient until spontaneous respiration is reliably re-

established. If the response to opioid antagonists is suboptimal or not sustained, additional antagonist

should be given as directed in the product’s prescribing information.

In an individual physically dependent on opioids, administration of an opioid receptor antagonist may

precipitate an acute withdrawal. The severity of the withdrawal produced will depend on the degree of

physical dependence and the dose of the antagonist administered. If a decision is made to treat serious

respiratory depression in the physically dependent patient, administration of the antagonist should be

begun with care and by titration with smaller than usual doses of the antagonist.

Methadone hydrochloride is chemically described as 6-(dimethylamino)-4,4-diphenyl-3-hepatanone

hydrochloride. Methadone hydrochloride USP 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 Tablet USP contains 5 or 10 mg of methadone hydrochloride USP and

the following inactive ingredients: magnesium stearate, microcrystalline cellulose and pregelatinized

12.1 Mechanism of Action

Methadone hydrochloride is a mu-agonist; a synthetic opioid analgesic with multiple actions

qualitatively similar to those of morphine, the most prominent of which involves the central nervous

system and organs composed of smooth muscle. The principal therapeutic uses for methadone are for

analgesia and for detoxification or maintenance in opioid addiction. The methadone withdrawal

syndrome, although qualitatively similar to that of morphine, differs in that the onset is slower, the

course is more prolonged, and the symptoms are less severe.

Some data also indicate that methadone acts as an antagonist at the N-methyl-D-aspartate (NMDA)

receptor. The contribution of NMDA receptor antagonism to methadone’s efficacy is unknown. Other

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

12.3 Pharmacokinetics

Absorption: Following oral administration the bioavailability of methadone ranges between 36 to 100%

and peak plasma concentrations are achieved between 1 to 7.5 hours. Dose proportionality of methadone

pharmacokinetics is not known. However, after administration of daily oral doses ranging from 10 to

225 mg, the steady-state plasma concentrations ranged between 65 to 630 ng/mL and the peak

concentrations ranged between 124 to 1255 ng/mL. Effect of food on the bioavailability of methadone

has not been evaluated.

Distribution: Methadone is a lipophilic drug and the steady-state volume of distribution ranges between

1.0 to 8.0 L/kg. In plasma, methadone is predominantly bound to α1-acid glycoprotein (85% to 90%).

Methadone is secreted in saliva, breast milk, amniotic fluid and umbilical cord plasma.

Metabolism: Methadone is primarily metabolized by N-demethylation to an inactive metabolite, 2-

ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidene (EDDP). Cytochrome P450 enzymes, primarily

CYP3A4, CYP2B6, and CYP2C19 and to a lesser extent CYP2C9 and CYP2D6, are responsible for

conversion of methadone to EDDP and other inactive metabolites, which are excreted mainly in the

urine. Methadone appears to be a substrate for P-glycoprotein but its pharmacokinetics do not appear to

be significantly altered in case of P-glycoprotein polymorphism or inhibition.

Excretion: The elimination of methadone is mediated by extensive biotransformation, followed by renal

and fecal excretion. Published reports indicate that after multiple dose administration the apparent

plasma clearance of methadone ranged between 1.4 and 126 L/h, and the terminal half-life (T1/2) was

highly variable and ranged between 8 to 59 hours in different studies. Methadone is a basic (pKa=9.2)

compound and the pH of the urinary tract can alter its disposition in plasma. Also, since methadone is

lipophilic, it has been known to persist in the liver and other tissues. The slow release from the liver

and other tissues may prolong the duration of methadone action despite low plasma concentrations.

Drug Interactions: Cytochrome P450 Interactions: Methadone undergoes hepatic N-demethylation by

cytochrome P450 (CYP) isoforms, principally CYP3A4, CYP2B6, CYP2C19, and to a lesser extent by

CYP2C9 and CYP2D6. Coadministration of methadone with CYP inducers may result in more rapid

metabolism and potential for decreased effects of methadone, whereas administration with CYP

inhibitors may reduce metabolism and potentiate methadone’s effects. Although antiretroviral drugs

such as efavirenz, nelfinavir, nevirapine, ritonavir, lopinavir+ritonavir combination are known to inhibit

some CYPs, they are shown to reduce the plasma levels of methadone, possibly due to CYP induction

activity [see Drug Interactions (7.2)]. Therefore, drugs administered concomitantly with methadone

should be evaluated for interaction potential; clinicians are advised to evaluate individual response to

drug therapy.

Cytochrome P450 Inducers: The following drug interactions were reported following coadministration

of methadone with known inducers of cytochrome P450 enzymes:

Rifampin: In patients well-stabilized on methadone, concomitant administration of rifampin resulted in a

marked reduction in serum methadone levels and a concurrent appearance of withdrawal symptoms.

Phenytoin: In a pharmacokinetic study with patients on methadone maintenance therapy, phenytoin

administration (250 mg twice daily initially for 1 day followed by 300 mg daily for 3 to 4 days) resulted

in an approximately 50% reduction in methadone exposure and withdrawal symptoms occurred

concurrently. Upon discontinuation of phenytoin, the incidence of withdrawal symptoms decreased and

methadone exposure increased to a level comparable to that prior to phenytoin administration.

St. John’s Wort, Phenobarbital, Carbamazepine: Administration of methadone with other CYP3A4

inducers may result in withdrawal symptoms.

Cytochrome P450 Inhibitors: Since the metabolism of methadone is mediated primarily by CYP3A4

isozyme, coadministration of drugs that inhibit CYP3A4 activity may cause decreased clearance of

methadone.

Voriconazole: Repeat dose administration of oral voriconazole (400 mg every 12 hours for 1 day, then

200 mg every 12 hours for 4 days) increased the peak plasma concentration (Cmax) and AUC of (R)-

methadone by 31% and 47%, respectively, in subjects receiving a methadone maintenance dose (30 to

100 mg daily). The Cmax and AUC of (S)-methadone increased by 65% and 103%, respectively.

Increased plasma concentrations of methadone have been associated with toxicity including QT

prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended

during coadministration. Dose reduction of methadone may be needed [see Drug Interactions (7.2)].

Antiretroviral drugs: Although antiretroviral drugs such as efavirenz, nelfinavir, nevirapine, ritonavir,

telaprevir, lopinavir+ritonavir combination are known to inhibit some CYPs, they are shown to reduce

the plasma levels of methadone, possibly due to CYP induction activity.

Abacavir, amprenavir, darunavir+ritonavir, efavirenz, nelfinavir, nevirapine, ritonavir, telaprevir,

lopinavir+ritonavir, saquinavir+ritonavir, tipranvir+ritonavir combination: Coadministration of these

anti-retroviral agents resulted in increased clearance or decreased plasma levels of methadone [see

Drug Interactions (7.2)].

Didanosine and Stavudine: Methadone decreased the AUC and peak levels for didanosine and stavudine,

with a more significant decrease for didanosine. Methadone disposition was not substantially altered

[see Drug Interactions (7.2)].

Zidovudine: Methadone increased the AUC of zidovudine which could result in toxic effects [see Drug

Interactions (7.2)].

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis: The results of carcinogenicity assessment in B6C2F1 mice and Fischer 344 rats

following dietary administration of two doses of methadone HCl have been published. Mice consumed

15 mg/kg/day or 60 mg/kg/day methadone for two years. These doses were approximately 0.6 and 2.5

times a human daily oral dose of 120 mg/day on a body surface area basis (mg/m2). There was a

significant increase in pituitary adenomas in female mice treated with 15 mg/kg/day but not with 60

mg/kg/day. Under the conditions of the assay, there was no clear evidence for a treatment- related

increase in the incidence of neoplasms in male rats. Due to decreased food consumption in males at the

high dose, male rats consumed 16 mg/kg/day and 28 mg/kg/day of methadone for two years. These

doses were approximately 1.3 and 2.3 times a human daily oral dose of 120 mg/day, based on body

surface area comparison. In contrast, female rats consumed 46 mg/kg/day or 88 mg/kg/day for two

years. These doses were approximately 3.7 and 7.1 times a human daily oral dose of 120 mg/day, based

on body surface area comparison. Under the conditions of the assay, there was no clear evidence for a

treatment-related increase in the incidence of neoplasms in either male or female rats.

Mutagenesis: There are several published reports on the potential genetic toxicity of methadone.

Methadone tested positive in the in vivo mouse dominant lethal assay and the in vivo mammalian

spermatogonial chromosome aberration test. Additionally, methadone tested positive in the E. coli DNA

repair system and Neurospora crassa and mouse lymphoma forward mutation assays. In contrast,

methadone tested negative in tests for chromosome breakage and disjunction and sex-linked recessive

lethal gene mutations in germ cells of Drosophila using feeding and injection procedures.

Fertility: Published animal studies show that methadone treatment of males can alter reproductive

function. Methadone produces a significant regression of sex accessory organs and testes of male mice

and rats.

16.1 Storage and Handling

Methadone hydrochloride tablets contain methadone which is a controlled substance. Like fentanyl,

morphine, oxycodone, hydromorphone, and oxymorphone, methadone is controlled under Schedule II of

the Federal Controlled Substances Act. Methadone hydrochloride 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 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

16.2 How Supplied

Methadone Hydrochloride Tablets USP

5 mg tablets supplied as round, white, biconvex tablets debossed with product identification “54” above

“210” on one side and scored on the other side.

: Bottle of 100 Tablets

: 4x25 Unit-Dose Tablets (reverse numbered)

10 mg tablets supplied as round, white, biconvex tablets debossed with product identification “54”

above “142” on one side and scored on the other side.

: Bottle of 100 Tablets

: 4x25 Unit-Dose Tablets (reverse numbered)

DEA order form required.

Advise the patient to read the FDA-approved patient labeling (Medication Guide)

Addiction, Abuse, and Misuse: Inform patients that the use of methadone hydrochloride, even when

taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose or death

[see Warnings and Precautions (5.1)]. Instruct patients not to share methadone hydrochloride with others

and to take steps to protect methadone hydrochloride from theft or misuse.

Life-threatening Respiratory Depression: Inform patients of the risk of life-threatening respiratory

depression, including information that the risk is greatest when starting methadone hydrochloride or

when the dose is increased, and that it can occur even at recommended doses [see Warnings and

Precautions (5.2)]. Advise patients how to recognize respiratory depression and to seek medical

attention if breathing difficulties develop.

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 securely and to dispose of unused methadone hydrochloride by flushing

the tablets down the toilet.

Symptoms of Arrhythmia: Instruct patients to seek medical attention immediately if they experience

symptoms suggestive of an arrhythmia (such as palpitations, near syncope, or syncope) when taking

methadone.

Neonatal Opioid Withdrawal Syndrome: Inform female patients of reproductive potential that prolonged

use of methadone hydrochloride during pregnancy can result in neonatal opioid withdrawal syndrome,

which may be life-threatening if not recognized and treated [see Warnings and Precautions (5.4)].

Interactions with Alcohol and other CNS Depressants: Inform patients that potentially serious additive

effects may occur if methadone hydrochloride is used with alcohol or other CNS depressants, and not

to use such drugs unless supervised by a health care provider.

Important Administration Instructions: Instruct patients how to properly take methadone hydrochloride,

including the following:

Use methadone hydrochloride exactly as prescribed to reduce the risk of life-threatening adverse

reactions (e.g., respiratory depression)

Do not discontinue methadone hydrochloride without first discussing the need for a tapering regimen

with the prescriber

Hypotension: Inform patients that methadone hydrochloride may cause orthostatic hypotension and

syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk

of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or

lying position).

Driving or Operating Heavy Machinery: Inform patients that methadone hydrochloride may impair the

ability to perform potentially hazardous activities such as driving a car or operating heavy machinery.

Advise patients not to perform such tasks until they know how they will react to the medication.

Constipation: Advise patients of the potential for severe constipation, including management instructions

and when to seek medical attention.

Anaphylaxis: Inform patients that anaphylaxis has been reported with ingredients contained in methadone

hydrochloride. Advise patients how to recognize such a reaction and when to seek medical attention.

Breastfeeding: Instruct nursing mothers using methadone hydrochloride to watch for signs of

methadone toxicity in their infants, which include increased sleepiness (more than usual), difficulty

breastfeeding, breathing difficulties, or limpness. Instruct nursing mothers to talk to the baby’s

healthcare provider immediately if they notice these signs. If they cannot reach the healthcare provider

right away, instruct them to take the baby to the emergency room or call 911 (or local emergency

services).

Disposal of Unused Methadone Hydrochloride: Advise patients to flush the unused tablets down the

toilet when methadone hydrochloride is no longer needed.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

4077442//10

Revised April 2016

MEDICATION GUIDE

Methadone Hydrochloride Tablets USP CII

(METH a done)

Rx Only

Methadone hydrochloride 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:

Get emergency help right away if you take too much methadone hydrochloride (overdose). When you

first start taking methadone hydrochloride, 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. They could die from taking it. Store methadone

hydrochloride away from children and in a safe place to prevent stealing or abuse. Selling or giving

away methadone hydrochloride is against the law.

Do not take methadone hydrochloride 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, tell your healthcare provider if you have a history of:

head injury, seizures

liver, kidney, thyroid problems

problems urinating

pancreas or gallbladder problems

heart rhythm problems (Long QT syndrome)

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 during pregnancy

can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized

and treated.

breastfeeding. Methadone hydrochloride passes into breast milk and may harm your baby.

taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking methadone

hydrochloride with certain other medicines may cause serious side effects.

When taking methadone hydrochloride:

Do not change your dose. Take methadone hydrochloride exactly as prescribed by your healthcare

provider.

Do not take more than your prescribed dose in 24 hours. If you take methadone hydrochloride for pain

and miss a dose, take methadone hydrochloride 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 for opioid addiction and miss a dose, take your next dose the

following day as scheduled. Do not take extra doses. Taking more than the prescribed dose may cause

you to overdose because methadone hydrochloride builds up in your body over time.

Do not crush, dissolve, snort or inject methadone hydrochloride 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 without talking to your healthcare provider.

After you stop taking methadone hydrochloride, flush any unused tablets down the toilet.

While taking methadone hydrochloride Do Not:

Drive or operate heavy machinery, until you know how methadone hydrochloride affects you.

Methadone hydrochloride 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 may cause you to overdose and die.

The possible side effects of methadone hydrochloride are:

constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your

healthcare provider if you have any of these symptoms and they are severe.

Get emergency medical help if you have:

trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue or throat,

extreme drowsiness, light-headedness when changing positions, or you are feeling faint.

These are not all the possible side effects of methadone hydrochloride. Call your doctor for medical

advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more

information go to dailymed.nlm.nih.gov.

Distributed by: West-Ward Pharmaceuticals Corp., Eatontown, NJ 07724, 1-800-962-8364

This Medication Guide has been approved by the U.S. Food and Drug Administration. Issue: April 2014

4077442//10

METHADONE HYDROCHLORIDE

methadone hydrochloride tablet

Product Information

Product T ype

HUMAN PRESCRIPTION

DRUG

Ite m Code (Source )

NDC:6 19 19 -

6 70 (NDC:0 0 54-4571)

Route of Administration

ORAL

DEA Sche dule

Active Ingredient/Active Moiety

Dire ct_Rx

Ingredient Name

Basis of Strength

Stre ng th

METHADO NE HYDRO CHLO RIDE (UNII: 229 8 0 9 9 35B) (METHADONE -

UNII:UC6 VBE7V1Z)

METHADONE

HYDROCHLORIDE

10 mg

Inactive Ingredients

Ingredient Name

Stre ng th

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

STARCH, CO RN (UNII: O8 232NY3SJ)

CELLULO SE, MICRO CRYSTALLINE (UNII: OP1R32D6 1U)

Product Characteristics

Color

white

S core

2 pieces

S hap e

ROUND

S iz e

9 mm

Flavor

Imprint Code

54;142

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 19 19 -6 70 -9 0

9 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 7/23/20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

NDA0 0 6 134

0 7/23/20 19

Labeler -

Direct_Rx (079254320)

Registrant -

Direct_Rx (079254320)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Dire c t_Rx

0 79 254320

re pa c k(6 19 19 -6 70 )

Revised: 7/2019

Similar products

Search alerts related to this product

View documents history

Share this information