METHADONE HYDROCHLORIDE- methadone hydrochloride concentrate

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

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Active ingredient:
METHADONE HYDROCHLORIDE (UNII: 229809935B) (METHADONE - UNII:UC6VBE7V1Z)
Available from:
ATLANTIC BIOLOGICALS CORP.
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
- For detoxification treatment of opioid addiction (heroin or other morphine-like drugs). - For maintenance treatment of opioid addiction (heroin or other morphine-like drugs), in conjunction with appropriate social and medical services.  Methadone products used for the treatment of opioid addiction in detoxification or maintenance programs are subject to the conditions for distribution and use required under 21 CFR, Title 42, Sec 8 (see DOSAGE AND ADMINISTRATION ). Methadone hydrochloride is 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 gastrointestinal obstruction, including paralytic ileus - Hypersensitivity (e.g., anaphylaxis) to methadone or any other ingredient in methadone hydrochloride oral concentrate   Methadone hydrochloride oral concentrate contains methadone, a Schedule II opioid agonist. Schedule II opioid substances, which also include hydromor
Product summary:
Methadone hydrochloride oral concentrate USP 10 mg/mL is supplied as a red, cherry flavored liquid concentrate, as follows: 1 fl. oz. Bottle (30 mL) ………………NDC 66689-694-30 (Supplied with calibrated dropper); 1 Liter Bottle (1000 mL) ……………..NDC 66689-694-79 Methadone Hydrochloride Oral Concentrate, USP 10 mg/mL, is supplied as a dye-free, sugar-free, unflavored liquid concentrate, as follows: 1 fl. oz. Bottle (30 mL) ………………NDC 66689-695-30  (Supplied with calibrated dropper); 1 Liter Bottle (1000 mL) ……………..NDC 66689-695-79 Dispense in tight containers, protected from light. Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].
Authorization status:
Abbreviated New Drug Application
Authorization number:
17856-0694-1, 17856-0694-2

METHADONE HYDROCHLORIDE- methadone hydrochloride concentrate

ATLANTIC BIOLOGICALS CORP.

----------

Methadone HCl Oral Concentrate

Methadone Hydrochloride Oral Concentrate, USP

and

Methadone Hydrochloride Oral Concentrate, USP

(dye-free, sugar-free, unflavored)

10 mg/mL

CII

Rx only

FOR ORAL USE ONLY

WARNING: LIFE-THREATENING RESPIRATORY DEPRESSION, LIFE-

THREATENING QT PROLONGATION, ACCIDENTAL INGESTION, ABUSE,

POTENTIAL INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450

ISOENZYMES and TREATMENT FOR OPIOID ADDICTION

Life-Threatening Respiratory Depression

Respiratory depression, including fatal cases, have been reported during initiation and

conversion of patients to methadone, and even when the drug has been used as

recommended and not misused or abused (seeWARNINGS). Proper dosing and titration

are essential and methadone hydrochloride oral concentrate should only be prescribed by

healthcare professionals who are knowledgeable in the use of methadone for detoxification

and maintenance treatment of opioid addiction. Monitor for respiratory depression,

especially during initiation of methadone hydrochloride oral concentrate or following a dose

increase. The peak respiratory depressant effect of methadone occurs later, and persists

longer than the peak pharmacologic effect, especially during the initial dosing period (see

WARNINGS).

Risks From Concomitant Use With Benzodiazepines or Other CNS Depressants

Concomitant use with benzodiazepines or other central nervous system (CNS)

depressants, including alcohol, is a risk factor for respiratory depression and death

(seeWARNINGSandPRECAUTIONS).

Reserve concomitant prescribing of benzodiazepines or other CNS depressants in

patients in methadone treatment to those for whom alternates to benzodiazepines or

other CNS depressants are inadequate.

Follow patients for signs and symptoms of respiratory depression and sedation. If the

patient is visibly sedated, evaluate the cause of sedation and consider delaying or

omitting daily methadone dosing.

Life-Threatening QT Prolongation

QT interval prolongation and serious arrhythmia (torsades de pointes) have occurred

during treatment with methadone (see WARNINGS). Most cases involve patients being

treated for pain with large, multiple daily doses of methadone, although cases have been

reported in patients receiving doses commonly used for maintenance treatment of opioid

addiction. Closely monitor patients with risk factors for development of prolonged QT

interval, a history of cardiac conduction abnormalities, and those taking medications

affecting cardiac conduction for changes in cardiac rhythm during initiation and titration of

methadone hydrochloride oral concentrate (see WARNINGS).

Accidental Ingestion

Accidental ingestion of methadone hydrochloride oral concentrate, especially by children,

can result in fatal overdose of methadone (seeWARNINGS).

Misuse, Abuse, and Diversion of Opioids

Methadone hydrochloride oral concentrate contains methadone, an opioid agonist and

Schedule II controlled substance with an abuse liability similar to other opioid agonists,

legal or illicit (seeWARNINGS).

Interactions with Drugs Affecting Cytochrome P450 Isoenzymes

The concomitant use of methadone hydrochloride oral concentrate with all cytochrome

P450 3A4, 2B6, 2C19, 2C9 or 2D6 inhibitors may result in an increase in methadone

plasma concentrations, which could cause potentially fatal respiratory depression. In

addition, discontinuation of concomitantly used cytochrome P450 3A4 2B6, 2C19, or 2C9

inducers may also result in an increase in methadone plasma concentration. Follow patients

closely for respiratory depression and sedation, and consider dosage reduction with any

changes of concomitant medications that can result in an increase in methadone levels

(seeWARNINGSandPRECAUTIONS, Drug Interactions).

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 (seeDOSAGE AND

ADMINISTRATION).

DESCRIPTION

Methadone Hydrochloride Oral Concentrate, USP, contains methadone, an opiate agonist, and is

available as a cherry flavored liquid concentrate for oral administration. Methadone Hydrochloride

Oral Concentrate, USP Sugar-free is a dye-free, sugar-free, unflavored liquid concentrate for oral

administration. Each liquid concentrate contains 10 mg of methadone hydrochloride per mL.

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

hydrochloride. Methadone hydrochloride is a white, essentially odorless, bitter-tasting crystalline

powder. It is very soluble in water, soluble in isopropanol and in chloroform, and practically insoluble

in ether and in glycerine. It is present in methadone hydrochloride oral concentrate as the racemic

mixture. Methadone hydrochloride has a melting point of 235°C, a pKa of 8.25 in water at 20°C, a

solution (1 part per 100) pH between 4.5 and 6.5, a partition coefficient of 117 at pH 7.4 in

octanol/water. Its structural formula is:

C H NOHCl MW = 345.91

Other ingredients of methadone hydrochloride oral concentrate, USP: artificial cherry flavor, sorbic

acid, potassium sorbate, FD&C red no. 40, D&C red no. 33, poloxamer 188, propylene glycol,

glycerin, sucrose, and purified water.

Other ingredients of Methadone Hydrochloride Oral Concentrate, USP (Dye-Free, Sugar-Free,

Unflavored): citric acid anhydrous, purified water, and sodium benzoate.

CLINICAL PHARMACOLOGY

Mechanism of Action

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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

analgesia and detoxification or maintenance treatment in opioid addiction. The methadone abstinence

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

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

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

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

Pharmacodynamics

Effects on the Central Nervous System

Methadone produces respiratory depression by direct action on brain stem respiratory centers. The

respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers

to both increases in carbon dioxide tension and electrical stimulation.

Methadone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are

not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar

findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

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

Effects on the Gastrointestinal Tract and Other Smooth Muscle

Methadone causes a reduction in motility associated with an increase in smooth muscle tone in the

antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive

contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone is

increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a

reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in

serum amylase.

Effects on the Cardiovascular System

Methadone produces peripheral vasodilation, which may result in orthostatic hypotension or syncope.

Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red

eyes, sweating, and/or orthostatic hypotension.

Effects on the Endocrine System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing

hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic

secretion of insulin and glucagon.

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen

deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.

The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various

medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels

have not been adequately controlled for in studies conducted to date.

Effects on the Immune System

Opioids have been shown to have a variety of effects on components of the immune system in in vitro

and animal models. The clinical significance of these findings is unknown. Overall, the effects of

opioids appear to be modestly immunosuppressive.

Concentration–Adverse Reaction Relationships

There is a relationship between increasing methadone plasma concentration and increasing frequency of

There is a relationship between increasing methadone plasma concentration and increasing frequency of

dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory

depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to

opioid-related adverse reactions.

Pharmacokinetics

Abs orption

Following oral administration the bioavailability of methadone ranges between 36 to 100% and peak

plasma concentrations are achieved between 1 and 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 α -acid glycoprotein (85% to 90%). Methadone is

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

Metabolis m

Methadone is primarily metabolized by N-demethylation to an inactive metabolite, 2-ethylidene-1, 5-

dimethyl-3,3-diphenylpyrrolidene (EDDP). Cytochrome P450 enzymes, primarily CYP3A4, CYP2B6,

CYP2C19, CYP2C9 and CYP2D6, are responsible for conversion of methadone to EDDP and other

inactive metabolites, which are excreted mainly in the urine.

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 (T

) was highly

variable and ranged between 8 and 59 hours in different studies. 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.

Specific Populations

Use During Pregnancy

The disposition of oral methadone has been studied in approximately 30 pregnant patients in the second

and third trimesters. Elimination of methadone was significantly changed in pregnancy. 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

second and third 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 (see PRECAUTIONS, Pregnancy, Labor and Delivery, andDOSAGE

AND ADMINISTRATION).

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 accumulating

methadone after multiple dosing.

Renal Impairment

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

Unmetabolized methadone and its metabolites are excreted in urine to a variable degree. Methadone is a

basic (pKa=9.2) compound and the pH of the urinary tract can alter its disposition in plasma. Urine

acidification has been shown to increase renal elimination of methadone. Forced diuresis, peritoneal

dialysis, hemodialysis, or charcoal hemoperfusion have not been established as beneficial for

increasing the elimination of methadone or its metabolites.

Sex

The pharmacokinetics of methadone have not been evaluated for sex specificity.

Race

The pharmacokinetics of methadone have not been evaluated for race specificity.

Age

Geriatric Population

The pharmacokinetics of methadone have not been evaluated in the geriatric population.

Pediatric Population

The pharmacokinetics of methadone have not been evaluated in the pediatric population.

Drug Interaction Studies

Cytochrome P450 Interactions

Methadone undergoes hepatic N-demethylation by cytochrome P450 isoforms, principally CYP3A4,

CYP2B6, CYP2C19, CYP2C9 and CYP2D6. Coadministration of methadone with inducers of these

enzymes may result in more rapid methadone metabolism, and potentially, decreased effects of

methadone. Conversely, administration with CYP inhibitors may reduce metabolism and potentiate

methadone’s effects. Pharmacokinetics of methadone may be unpredictable when coadministered with

drugs that are known to both induce and inhibit CYP enzymes. 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 their CYP induction

activity.

Cytochrome P450 Inducers

The following drug interactions were reported following coadministration of methadone with inducers

of cytochrome P450 enzymes:

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

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

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

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

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

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

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

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

inducers may result in withdrawal symptoms.

Cytochrome P450 Inhibitors

Voriconazole - Voriconazole can inhibit the activity of CYP3A4, CYP2C9 and CYP2C19. Repeat dose

administration of oral voriconazole (400 mg Q12h for 1 day, then 200 mg Q12h for 4 days) increased

the C

and AUC of (R)-methadone by 31% and 47%, respectively, in subjects receiving a methadone

maintenance dose (30 to 100 mg QD). The C

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.

Anti-Retroviral Agents

Although anti-retroviral drugs such as efavirenz, nelfinavir, nevirapine, ritonavir, and

lopinavir+ritonavir combination are known to inhibit CYPs, they are shown to reduce the plasma levels

of methadone, possibly due to their CYP induction activity.

Abacavir, amprenavir, efavirenz, nelfinavir, nevirapine, ritonavir, lopinavir+ritonavir combination –

Coadministration of these anti-retroviral agents resulted in increased clearance or decreased plasma

levels of methadone.

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.

INDICATIONS AND USAGE

1. For detoxification treatment of opioid addiction (heroin or other morphine-like drugs).

2. For maintenance treatment of opioid addiction (heroin or other morphine-like drugs), in conjunction

with appropriate social and medical services.

Limitations of Use

Methadone products used for the treatment of opioid addiction in detoxification or maintenance

programs are subject to the conditions for distribution and use required under 21 CFR, Title 42, Sec 8

(see DOSAGE AND ADMINISTRATION).

CONTRAINDICATIONS

Methadone hydrochloride is 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 gastrointestinal obstruction, including paralytic ileus

Hypersensitivity (e.g., anaphylaxis) to methadone or any other ingredient in methadone

hydrochloride oral concentrate

WARNINGS

Methadone hydrochloride oral concentrate and Methadone hydrochloride oral concentrate Sugar-

Free are for oral administration only. The preparation must not be injected. Methadone

hydrochloride oral concentrate and Methadone hydrochloride oral concentrate Sugar-Free, if

dispensed, should be packaged in child-resistant containers and kept out of reach of children to

prevent accidental ingestion.

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of methadone,

even when used as recommended. Respiratory depression, if not immediately recognized and treated,

may lead to respiratory arrest and death. Respiratory depression from opioids is manifested by a

reduced urge to breathe and a decreased rate of respiration, often associated with a “sighing” pattern of

breathing (deep breaths separated by abnormally long pauses). Carbon dioxide (CO ) retention from

opioid-induced respiratory depression can exacerbate the sedating effects of opioids. Management of

respiratory depression may include close observation, supportive measures, and use of opioid

antagonists, depending on the patient’s clinical status (see OVERDOSAGE).

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

methadone hydrochloride oral concentrate, 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 pharmacologic effect, especially during the initial dosing period. Monitor

patients closely for respiratory depression, when initiating therapy with methadone hydrochloride oral

concentrate and following dose increases.

Instruct patients against use by individuals other than the patient for whom methadone was prescribed

and to keep methadone out of the reach of children, as such inappropriate use may result in fatal

respiratory depression.

To reduce the risk of respiratory depression, proper dosing and titration of methadone are essential (see

DOSAGE AND ADMINISTRATION). Overestimating the methadone dosage when initiating

treatment can result in fatal overdose with the first dose.

To further reduce the risk of respiratory depression, consider the following:

Patients tolerant to other opioids may be incompletely tolerant to methadone. Incomplete cross-

tolerance is of particular concern for patients tolerant to other mu-opioid agonists. Deaths have been

reported during conversion from chronic, high-dose treatment with other opioid agonists. Follow

induction directions closely to avoid inadvertent overdose (see DOSAGE AND

ADMINISTRATION).

Proper dosing and titration are essential and methadone should be overseen only by healthcare

professionals who are knowledgeable in the pharmacokinetics and pharmacodynamics of

methadone.

Risks from Concomitant Use of Benzodiazepines or Other CNS Depressants with Methadone

Concomitant use of methadone and benzodiazepines or other CNS depressants increases the risk of

adverse reactions including overdose and death. Medication-assisted treatment of opioid use disorder,

however, should not be categorically denied to patients taking these drugs. Prohibiting or creating

barriers to treatment can pose an even greater risk of morbidity and mortality due to the opioid use

disorder alone.

As a routine part of orientation to methadone treatment, educate patients about the risks of concomitant

use of benzodiazepines, sedatives, opioid analgesics, or alcohol.

Develop strategies to manage use of prescribed or illicit benzodiazepines or other CNS depressants at

admission to methadone treatment, or if it emerges as a concern during treatment. Adjustments to

induction procedures and additional monitoring may be required. There is no evidence to support dose

limitations or arbitrary caps of methadone as a strategy to address benzodiazepine use in methadone-

treated patients. However, if a patient is sedated at the time of methadone dosing, ensure that a

medically-trained healthcare provider evaluates the cause of sedation and delays or omits the methadone

dose if appropriate.

Cessation of benzodiazepines or other CNS depressants is preferred in most cases of concomitant use.

In some cases monitoring in a higher level of care for taper may be appropriate. In others, gradually

tapering a patient off a prescribed benzodiazepine or other CNS depressant or decreasing to the lowest

effective dose may be appropriate.

For patients in methadone treatment, benzodiazepines are not the treatment of choice for anxiety or

insomnia. Before co-prescribing benzodiazepines, ensure that patients are appropriately diagnosed and

consider alternative medications and non-pharmacologic treatments to address anxiety or insomnia.

Ensure that other healthcare providers prescribing benzodiazepines or other CNS depressants are

aware of the patient’s methadone treatment and coordinate care to minimize the risks associated with

concomitant use.

In addition, take measures to confirm that patients are taking the medications prescribed and not diverting

or supplementing with illicit drugs. Toxicology screening should test for prescribed and illicit

benzodiazepines (see PRECAUTIONS, Drug Interactions).

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 hydrochloride oral concentrate

treatment for the presence of modifiable risk factors, such as concomitant medications with cardiac

effects, drugs which might cause electrolyte abnormalities, and drugs which might act as inhibitors of

methadone metabolism.

Only initiate therapy with methadone hydrochloride oral concentrate 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.

Accidental Ingestion

Accidental ingestion of even one dose of methadone hydrochloride oral concentrate, especially by

children, can result in respiratory depression and death due to an overdose. Keep methadone

hydrochloride oral concentrate out of reach of children to prevent accidental ingestion.

Misuse, Abuse, and Diversion of Opioids

Methadone hydrochloride oral concentrate contain methadone, an opioid agonist and a Schedule II

controlled substance. Methadone can be abused in a manner similar to other opioid agonists, legal or

illicit. Opioid agonists are sought by drug abusers and people with addiction disorders and are subject

to criminal diversion.

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.

Neonatal Opioid Withdrawal Syndrome

Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use

of opioids during pregnancy, whether that use is medically-authorized or illicit. Unlike opioid

withdrawal syndrome in adults, NOWS may be life-threatening if not recognized and treated in the

neonate. Healthcare professionals should observe newborns for signs of NOWS and manage

accordingly (seePRECAUTIONS, Pregnancy).

Advise pregnant women receiving opioid addiction treatment with methadone hydrochloride oral

concentrate of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment

will be available. This risk must be balanced against the risk of untreated opioid addiction which often

results in continued or relapsing illicit opioid use and is associated with poor pregnancy outcomes.

Therefore, prescribers should discuss the importance and benefits of management of opioid addiction

throughout pregnancy.

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

Discontinuation P450 3A4, 2B6, 2C19, or 2C9 Inducers

Concomitant use of methadone hydrochloride oral concentrate with CYP3A4, CYP2B6, CYP2C19,

CYP2C9, or CYP2D6 inhibitors, may increase plasma concentrations of methadone, prolong opioid

adverse reactions, and may cause potentially fatal respiratory depression, particularly when an inhibitor

is added after a stable dose of methadone hydrochloride oral concentrate is achieved. Similarly,

discontinuation of concomitant CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers in methadone

hydrochloride oral concentrate-treated patients may increase methadone plasma concentrations resulting

in fatal respiratory depression. Consider dosage reduction of methadone hydrochloride oral

concentrate when using concomitant CYP3A4, CYP2B6, CYP2C19, CYP2C9 or CYP2D6 inhibitors or

discontinuing CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers in methadone-treated patients, and

follow patients closely at frequent intervals for signs and symptoms of respiratory depression and

sedation.

Addition of CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers or discontinuation of a CYP3A4,

CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors in patients treated with methadone hydrochloride

oral concentrate may decrease methadone plasma concentrations, reducing efficacy or, and may, lead to

a withdrawal symptoms in patients physically dependent on methadone. When using methadone

hydrochloride oral concentrate with CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers or

discontinuing CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors, follow patients for signs

or symptoms of opioid withdrawal and consider increasing the methadone hydrochloride oral

concentrate dosage as needed.

Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in

Elderly, Cachectic, or Debilitated Patients

The use of methadone hydrochloride oral concentrate in patients with acute or severe bronchial asthma

in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Patients with Chronic Pulmonary Disease - Methadone hydrochloride oral concentrate-treated patients

with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially

decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at

increased risk of decreased respiratory drive including apnea, even at recommended dosages of

methadone hydrochloride oral concentrate (see WARNINGS, Life-Threatening Respiratory

Depres s ion).

Elderly, Cachectic, or Debilitated Patients - Life-threatening respiratory depression is more likely to

occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or

altered clearance compared to younger, healthier patients (see WARNINGS, Life-Threatening

Respiratory Depression).

Monitor such patients closely, particularly when initiating and titrating methadone hydrochloride oral

concentrate and when methadone hydrochloride oral concentrate is given concomitantly with other

drugs that depress respiration.

Serotonin Syndrome with Concomitant Use of Serotonergic Drugs

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during

concomitant use of methadone hydrochloride oral concentrate with serotonergic drugs. Serotonergic

drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake

inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that

affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and drugs that

impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric

disorders and also others, such as linezolid and intravenous methylene blue) (see PRECAUTIONS,

Drug Interactions). This may occur within the recommended dosage range.

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma),

autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations

(e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting,

diarrhea). The onset of symptoms generally occurs within several hours to a few days of concomitant

use, but may occur later than that. Discontinue methadone hydrochloride oral concentrate if serotonin

syndrome is suspected.

Adrenal Insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than

one month of use. Presentation of adrenal insufficiency may include nonspecific symptoms and signs

including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal

insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal

insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the

patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until

adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid

without recurrence of adrenal insufficiency. The information available does not identify any particular

opioids as being more likely to be associated with adrenal insufficiency.

Severe Hypotension

Methadone may cause severe hypotension including orthostatic hypotension and syncope in ambulatory

patients. There is an increased risk in patients whose ability to maintain normal blood pressure is

compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs

(e.g., phenothiazines or general anesthetics) (see PRECAUTIONS, Drug Interactions). Monitor these

patients for signs of hypotension after initiating or titrating the dosage of methadone hydrochloride oral

concentrate. In patients with circulatory shock, methadone hydrochloride oral concentrate may cause

vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of methadone

hydrochloride oral concentrate in patients with circulatory shock.

Use in Patients with Head Injury or Increased Intracranial Pressure

In patients who may be susceptible to the intracranial effects of CO retention (e.g., those with evidence

of increased intracranial pressure or brain tumors), methadone hydrochloride oral concentrate may

reduce respiratory drive, and the resultant CO retention can further increase intracranial pressure.

Monitor such patients for signs of sedation and respiratory depression, particularly when initiating

therapy with methadone.

Opioids may also obscure the clinical course in a patient with a head injury.

Avoid the use of methadone in patients with impaired consciousness or coma.

Risks of Use in Patients with Gastrointestinal Conditions

Methadone hydrochloride oral concentrate is contraindicated in patients with known or suspected

gastrointestinal obstruction, including paralytic ileus. The methadone in methadone hydrochloride oral

concentrate may cause spasm of the sphincter of Oddi. Opioids may cause increases in the serum

concentrate may cause spasm of the sphincter of Oddi. Opioids may cause increases in the serum

amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening

symptoms.

Increased Risks of Seizure in Patients with Seizure Disorders

Methadone may increase frequency of seizures in patients with seizure disorders, and increase the risks

of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history

of seizure disorders for worsened seizure control during methadone hydrochloride oral concentrate

therapy.

Withdrawal

Avoid the use of mixed agonist/antagonist (i.e., pentazocine, nalbuphine, and butorphanol) or partial

agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist, including

methadone hydrochloride oral concentrate. In these patients, mixed agonists/antagonist and partial

agonist analgesics may precipitate withdrawal symptoms (see PRECAUTIONS, Drug Interactions).

When discontinuing methadone hydrochloride oral concentrate, gradually taper the dosage (see

DOSAGE AND ADMINISTRATION). Do not abruptly discontinue methadone hydrochloride oral

concentrate.

Use in Ambulatory Patients

Driving or Operating Heavy Machinery

Inform patients that methadone hydrochloride oral concentrate may impair the ability to perform

potentially hazardous activities such as driving or operating heavy machinery. Advise patients not to

perform such tasks until they know how they will react to the medication (see PRECAUTIONS,

Information for Patients).

Laboratory Test Interactions

False positive urine drug screens for methadone have been reported for several drugs including

diphenhydramine, doxylamine, clomipramaine, chlorpromazine, thioridazine, quetiapine, and verapamil.

PRECAUTIONS

Information for Patients

Life-Threatening Respiratory Depression

Discuss the risk of respiratory depression with patients, explaining that the risk is greatest when starting

methadone hydrochloride oral concentrate or when the dose is increased (see WARNINGS). Advise

patients how to recognize respiratory depression and to seek medical attention if they are experiencing

breathing difficulties.

Interactions with Benzodiazepines and Other CNS Depressants

Inform patients and caregivers that potentially fatal addictive effects may occur if methadone

hydrochloride oral concentrate is used with benzodiazepines or other CNS depressants, including

alcohol. Counsel patients that such medications should not be used concomitantly unless supervised by a

healthcare provider (see WARNINGS and PRECAUTIONS, Drug Interactions).

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 hydrochloride oral

concentrate (see WARNINGS).

Accidental Ingestion

Inform patients that accidental ingestion, especially by children, may result in respiratory depression or

death (see WARNINGS). Instruct patients to take steps to store methadone hydrochloride oral

concentrate securely. Advise patients to dispose of unused methadone hydrochloride oral concentrate

by flushing down the toilet.

Abuse Potential

Inform patients that methadone hydrochloride oral concentrate contains methadone, a Schedule II

controlled substance that is subject to abuse (see WARNINGS). Instruct patients not to share methadone

hydrochloride oral concentrate with others and to take steps to protect methadone hydrochloride oral

concentrate from theft or misuse.

Important Administration Instructions (see DOSAGE AND ADMINISTRATION)

Instruct patients how to properly take methadone hydrochloride oral concentrate, including the

following:

Methadone hydrochloride oral concentrate is for oral administration only. The preparation must not

be injected.

Inform patients that methadone hydrochloride oral concentrate should be taken only as directed to

reduce the risk of life-threatening adverse reactions (e.g., respiratory depression), and the dose

should not be adjusted without consulting a physician or other healthcare professional.

Reassure patients initiating treatment with methadone hydrochloride oral concentrate for opioid

dependence that the dose of methadone will “hold” for longer periods of time as treatment

progresses.

Apprise patients seeking to discontinue treatment with methadone for opioid dependence of the high

risk of relapse to illicit drug use associated with discontinuation of methadone hydrochloride oral

concentrate maintenance treatment.

Advise patients not to discontinue methadone hydrochloride oral concentrate without first

discussing the need for a tapering regimen with the prescriber.

Serotonin Syndrome

Inform patients that methadone hydrochloride oral concentrate could cause a rare but potentially life-

threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of

the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop.

Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications

(see WARNINGS and PRECAUTIONS, Drug Interactions).

MAOI Interaction

Inform patients to avoid taking methadone hydrochloride oral concentrate while using any drugs that

inhibit monoamine oxidase. Patients should not start MAOIs while taking methadone hydrochloride oral

concentrate (see WARNINGS and PRECAUTIONS, Drug Interactions).

Adrenal Insufficiency

Inform patients that methadone hydrochloride oral concentrate could cause adrenal insufficiency, a

potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms

and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure.

Advise patients to seek medical attention if they experience a constellation of these symptoms (see

WARNINGS).

Anaphylaxis

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

hydrochloride oral concentrate. Advise patients how to recognize such a reaction and when to seek

medical attention (see ADVERSE REACTIONS).

Neonatal Opioid Withdrawal

Advise women that if they are pregnant while being treated with methadone hydrochloride oral

concentrate, the baby may have signs of withdrawal at birth and that withdrawal is treatable (see

WARNINGS).

Lactation

Instruct nursing mothers using methadone hydrochloride oral concentrate 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 their baby’s

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

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

services) (see PRECAUTIONS, Pregnancy).

Cons tipation

Advise patients of the potential for severe constipation, including management instructions and when to

seek medical attention (see CLINICAL PHARMACOLOGY and ADVERSE REACTIONS).

Drug Interactions

Benzodiazepines and Other Central Nervous System (CNS) Depressants

Clinical Impact:

Due to additive pharmacologic effect, the concomitant use of

benzodiazepines or other CNS depressants, including alcohol, increases the

risk of respiratory depression, profound sedation, coma, and death.

Intervention:

Cessation of benzodiazepines or other CNS depressants is preferred in most

cases of concomitant use. In some cases, monitoring in a higher level of care

for taper may be appropriate. In others, gradually tapering a patient off of a

prescribed benzodiazepine or other CNS depressant or decreasing to the

lowest effective dose may be appropriate.

Before co-prescribing benzodiazepines for anxiety or insomnia, ensure that

patients are appropriately diagnosed and consider alternative medications and

non-pharmacologic treatments (see WARNINGS).

Examples:

Alcohol, benzodiazepines, and other sedatives/hypnotics, anxiolytics,

tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other

opioids.

Inhibitors of CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6

Clinical Impact:

Methadone undergoes hepatic N-demethylation by several cytochrome P450

(CYP) isoforms, including CYP3A4, CYP2B6, CYP2C19, CYP2C9, and

CYP2D6. The concomitant use of methadone and CYP3A4, CYP2B6,

CYP2C19, CYP2C9, or CYP2D6 inhibitors can increase the plasma

concentration of methadone, resulting in increased or prolonged opioid

effects, and may result in a fatal overdose, particularly when an inhibitor is

added after a stable dose of methadone is achieved. These effects may be

more pronounced with concomitant use of drugs that inhibit more than one of

the CYP enzymes listed above.

After stopping a CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6

inhibitor, as the effects of the inhibitor decline, the methadone plasma

concentration can decrease, resulting in decreased opioid efficacy or

withdrawal symptoms in patients physically dependent on methadone.

Intervention:

If concomitant use is necessary, consider dosage reduction of methadone

until stable drug effects are achieved. Monitor patients for respiratory

depression and sedation at frequent intervals.

If a CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitor is

discontinued, follow patients for signs of opioid withdrawal and consider

increasing the methadone dosage until stable drug effects are achieved.

Examples:

Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g.,

ketoconazole), protease inhibitors (e.g., ritonavir), fluconazole, fluvoxamine,

some selective serotonin reuptake inhibitors (SSRIs) (e.g., sertraline,

fluvoxamine)

Inducers of CYP3A4, CYP2B6, CYP2C19, or CYP2C9

Clinical Impact:

The concomitant use of methadone and CYP3A4, CYP2B6, CYP2C19, or

CYP2C9 inducers can decrease the plasma concentration of methadone,

resulting in decreased efficacy or onset of withdrawal symptoms in patients

physically dependent on methadone. These effects could be more

pronounced with concomitant use of drugs that can induce multiple CYP

enzymes.

After stopping a CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducer, as the

effects of the inducer decline, the methadone plasma concentration can

increase, which could increase or prolong both the therapeutic effects and

adverse reactions, and may cause serious respiratory depression, sedation, or

death.

Intervention:

If concomitant use is necessary, consider increasing the methadone dosage

until stable drug effects are achieved. Monitor for signs of opioid

withdrawal. If a CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducer is

discontinued, consider methadone dosage reduction and monitor for signs of

respiratory depression and sedation.

Examples:

Rifampin, carbamazepine, phenytoin, St. John’s Wort, Phenobarbital

Potentially Arrhythmogenic Agents

Clinical Impact:

Pharmacodynamic interactions may occur with concomitant use of methadone

and potentially arrhythmogenic agents or drugs capable of inducing

electrolyte disturbances (hypomagnesemia, hypokalemia).

Intervention:

Monitor patients closely for cardiac conduction changes.

Examples:

Drugs known to have potential to prolong QT interval: Class I and III

antiarrhythmics, some neuroleptics and tricyclic antidepressants, and calcium

channel blockers. Drugs capable of inducing electrolyte disturbances:

Diuretics, laxatives, and, in rare cases, mineralocortocoid hormones.

Serotonergic Drugs

Clinical Impact:

The concomitant use of opioids with other drugs that affect the serotonergic

neurotransmitter system has resulted in serotonin syndrome (see

WARNINGS).

Intervention:

If concomitant use is warranted, carefully observe the patient, particularly

during treatment initiation and dose adjustment. Discontinue methadone

hydrochloride oral concentrate if serotonin syndrome is suspected.

Examples:

Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine

reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-

HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter

system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO)

inhibitors (those intended to treat psychiatric disorders and also others, such

as linezolid and intravenous methylene blue).

Monoamine Oxidase Inhibitors (MAOIs)

Clinical Impact:

MAOI interactions with opioids may manifest as serotonin syndrome or

opioid toxicity (e.g., respiratory depression, coma) (see WARNINGS).

Intervention:

The use of methadone hydrochloride oral concentrate is not recommended

for patients taking MAOIs or within 14 days of stopping such treatment.

Examples:

phenelzine, tranylcypromine, linezolid

Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics

Clinical Impact:

Patients maintained on methadone may experience withdrawal symptoms when

given opioid antagonists, mixed agonist/antagonists, and partial agonists.

Intervention:

Avoid concomitant use.

Examples:

butorphanol, nalbuphine, pentazocine, buprenorphine

Muscle Relaxants

Clinical Impact:

Methadone may enhance the neuromuscular blocking action of skeletal

muscle relaxants and produce an increased degree of respiratory depression.

Intervention:

Monitor patients for signs of respiratory depression that may be greater than

otherwise expected and decrease the dosage of methadone hydrochloride

oral concentrate and/or the muscle relaxant as necessary.

Diuretics

Clinical Impact:

Opioids can reduce the efficacy of diuretics by inducing the release of

antidiuretic hormone.

Intervention:

Monitor patients for signs of diminished diuresis and/or effects on blood

pressure and increase the dosage of the diuretic as needed.

Anticholinergic Drugs

Clinical Impact:

The concomitant use of anticholinergic drugs may increase risk of urinary

retention and/or severe constipation, which may lead to paralytic ileus.

Intervention:

Monitor patients for signs of urinary retention or reduced gastric motility

when methadone hydrochloride oral concentrate is used concomitantly with

anticholinergic drugs.

Paradoxical Effects of Antiretroviral Agents on Methadone

Concurrent use of certain protease inhibitors with CYP3A4 inhibitory activity, alone and in combination,

such as abacavir, amprenavir, darunavir+ritonavir, efavirenz, nelfinavir, nevirapine, ritonavir, telaprevir,

lopinavir+ritonavir, saquinavir+ritonavir, and tipranvir+ritonavir, has resulted in increased clearance or

decreased plasma levels of methadone. This may result in reduced efficacy of methadone

hydrochloride oral concentrate and could precipitate a withdrawal syndrome. Monitor patients receiving

methadone hydrochloride oral concentrate and any of these antiretroviral therapies closely for evidence

of withdrawal effects and adjust the methadone hydrochloride oral concentrate dose accordingly.

Effects of Methadone 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.

Desipramine – Plasma levels of desipramine have increased with concurrent methadone administration.

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 (HDD). 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 the HDD. 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 the HDD. 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 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. In contrast,

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.

Impairment of Fertility - Published animal studies provide additional data indicating that methadone

treatment of males can alter reproductive function. Methadone produces decreased sexual activity

(mating) of male rats at 10 mg/kg/day (corresponding to 0.3 times the human daily oral dose of 120

mg/day based on body surface area). Methadone also produces a significant regression of sex

accessory organs and testes of male mice and rats at 0.2 and 0.8 times the HDD, respectively.

Methadone treatment of pregnant rats from Gestation Day 14 to 19 reduced fetal blood testosterone and

androstenedione in male. Decreased serum levels of testosterone were observed in male rats that were

treated with methadone (1.3 to 3.3 mg/kg/day for 14 days, corresponding to 0.1 to 0.3 times the HDD) or

10 to 15 mg/kg/day for 10 days (0.8 to 1.2 times the HDD).

Pregnancy

Pregnancy Category C. Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable

outcome of prolonged use of opioids during pregnancy(see WARNINGS).

There are no controlled studies of methadone use in pregnant women that can be used to establish

safety. However, an expert 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). 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 complicate the

interpretation of investigations of the children of women who take methadone during pregnancy. These

include the maternal use of illicit drugs, other maternal factors such as nutrition, infection, and

psychosocial circumstances, limited information regarding dose and duration of methadone use during

pregnancy, and the fact that most maternal exposure appears to occur after the first trimester of

pregnancy. Reported studies have generally compared the benefit of methadone to the risk of untreated

addiction to illicit drugs.

Methadone has been detected in amniotic fluid and cord plasma at concentrations proportional to

maternal plasma and in newborn urine at lower concentrations than corresponding maternal urine.

A retrospective series of 101 pregnant, opiate-dependent women who underwent inpatient opiate

detoxification with methadone did not demonstrate any increased risk of miscarriage in the second

trimester or premature delivery in the third trimester.

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. However, children born to women treated with methadone during pregnancy

have been shown to demonstrate mild but persistent deficits in performance on psychometric and

behavioral tests.

In published animal reproduction studies, methadone administered subcutaneously during the early

gestational period produced neural tube defects (i.e., exencephaly and cranioschisis) in the hamster at

doses 2 times the human daily oral dose of 120 mg/day on a mg/m basis (HDD) and in mice at doses

equivalent to the HDD. Administration of methadone to pregnant animals during organogenesis and

through lactation resulted decreased litter size, pup mortality, decreased pup body weights,

developmental delays, and long-term neurochemical changes in the brain of offspring which correlate

with altered behavioral responses that persist through adulthood at exposures comparable to and less

than the HDD. Administration of methadone to male rodents prior to mating with untreated females

resulted in increased neonatal mortality and significant differences in behavioral tests in the offspring at

exposures comparable to and less than the HDD (see Data). Based on animal data, advise pregnant

women of the potential risk to a fetus.

Neonatal opioid withdrawal syndrome may occur in newborn infants of mothers who are receiving

treatment with methadone hydrochloride oral concentrate.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern,

high pitched cry, tremor, vomiting, diarrhea, and/or failure to gain weight. Signs of neonatal withdrawal

usually occur in the first days after birth. The duration and severity of neonatal opioid withdrawal

syndrome may vary. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage

accordingly (see WARNINGS, Neonatal Opioid Withdrawal Syndrome).

Abnormal fetal nonstress tests (NSTs) 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.

Data

Animal Data

Formal reproductive and developmental toxicology studies for methadone have not been conducted.

Exposure margins for the following published study reports are based on a human daily dose (HDD) of

120 mg methadone using a body surface area comparison.

In a published study in pregnant hamsters, a single subcutaneous dose of methadone ranging from 31

mg/kg (2 times the HDD) to 185 mg/kg on Gestation Day 8 resulted in a decrease in the number of

fetuses per litter and an increase in the percentage of fetuses exhibiting neural tube defects including

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

in maternal death. In a study in pregnant mice, a single subcutaneous dose of 22 to 24 mg/kg methadone

(approximately equivalent to the HDD) administered on Gestation Day 9 produced exencephaly in 11%

of the embryos. In another study in pregnant mice, subcutaneous doses up to 28 mg/kg/day methadone

(equivalent to the HDD) administered from Gestation Day 6 to 15 resulted in no malformations, but there

were increased postimplantation loss and decreased live fetuses at 10 mg/kg/day or greater (0.4 times

the HDD) and decreased ossification and fetal body weight at 20 mg/kg/day or greater (0.8 times the

HDD). In a second study of pregnant mice dosed with subcutaneous doses up to 28 mg/kg/day

methadone from Gestation Day 6 to 15, there was decreased pup viability, delayed onset of development

of negative phototaxis and eye opening, increased righting reflexes at 5 mg/kg/day or greater (0.2 times

the HDD), and decreased number of live pups at birth and decreased pup weight gain at 20 mg/kg/day or

greater (0.8 times the HDD). No effects were reported in a study of pregnant rats and rabbits at oral

doses up to 40 mg/kg (3 and 6 times, respectively, the HDD) administered from Gestation Days 6 to 15

and 6 to 18, respectively.

When pregnant rats were treated with intraperitoneal doses of 2.5, 5, or 7.5 mg/kg methadone from one

week prior to mating, through gestation until the end of lactation period, 5 mg/kg or greater (0.4 times

the HDD) methadone resulted in decreases in litter size and live pups born and 7.5 mg/kg (0.6 times the

HDD) resulted in decreased birth weights. Furthermore, decreased pup viability and pup body weight

gain at 2.5 mg/kg or greater (0.2 times the HDD) were noted during the preweaning period.

Additional animal data demonstrates evidence for neurochemical changes in the brains of offspring from

methadone-treated pregnant rats, including changes to the cholinergic, dopaminergic, noradrenergic and

serotonergic systems at doses below the HDD. Other animal studies have reported that prenatal and/or

postnatal exposure to opioids including methadone alters neuronal development and behavior in the

offspring including alterations in learning ability, motor activity, thermal regulation, nociceptive

responses, and sensitivity to drugs at doses below the HDD. Treatment of pregnant rats subcutaneously

with 5 mg/kg methadone from Gestation Day 14 to 19 (0.4 times the HDD) reduced fetal blood

testosterone and androstenedione in males.

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

were treated with methadone at doses comparable to and less than the HDD for 1 to 12 days before

and/or during mating (with more pronounced effects in the first 4 days). In these studies, the female

rodents were not treated with methadone, indicating paternally-mediated developmental toxicity.

Specifically, methadone administered to the male rat prior to mating with methadone-naïve females

resulted in decreased weight gain in progeny after weaning. The male progeny demonstrated reduced

thymus weights, whereas the female progeny demonstrated increased adrenal weights. Behavioral

testing of these male and female progeny revealed significant differences in behavioral tests compared

to control animals, suggesting that paternal methadone exposure can produce physiological and

behavioral changes in progeny in this model. Examination of uterine contents of methadone-naïve female

mice bred to methadone-treated male mice (once a day for three consecutive days) indicated that

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

at 1 mg/kg/day or greater (0.04 times the HDD). Chromosome analysis revealed a dose-dependent

increase in the frequency of chromosomal abnormalities at 1 mg/kg/day or greater.

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

methadone-naïve females did not produce any adverse effects, suggesting that prolonged methadone

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

Mechanistic studies in this rat model suggest that the developmental effects of “paternal” methadone on

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

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

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

Labor and Delivery

As with all opioids, administration of this product to the mother shortly before delivery may result in

some degree of respiratory depression in the newborn, especially if higher doses are used. Methadone

is not recommended for obstetric analgesia because its long duration of action increases the probability

of respiratory depression in the newborn. Narcotics with mixed agonist/antagonist properties should not

be used for pain control during labor in patients chronically treated with methadone as they may

precipitate acute withdrawal.

Lactation

Risk Summary

Based on two studies in 22 breastfeeding women maintained on methadone treatment, methadone was

present in low levels in human milk, and did not show adverse reactions in breastfed infants. The

developmental and health benefits of breastfeeding should be considered along with the mother’s

clinical need for methadone and any potential adverse effects on the breastfed child from the drug or

from the underlying maternal condition.

Clinical Considerations

Advise breastfeeding women taking methadone to monitor the infant for increased drowsiness and

breathing difficulties.

Data

In a study of ten breastfeeding women maintained on oral methadone doses of 10 to 80 mg/day,

methadone concentrations from 50 to 570 mcg/L in milk were reported, which, in the majority of

samples, were lower than maternal serum drug concentrations at steady state.

In a study of twelve breastfeeding women maintained on oral methadone doses of 20 to 80 mg/day,

methadone concentrations from 39 to 232 mcg/L in milk were reported. 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.

There have been rare cases of sedation and respiratory depression in infants exposed to methadone

through breast milk.

Females and Males of Reproductive Potential

Infertility

Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is

not known whether these effects on fertility are reversible(see ADVERSE REACTIONS).

Reproductive function in human males may be decreased by methadone treatment. Reductions in

ejaculate volume and seminal vesicle and prostate secretions have been reported in methadone-treated

individuals. In addition, reductions in serum testosterone levels and sperm motility, and abnormalities in

sperm morphology have been reported.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 18 years have not been established.

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,

dose selection for elderly patients should be cautious, usually starting at the low end of the dosing

range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of

concomitant disease or other drug therapy.

Methadone is known to be substantially excreted by the kidney, and the risk of adverse reactions to this

drug may be greater in patients with impaired renal function. Because elderly patients are more likely to

have decreased renal function, care should be taken in dose selection, and it may be useful to monitor

renal function.

Hepatic Impairment

The use of methadone has not been extensively evaluated in patients with hepatic insufficiency.

Methadone is metabolized in the liver and patients with liver impairment may be at risk of accumulating

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.

Renal Impairment

The use of methadone has 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.

ADVERSE REACTIONS

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. In such

individuals, lower doses are advisable.

Other adverse reactions include the following: (listed alphabetically under each subsection)

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

Cardiovascular (see WARNINGS, Cardiac Conduction Effects) – arrhythmias, bigeminal rhythms,

bradycardia, cardiomyopathy, ECG abnormalities, extrasystoles, flushing, heart failure, hypotension,

palpitations, phlebitis, QT interval prolongation, syncope, T-wave inversion, tachycardia, torsade de

pointes, ventricular fibrillation, ventricular tachycardia

Digestive – abdominal pain, anorexia, biliary tract spasm, constipation, dry mouth, glossitis

Hematologic and Lymphatic – reversible thrombocytopenia has been described in opioid addicts with

chronic hepatitis

Metabolic and Nutritional – hypokalemia, hypomagnesemia, weight gain

Nervous – agitation, confusion, disorientation, dysphoria, euphoria, insomnia, seizures

Respiratory – pulmonary edema, respiratory depression (see WARNINGS, Respiratory Depression)

Skin and Appendages – pruritus, urticaria, other skin rashes, and rarely, hemorrhagic urticaria

Special Senses – hallucinations, visual disturbances

Urogenital – amenorrhea, antidiuretic effect, reduced libido and/or potency, urinary retention or

hesitancy

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of methadone

hydrochloride oral concentrate.

Serotonin syndrome - Cases of serotonin syndrome, a potentially life-threatening condition, have been

reported during concomitant use of opioids with serotonergic drugs (see WARNINGSand

PRECAUTIONS, Drug Interactions).

Adrenal insufficiency - Cases of adrenal insufficiency have been reported with opioid use, more often

following greater than one month of use (see WARNINGS).

Anaphylaxis - Anaphylactic reaction has been reported with ingredients contained in methadone

hydrochloride oral concentrate (see CONTRAINDICATIONS).

Androgen deficiency - Cases of androgen deficiency have occurred with chronic use of opioids(see

CLINICAL PHARMACOLOGY).

DRUG ABUSE AND DEPENDENCE

Methadone hydrochloride oral concentrate contains methadone, a Schedule II opioid agonist. Schedule

II opioid substances, which also include hydromorphone, morphine, oxycodone, and oxymorphone,

have the highest potential for abuse and risk of fatal overdose due to respiratory depression.

Methadone, like morphine and other opioids used for analgesia, has the potential for being abused and is

subject to criminal diversion.

Abuse of methadone hydrochloride oral concentrate poses a risk of overdose and death. This risk is

increased with concurrent abuse of methadone hydrochloride oral concentrate with alcohol and other

substances. In addition, parenteral drug abuse is commonly associated with transmission of infectious

disease such as hepatitis and HIV.

Because methadone hydrochloride oral concentrate may be diverted for non-medical use, careful

record keeping of ordering and dispensing information, including quantity and frequency is strongly

advised.

Proper assessment 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.

Methadone hydrochloride oral concentrate, when used for the treatment of opioid addiction in

detoxification or maintenance programs, may be dispensed only by opioid treatment programs certified

by the Substance Abuse and Mental Health Services Administration (and agencies, practitioners or

institutions by formal agreement with the program sponsor).

Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use

of opioids during pregnancy (see WARNINGS, Neonatal Opioid Withdrawal Syndrome, and

PRECAUTIONS, Pregnancy).

Physical dependence can develop during chronic opioid therapy.

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 (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 significant dose reduction of a drug. Withdrawal is also

precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone,

nalmefene) or mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial

agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree

until after several days to weeks of continued opioid usage. Physical dependence is expected during

opioid agonist therapy of opioid addiction.

Methadone hydrochloride oral concentrate should not be abruptly discontinued (see DOSAGE AND

ADMINISTRATION). If methadone hydrochloride oral concentrate is abruptly discontinued in a

physically dependent patient, a withdrawal syndrome may occur. Some or all of the following can

characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia,

and mydriasis. Other 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(see DOSAGE AND ADMINISTRATION, Medically

Supervised Withdrawal After a Period of Maintenance Treatment).

OVERDOSAGE

Clinical Presentation

Acute overdosage with methadone can be manifested by respiratory depression somnolence

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

in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction,

atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose

situations. In severe overdosage, particularly by the intravenous route, apnea, circulatory collapse,

cardiac arrest, and death may occur.

Treatment of Overdose

In the case of overdose, priorities are the reestablishment of a patent and protected airway and

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

oxygen and 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, naloxone or nalmefene, are specific antidotes to respiratory depression

resulting from opioid overdose. For clinically significant respiratory or circulatory depression

secondary to methadone overdose, administer an opioid antagonist. Opioid antagonists should not be

administered in the absence of clinically significant respiratory or circulatory depression secondary to

methadone overdose.

The physician must remember that methadone is a long-acting depressant (36 to 48 hours), whereas

opioid antagonists act for much shorter periods (one to three hours). Because the duration of opioid

reversal is expected to be less than the duration of action of methadone, carefully monitor the patient

until spontaneous respiration is reliably established. If the response to an opioid antagonist is

suboptimal or only brief in nature, administer additional antagonist as directed by the product’s

prescribing information.

In an individual physically dependent on opioids, the administration of the usual dose of an opioid

antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms

experienced will depend on the degree of physical dependence and the dose of the antagonist

administered. If a decision is made treat serious respiratory depression in the physically dependent

patient, administration of the antagonist should be initiated with care and by titration with smaller than

usual doses of the antagonist.

DOSAGE AND ADMINISTRATION

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 21 CFR 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 21 CFR 1306.07(b)).

Important General Information

Consider the following important factors that differentiate methadone from other opioids:

The peak respiratory depressant effect of methadone occurs later and persists longer than its peak

pharmacologic 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 opioid agonists.

There is high interpatient variability in absorption, metabolism, and relative analgesic potency.

Population-based conversion ratios between methadone and other opioids are not accurate when

applied to individuals.

With repeated dosing, methadone is retained in the liver and then slowly released, prolonging the

duration of potential toxicity.

Steady-state plasma concentrations are not attained until 3 to 5 days after initiation of dosing.

Methadone hydrochloride oral concentrate has a narrow therapeutic index, especially when

combined with other drugs.

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

For detoxification and maintenance of opiate dependence, methadone should be administered in

accordance with the treatment standards cited in 42 CFR Section 8.12, including limitations on

unsupervised administration.

The initial methadone dose should be administered, under supervision, when there are no signs of

sedation or intoxication, and the patient shows symptoms of withdrawal. Initially, a single dose of 20 to

30 mg of methadone will often be sufficient to suppress withdrawal symptoms. The initial dose should

not exceed 30 mg.

If same-day dosing adjustments are to be made, the patient should be asked to wait 2 to 4 hours for

further evaluation, when peak levels have been reached. An additional 5 to 10 mg of methadone may be

provided if withdrawal symptoms have not been suppressed or if symptoms reappear.

The total daily dose of methadone on the first day of treatment should not ordinarily exceed 40 mg.

Dose adjustments should be made 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). Dose adjustment should

be cautious; deaths have occurred in early treatment due to the cumulative effects of the first several

days’ dosing. Patients should be reminded that the dose will “hold” for a longer period of time as tissue

stores of methadone accumulate.

Initial doses should be lower for patients whose tolerance is expected to be low at treatment entry. Loss

of tolerance should be considered in any patient who has not taken opioids for more than 5 days. Initial

doses should not be determined by previous treatment episodes or dollars spent per day on illicit drug

use.

During the induction phase of methadone maintenance treatment, patients may show typical withdrawal

symptoms, which should be differentiated from methadone-induced side effects. They may exhibit some

or all of the following signs and symptoms associated with acute withdrawal from heroin or other

opiates: lacrimation, rhinorrhea, sneezing, yawning, excessive perspiration, goose-flesh, fever,

chilliness 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.

Short-Term Detoxification

For patients preferring a brief course of stabilization followed by a period of medically supervised

withdrawal, it is generally recommended that the patient be titrated to a total daily dose of about 40 mg

in divided doses to achieve an adequate stabilizing level. Stabilization can be continued for 2 to 3 days,

after which the dose of methadone should be gradually decreased. The rate at which methadone is

decreased should be determined separately for each patient. The dose of methadone can be decreased

on a daily basis or at 2-day intervals, but the amount of intake should remain sufficient to keep

withdrawal symptoms at a tolerable level. In hospitalized patients, a daily reduction of 20% of the total

daily dose may be tolerated. In ambulatory patients, a somewhat slower schedule may be needed.

Titration and Maintenance Treatment of Opioid Dependence

Patients in maintenance treatment should be titrated to a dose at which opioid symptoms are prevented

for 24 hours, drug hunger or craving is reduced, the euphoric effects of self-administered opioids are

blocked or attenuated, and the patient is tolerant to the sedative effects of methadone. Most commonly,

clinical stability is achieved at doses between 80 to 120 mg/day. During prolonged administration of

methadone, monitor patients for persistent constipation and manage accordingly.

Medically Supervised Withdrawal After a Period of Maintenance Treatment

There is considerable variability in the appropriate rate of methadone taper in patients choosing

medically supervised withdrawal from methadone treatment. It is generally suggested that dose

reductions should be less than 10% of the established tolerance or maintenance dose, and that 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.

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). Opioid withdrawal symptoms have been associated with an increased

risk of relapse to illicit drug use in susceptible patients.

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 nonmethadone-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.

Dosage Adjustment During Pregnancy

Methadone clearance may be increased during pregnancy. During pregnancy, 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 CLINICAL PHARMACOLOGY,

Pharmacokinetics, Specific Populations,and PRECAUTIONS, Pregnancy).

HOW SUPPLIED

Methadone hydrochloride oral concentrate USP 10 mg/mL is supplied as a red, cherry flavored liquid

concentrate, as follows:

1 fl. oz. Bottle (30 mL) ………………NDC 66689-694-30 (Supplied with calibrated dropper);

1 Liter Bottle (1000 mL) ……………..NDC 66689-694-79

Methadone Hydrochloride Oral Concentrate, USP 10 mg/mL, is supplied as a dye-free, sugar-free,

unflavored liquid concentrate, as follows:

1 fl. oz. Bottle (30 mL) ………………NDC 66689-695-30 (Supplied with calibrated dropper);

1 Liter Bottle (1000 mL) ……………..NDC 66689-695-79

Dispense in tight containers, protected from light. Store at 20° to 25°C (68° to 77°F) [see USP

Controlled Room Temperature].

DISTRIBUTED BY:

ATLANTIC BIOLOGICALS CORP.

20101 N.E 16TH PLACE

MIAMI, FL 33179

PRINCIPAL DISPLAY PANEL (CHERRY FLAVOR)

NDC 17856-0694-1

METHADONE HYDROCHLORIDE

ORAL CONCENTRATE, USP CII

2.5mg/0.25mL

(Cherry Flavored)

STORAGE: Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See

USP Controlled Room Temperature].

Dispense in a tight container protected from light.

At the time of dispensing, replace cap with safety cap dropper.

Rx Only

NDC 17856-0694-2

METHADONE HYDROCHLORIDE

ORAL CONCENTRATE, USP CII

5mg/0.5mL

(Cherry Flavored)

STORAGE: Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See

USP Controlled Room Temperature].

Dispense in a tight container protected from light.

At the time of dispensing, replace cap with safety cap dropper.

Rx Only

OVERWRAP LABEL

METHADONE HYDROCHLORIDE

methadone hydrochloride concentrate

Product Information

Product T ype

HUMAN

PRESCRIPTION DRUG

Ite m Code (Source )

NDC:178 56 -

0 6 9 4(NDC:6 6 6 8 9 -6 9 4)

Route of Administration

ORAL

DEA Sche dule

Active Ingredient/Active Moiety

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

in 1 mL

ATLANTIC BIOLOGICALS CORP.

Inactive Ingredients

Ingredient Name

Stre ng th

SO RBIC ACID (UNII: X0 45WJ9 8 9 B)

PO TASSIUM SO RBATE (UNII: 1VPU26 JZZ4)

PO LO XAMER 18 8 (UNII: LQA7B6 G8 JG)

GLYCERIN (UNII: PDC6 A3C0 OX)

PRO PYLENE GLYCO L (UNII: 6 DC9 Q16 7V3)

SUCRO SE (UNII: C151H8 M554)

WATER (UNII: 0 59 QF0 KO0 R)

Product Characteristics

Color

S core

S hap e

S iz e

Flavor

CHERRY

Imprint Code

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:178 56 -0 6 9 4-1 6 0 in 1 BOX, UNIT-DOSE

0 8 /28 /20 19

1

0 .25 mL in 1 SYRINGE; Type 0 : No t a Co mbinatio n Pro duct

2

NDC:178 56 -0 6 9 4-2 6 0 in 1 BOX, UNIT-DOSE

0 8 /28 /20 19

2

0 .5 mL in 1 SYRINGE; Type 0 : No t a Co mbinatio n Pro duct

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 40 0 8 8

0 8 /28 /20 19

Labeler -

AT LANT IC BIOLOGICALS CORP. (047437707)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

ATLANTIC BIOLOGICALS CORP.

0 4743770 7

relabel(178 56 -0 6 9 4) , repack(178 56 -0 6 9 4)

Revised: 8/2019

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