Diskets

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 (CO2) 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 (10)].

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Diskets, 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 Diskets 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 (2.3)]. 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 (2.3)]. • 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.

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 Diskets Dispersible Tablets 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 Diskets Dispersible Tablets 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 Diskets Dispersible Tablets, especially by children, can result in respiratory depression and death due to an overdose. Keep Diskets Dispersible Tablets out of reach of children to prevent accidental ingestion.

Misuse, Abuse, and Diversion of Opioids

Diskets Dispersible Tablets 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 [see Use in Specific Populations (8.1)].

Advise pregnant women receiving opioid addiction treatment with Diskets of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1)]. 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 of P450 3A4, 2B6, 2C19, or 2C9 Inducers

Concomitant use of Diskets 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 Diskets is achieved. Similarly, discontinuation of concomitant CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers in Diskets-treated patients may increase methadone plasma concentrations resulting in fatal respiratory depression. Consider dosage reduction of Diskets when using concomitant CYP3A4, CYP2B6, CYP2C19, CYP2C9 or CYP2D6 inhibitors or discontinuing CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers in methadone-treated patients, and follow patients closely at frequent intervals for signs and symptoms of respiratory depression and sedation [see Drug Interactions (7)].

Addition of CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers or discontinuation of CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors in patients treated with Diskets may decrease methadone plasma concentrations, reducing efficacy and may lead to opioid withdrawal symptoms in patients physically dependent on methadone. When using Diskets 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 Diskets dosage as needed [see Drug Interactions (7)].

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

The use of Diskets 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

Diskets-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 Diskets [see Warnings and Precautions (5.1)].

Elderly, Cachectic, or Debilitated Patients

Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see Warnings and Precautions (5.1)].

Monitor such patients closely, particularly when initiating and titrating Diskets and when Diskets is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.8)].

Risks Due to Concomitant Use with CNS Depressants and Illicit Drugs

Profound sedation, respiratory depression, coma, and death may result if methadone is used concomitantly with other CNS depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). When considering the use of Diskets Dispersible Tablets in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient’s response, including the degree of tolerance that has developed to CNS depression. Additionally, consider the patient’s use, if any, of alcohol or illicit drugs that cause CNS depression. If methadone therapy is to be initiated in a patient taking a CNS depressant, start with a lower methadone dose than usual and monitor patients for signs of sedation and respiratory depression and consider using a lower dose of the concomitant CNS depressant [see Drug Interactions (7)].

Deaths associated with illicit use of methadone have frequently involved concomitant benzodiazepine abuse.

5.9 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs

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

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

5.10 Adrenal Insufficiency

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

Severe Hypotension

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

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

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

Diskets Dispersible Tablets are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The methadone in Diskets 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 Diskets Dispersible Tablets therapy.

Withdrawal

Avoid the use of mixed agonist/antagonist (i.e., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist, including Diskets Dispersible Tablets. In these patients, mixed agonists/antagonist and partial agonist analgesics may precipitate withdrawal symptoms [see Drug Interactions (7)].

When discontinuing Diskets Dispersible Tablets, gradually taper the dosage [see Dosage and Administration (2.4, 2.5)]. Do not abruptly discontinue Diskets Dispersible Tablets [see Drug Abuse and Dependence (9.3)].

Risks of Driving and Operating Machinery

Diskets Dispersible Tablets may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of Diskets Dispersible Tablets and know how they will react to the medication [see Patient Counseling Information (17)].

5.17 Laboratory Test Interactions

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

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 Diskets Dispersible Tablets 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 Diskets Dispersible Tablets 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 [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or withdrawal symptoms in patients physically dependent on methadone.
Intervention:	If concomitant use is necessary, consider dosage reduction of Diskets Dispersible Tablets 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 Diskets Dispersible Tablets 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 Diskets Dispersible Tablets and CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers can decrease the plasma concentration of methadone [see Clinical Pharmacology (12.3)], 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 [see Clinical Pharmacology (12.3)], 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 Diskets Dispersible Tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducer is discontinued, consider Diskets Dispersible Tablets 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, mineralocorticoid hormones.
Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of CNS depressants can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Consider dose reduction of one or both drugs. Monitor patients for respiratory depression, sedation, and hypotension [see Warnings and Precautions (5.8)].
Examples:	Alcohol, benzodiazepines, and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids.
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 and Precautions (5.9)].
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Diskets 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 effect 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 and Precautions (5.1)].
Intervention:	The use of Diskets 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 Diskets 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 Diskets are 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 Diskets Dispersible Tablets and could precipitate a withdrawal syndrome. Monitor patients receiving Diskets Dispersible Tablets and any of these anti-retroviral therapies closely for evidence of withdrawal effects and adjust the Diskets Dispersible Tablets 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.

Effects of Methadone on Antidepressants

Desipramine:Blood levels of desipramine have increased with concurrent methadone administration.

Diskets Dispersible Tablets (Methadone Hydrochloride Tablets for Oral Suspension USP)

40 mg supplied as light pinkish orange, pillow shaped, compressed dispersible tablet with product identification “54 883” debossed on one side and cross scored on the other side.

NDC 0054-4538-25: Bottle of 100 Dispersible Tablets

Diskets Dispersible Tablets, if dispensed, must be packaged in child-resistant containers and kept out of reach of children to prevent accidental ingestion.

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

NDC 0054-4538-25

Rx only

Diskets  methadone hydrochloride tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0054-4538 Route of Administration ORAL DEA Schedule CII

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength METHADONE HYDROCHLORIDE (METHADONE) METHADONE HYDROCHLORIDE 40 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE   MAGNESIUM STEARATE   CELLULOSE, MICROCRYSTALLINE   POTASSIUM PHOSPHATE, MONOBASIC   STARCH, CORN   STEARIC ACID   FD&C YELLOW NO. 6

Product Characteristics Color ORANGE (Light Pinkish) Score 4 pieces Shape SQUARE Size 20mm Flavor Imprint Code 54;883 Contains

Packaging # Item Code Package Description 1 NDC:0054-4538-25 100 TABLET in 1 BOTTLE, PLASTIC

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA017058 03/14/1973

Labeler - West-Ward Pharmaceuticals Corp. (080189610)

Establishment
Name	Address	ID/FEI	Operations
West-Ward Columbus Inc.		058839929	MANUFACTURE(0054-4538)

Revised: 02/2017   West-Ward Pharmaceuticals Corp.

If you take methadone for pain: Take the missed dose as soon as you remember, then take your next dose 8 to 12 hours later.

If you take methadone for drug addiction: Take your missed dose the next day at the regular time. If you miss your doses for longer than 3 days in a row, call your doctor for instructions. You may need to restart at a lower dose.

Do not use extra medicine to make up a missed dose.

US REMS: The US FDA requires a Risk Evaluation and Mitigation Strategy (REMS) for EXTENDED-RELEASE (ER) AND LONG-ACTING (LA) OPIOID ANALGESICS including DOLOPHINE and methadone hydrochloride tablets. This Shared System includes a medication guide and elements to assure safe use. For additional information: www.fda.gov/REMS

US BOXED WARNINGS: ADDICTION, ABUSE, and MISUSE: This drug exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing, and monitor all patients regularly for the development of these behaviors or conditions.
LIFE-THREATENING RESPIRATORY DEPRESSION: Serious, life-threatening, or fatal respiratory depression may occur. Monitor for respiratory depression, especially during initiation or following a dose increase.
ACCIDENTAL INGESTION: Accidental ingestion of even 1 dose, especially by children, can result in a fatal overdose.
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.
NEONATAL OPIOID WITHDRAWAL SYNDROME: Prolonged use of this drug 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.
TREATMENT FOR OPIOID ADDICTION: Conditions for distribution and use of methadone products for detoxification and maintenance of opioid dependence should be administered in accordance with the treatment standards cited in 42 CFR Section 8, including limitations on unsupervised administration.

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

US Controlled Substance: Schedule II

Administration advice:
-This drug should be taken at approximately the same time every day; taking in the evening one day and the morning the following day can lead to an overdose.
-If this drug is not taken for 3 consecutive days, the patient may lose tolerance and be at-risk for an overdose; dose adjustment may be necessary.
-Missed doses: Chronic Pain: Take as soon as remembered and take the next dose 8 to 12 hours later, if it is almost time for your next dose, skip the missed dose and continue on regular dosing schedule; do not take more than prescribed amount in a 24 hour period.
-Missed doses: Opioid Dependence: Take the next dose the following day as scheduled; do not take extra doses.

Oral:
-DISKETS are intended for dispersion in approximately 120 mL of liquid; take immediately after dispersing into water, orange juice, or other acidic fruit beverage.
-Each 40 mg DISKET is cross-scored; a single DISKET may be broken in half to yield two 20 mg doses or in quarters to yield four 10 mg doses.
Oral liquid doses:
-All orders should include mg strength as there are multiple concentrations available.

Parenteral:
-May be administered IV, IM or subcutaneously; IM or subcutaneous injections have not been well studied and absorption appears to be unpredictable; local tissue reactions may occur.

Storage requirements:
-Protect from light

General:
-Acidification of the urine may enhance urinary excretion of this drug.
-Treatment with this drug should be managed by physicians with suitable experience.
-Because of the greater risk of overdose and death with this long-acting opioid, when used for pain management, this drug should only be used in patients for whom alternative treatment options are ineffective, not tolerated, or would otherwise be inadequate to provide sufficient pain management.
-For patients receiving other opioid analgesics and switching to this drug, it is safer to underestimate a patient's 24-hour oral requirement and provide rescue medication than overestimate and manage an adverse reaction; there is substantial inter-patient variation in the relative potency of different opioid drugs that conversion tables are not able to capture.
-During chronic therapy, periodically reassess the continued need for opioid analgesics.

Monitoring:
-Monitor closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy and following dose increases.
-Monitor regularly for the development of addiction, abuse, and misuse.
-Monitor for signs of hypotension upon initiating therapy and following dose increases, especially those whose blood pressure is compromised.
-Monitor for signs and symptoms of QT prolongation, if used in at-risk patients or concomitantly with drugs that prolong the QT interval, consider monitoring ECG and electrolytes at baseline and periodically during treatment.
-During the induction phase as patients are being withdrawn from illicit opioids, monitor of opioid withdrawal symptoms such as lacrimation, rhinorrhea, sneezing, yawning, excessive perspiration, goose-flesh, fever, chilling, irritability, weakness, anxiety, depression, dilated pupils, tremors, tachycardia, abdominal cramps, body aches, involuntary twitching, anorexia, nausea, vomiting, diarrhea, intestinal spasms.

Patient advice:
-Advise patients to seek medical attention immediately if they experience palpitations, near syncope, syncope, or other cardiac symptoms while taking this drug.
-This drug should be stored safely out of the sight and reach of children; accidental use by a child is a medical emergency and can result in death.
-Taking this drug, even when taken as recommended can result in addiction, abuse, and misuse; instruct patients not to share their drug with others and protect their drug from theft or misuse.
-Patients should understand the risks of life-threatening respiratory depression, and be informed as to when this risk is greatest.
-This drug may cause drowsiness, dizziness, or impair thinking or motor skills; patients should avoid driving or operating machinery until adverse effects are determined.
-Women of child bearing potential should understand that prolonged use during pregnancy can result in neonatal opioid withdrawal syndrome and that prompt recognition and treatment will be necessary.
-Patients should be instructed in proper disposal.

If you are between the ages of 18 and 60, take no other medication or have no other medical conditions, side effects you are more likely to experience include:

• Sedation, drowsiness, or dizziness which may affect a person's ability to drive or operate machinery. Alcohol should be avoided as it can contribute to the sedative effect of methadone.
• Methadone tablets may cause serious, life-threatening respiratory depression (unusually shallow and slow breathing). More likely to occur in the elderly or frail, in children, or in those with pre-existing breathing problems. This effect on breathing persists for longer and occurs later than the peak pain-relieving effects of methadone. Alcohol can also worsen this effect.
• May also cause increased sweating, nausea, vomiting, headache, severe constipation, seizures and several other adverse effects.
• Because of the high risk of addiction and potential for abuse, methadone should only be used in patients intolerant or unresponsive to other analgesics (either opioid or nonopioid analgesics). Methadone is considered a drug of abuse and legitimate supplies may be sought out by drug users. Misuse of methadone may lead to overdosage or death.
• May cause serious heart rhythm disorders (such as QT prolongation), even at usual dosages.
• Use during pregnancy can cause a withdrawal syndrome in newborn babies which can be life-threatening if not recognized and treated.
• May cause a severe lowering of blood pressure, or a sudden drop in blood pressure when going from a sitting or lying down position to standing.
• May interact with a number of other drugs including other opioids, benzodiazepines, and other central nervous system depressants resulting in profound sedation, respiratory depression, and sometimes death. May also interact with drugs metabolized through a number of CYP hepatic enzyme systems or drugs that also release serotonin (such as antidepressants, antipsychotics, and tramadol).
• Methadone accumulates within the liver and repeated and overdosing may enhance its toxic effects. Although it only lasts for 4 to 8 hours, it can take up to 59 hours for 50% of a dose to be eliminated from the body.
• Methadone has a narrow therapeutic window which means there is a fine line between too much methadone (and toxic effects) and too little (meaning it is ineffective). There is a wide variation in the way individuals absorb, metabolize, and respond to methadone, which increases the risk of a person receiving a toxic or ineffective dose. This means opioid equivalency charts should not be used when changing from an opioid to methadone and vice versa.

Notes: In general, seniors or children, people with certain medical conditions (such as liver or kidney problems, heart disease, diabetes, seizures) or people who take other medications are more at risk of developing a wider range of side effects. For a complete list of all side effects, click here.

• The analgesic effect of methadone lasts between four and eight hours; however, it takes anywhere from eight to 59 hours for a dose to be eliminated from the body. With prolonged dosing, methadone is retained in the liver and then slowly released, prolonging how long it works for how long side effects may last for. The full analgesic effects of methadone may take from three to five days to develop.
• The peak respiratory depressant effect of methadone occurs later and persists for longer than its peak analgesic effect.

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LactMed Record Number

367

Last Revision Date

20170905

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Information presented in this database is not meant as a substitute for professional judgment. You should consult your healthcare provider for breastfeeding advice related to your particular situation. The U.S. government does not warrant or assume any liability or responsibility for the accuracy or completeness of the information on this Site.