METHADOSE

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Overview

What is METHADOSE?

METHADOSE Oral Concentrate (methadone hydrochloride oral concentrate USP) contains methadone, an opioid agonist, and is available as a cherry flavored liquid concentrate for oral administration. METHADOSE Sugar-Free Oral Concentrate (methadone hydrochloride oral concentrate USP) is a dye-free, sugar-free, unflavored liquid concentrate of methadone hydrochloride 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 METHADOSE 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:

Other ingredients of METHADOSE oral concentrate: artificial cherry flavor, citric acid anhydrous, FD&C Red No 40, D&C Red No 33, methylparaben, poloxamer 407, propylene glycol, propylparaben, purified water, sodium citrate dihydrate, sucrose.

Other ingredients of METHADOSE sugar-free oral concentrate: citric acid anhydrous, purified water, sodium benzoate.

What does METHADOSE look like?

What are the available doses of METHADOSE?

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What should I talk to my health care provider before I take METHADOSE?

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How should I use METHADOSE?

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 ( ).

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:

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

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 ( ). 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 non-methadone-treated patients with similar painful conditions. When opioids are required for management of acute pain in methadone maintenance patients, somewhat higher and/or more frequent doses will often be required than would be the case for non-tolerant patients due to the opioid tolerance induced by methadone.

Dosage Adjustment During Pregnancy

Methadone clearance may be increased during pregnancy. During pregnancy, a woman’s methadone dose may need to be increased or the dosing interval decreased. Methadone should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus ( ).

What interacts with METHADOSE?

METHADOSE 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 METHADOSE

What are the warnings of METHADOSE?

Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. Patients apt to be exposed to direct sunlight or ultraviolet light should be advised that this reaction can occur with tetracycline drugs, and treatment should be discontinued at the first evidence of skin erythema.

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 ( ).

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of METHADOSE, 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 METHADOSE 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 ( ). 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:

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 ).

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 laboratory studies, and methadone has been shown to inhibit cardiac potassium channels in 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 METHADOSE 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 METHADOSE 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 METHADOSE, especially by children, can result in respiratory depression and death due to an overdose. Keep METHADOSE out of reach of children to prevent accidental ingestion.

Misuse, Abuse, and Diversion of Opioids

METHADOSE 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 ( ).

Advise pregnant women receiving opioid addiction treatment with METHADOSE 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 METHADOSE 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 METHADOSE is achieved. Similarly, discontinuation of concomitant CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers in METHADOSE-treated patients may increase methadone plasma concentrations resulting in fatal respiratory depression. Consider dosage reduction of METHADOSE 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 METHADOSE may decrease methadone plasma concentrations, reducing efficacy or, and may, lead to a withdrawal symptoms in patients physically dependent on methadone. When using METHADOSE 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 METHADOSE dosage as needed.

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

The use of METHADOSE in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Monitor such patients closely, particularly when initiating and titrating METHADOSE and when METHADOSE 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 METHADOSE 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) ( ). 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 METHADOSE 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 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) ( ). Monitor these patients for signs of hypotension after initiating or titrating the dosage of METHADOSE. In patients with circulatory shock, METHADOSE may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of METHADOSE 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) METHADOSE 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

METHADOSE is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The methadone in METHADOSE 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 METHADOSE 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 METHADOSE. In these patients, mixed agonists/antagonist and partial agonist analgesics may precipitate withdrawal symptoms ( ).

When discontinuing METHADOSE, gradually taper the dosage ( ). Do not abruptly discontinue METHADOSE.

Use in Ambulatory Patients

Driving or Operating Heavy Machinery

Inform patients that METHADOSE 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 ( ).

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.

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What are the precautions of METHADOSE?

Information for Patients

Life-Threatening Respiratory Depression

Discuss the risk of respiratory depression with patients, explaining that the risk is greatest when starting METHADOSE or when the dose is increased ( ). 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 additive effects may occur if METHADOSE 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 ( ).

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 METHADOSE ( ).

Accidental Ingestion

Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death ( ). Instruct patients to take steps to store METHADOSE securely. Advise patients to dispose of unused METHADOSE by flushing down the toilet.

Abuse Potential

Inform patients that METHADOSE contain methadone, a Schedule II controlled substance that is subject to abuse ( ). Instruct patients not to share METHADOSE with others and to take steps to protect METHADOSE from theft or misuse.

Important Administration Instructions

Instruct patients how to properly take METHADOSE, including the following:

Serotonin Syndrome

Inform patients that METHADOSE 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 ( ).

MAOI Interaction

Inform patients to avoid taking METHADOSE while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking METHADOSE ( ).

Adrenal Insufficiency

Inform patients that METHADOSE 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 ( ).

Anaphylaxis

Inform patients that anaphylaxis has been reported with ingredients contained in METHADOSE. Advise patients how to recognize such a reaction and when to seek medical attention ( ).

Neonatal Opioid Withdrawal

Advise women that if they are pregnant while being treated with METHADOSE, the baby may have signs of withdrawal at birth and that withdrawal is treatable ( ).

Lactation

Instruct nursing mothers using METHADOSE 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) ( ).

Constipation

Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention ( ).

Drug Interactions

Drug Interactions

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 METHADOSE and could precipitate a withdrawal syndrome. Monitor patients receiving METHADOSE any of these anti-retroviral therapies closely for evidence of withdrawal effects and adjust the METHADOSE dose accordingly.

Effects of Methadone on Antiretroviral Agents

Didanosine and Stavudine

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Zidovudine

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Desipramine

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Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis –

Mutagenesis –

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in vivo

in vivo

E. coli

Neurospora crassa

Impairment of Fertility –

Pregnancy

Pregnancy Category C.

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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 ( ). 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 METHADOSE.

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 ( ).

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 ( ). 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.

Benzodiazepines and Other Central Nervous System (CNS) Depressants

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.

Alcohol, benzodiazepines, and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids.

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

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

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.

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

Potentially Arrhythmogenic Agents

Pharmacodynamic interactions may occur with concomitant use of methadone and potentially arrhythmogenic agents or drugs capable of inducing electrolyte disturbances (hypomagnesemia, hypokalemia).

Monitor patients closely for cardiac conduction changes.

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

The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome ( ).

If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue METHADOSE if serotonin syndrome is suspected.

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)

MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) ( ).

The use of METHADOSE is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.

phenelzine, tranylcypromine, linezolid

Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics

Patients maintained on methadone may experience withdrawal symptoms when given opioid antagonists, mixed agonist/antagonists, and partial agonists.

Avoid concomitant use.

butorphanol, nalbuphine, pentazocine, buprenorphine

Muscle Relaxants

Methadone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.

Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of METHADOSE and/or the muscle relaxant as necessary.

Diuretics

Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.

Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.

Anticholinergic Drugs

The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

Monitor patients for signs of urinary retention or reduced gastric motility when METHADOSE is used concomitantly with anticholinergic drugs.

METHADOSE is for oral administration only. The preparation .
Inform patients that METHADOSE 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 METHADOSE 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 METHADOSE maintenance treatment.
Advise patients not to discontinue METHADOSE without first discussing the need for a tapering regimen with the prescriber.

What are the side effects of METHADOSE?

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

–

Cardiovascular

see

–

Digestive

–

Hematologic and Lymphatic

–

Metabolic and Nutritional

–

Nervous

–

Respiratory

–

see

Skin and Appendages

–

Special Senses

–

Urogenital –

Postmarketing Experience

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

Serotonin syndrome

–

see

and

Adrenal insufficiency

–

see

Anaphylaxis

–

see

Androgen deficiency

–

see

What should I look out for while using METHADOSE?

METHADOSE is contraindicated in patients with:

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 ( ).

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of METHADOSE, 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 METHADOSE 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 ( ). 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:

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 ).

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 laboratory studies, and methadone has been shown to inhibit cardiac potassium channels in 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 METHADOSE 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 METHADOSE 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 METHADOSE, especially by children, can result in respiratory depression and death due to an overdose. Keep METHADOSE out of reach of children to prevent accidental ingestion.

Misuse, Abuse, and Diversion of Opioids

METHADOSE 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 ( ).

Advise pregnant women receiving opioid addiction treatment with METHADOSE 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 METHADOSE 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 METHADOSE is achieved. Similarly, discontinuation of concomitant CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers in METHADOSE-treated patients may increase methadone plasma concentrations resulting in fatal respiratory depression. Consider dosage reduction of METHADOSE 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 METHADOSE may decrease methadone plasma concentrations, reducing efficacy or, and may, lead to a withdrawal symptoms in patients physically dependent on methadone. When using METHADOSE 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 METHADOSE dosage as needed.

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

The use of METHADOSE 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

–

see

Elderly, Cachectic, or Debilitated Patients

see

Monitor such patients closely, particularly when initiating and titrating METHADOSE and when METHADOSE 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 METHADOSE 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) ( ). 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 METHADOSE 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 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) ( ). Monitor these patients for signs of hypotension after initiating or titrating the dosage of METHADOSE. In patients with circulatory shock, METHADOSE may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of METHADOSE 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) METHADOSE 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

METHADOSE is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The methadone in METHADOSE 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 METHADOSE 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 METHADOSE. In these patients, mixed agonists/antagonist and partial agonist analgesics may precipitate withdrawal symptoms ( ).

When discontinuing METHADOSE, gradually taper the dosage ( ). Do not abruptly discontinue METHADOSE.

Use in Ambulatory Patients

Driving or Operating Heavy Machinery

Inform patients that METHADOSE 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 ( ).

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.

What might happen if I take too much METHADOSE?

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 situationsIn 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)

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.

How should I store and handle METHADOSE?

VFEND I.V. for Injection unreconstituted vials should be stored at 15° – 30°C (59° – 86°F) [see USP Controlled Room Temperature]. VFEND is a single dose unpreserved sterile lyophile. From a microbiological point of view, following reconstitution of the lyophile with Water for Injection, the reconstituted solution should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and should not be longer than 24 hours at 2° to 8°C (36° to 46°F). Chemical and physical in-use stability has been demonstrated for 24 hours at 2° to 8°C (36° to 46°F). This medicinal product is for single use only and any unused solution should be discarded. Only clear solutions without particles should be used [].METHADOSE Oral Concentrate (methadone hydrochloride oral concentrate USP) 10 mg per mL is supplied as a red, cherry flavored liquid concentrate.1 Liter Bottle……………NDC 0406-0527-1015 Liter Bottle..…………NDC 0406-0527-15 METHADOSE Sugar-Free Oral Concentrate (methadone hydrochloride oral concentrate USP) 10 mg per mL is supplied as a dye-free, sugar-free, unflavored liquid concentrate.1 Liter Bottle……………NDC 0406-8725-1015 Liter Bottle..…………NDC 0406-8725-15 Dispense in tight containers, protected from light. Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].Mallinckrodt, the “M” brand mark, the Mallinckrodt Pharmaceuticals logo and other brands are trademarks of a Mallinckrodt company. © 2018 Mallinckrodt.SpecGx LLCWebster Groves, MO 63119 USAMade in USA Rev 02/2018Mallinckrodt™METHADOSE Oral Concentrate (methadone hydrochloride oral concentrate USP) 10 mg per mL is supplied as a red, cherry flavored liquid concentrate.1 Liter Bottle……………NDC 0406-0527-1015 Liter Bottle..…………NDC 0406-0527-15 METHADOSE Sugar-Free Oral Concentrate (methadone hydrochloride oral concentrate USP) 10 mg per mL is supplied as a dye-free, sugar-free, unflavored liquid concentrate.1 Liter Bottle……………NDC 0406-8725-1015 Liter Bottle..…………NDC 0406-8725-15 Dispense in tight containers, protected from light. Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].Mallinckrodt, the “M” brand mark, the Mallinckrodt Pharmaceuticals logo and other brands are trademarks of a Mallinckrodt company. © 2018 Mallinckrodt.SpecGx LLCWebster Groves, MO 63119 USAMade in USA Rev 02/2018Mallinckrodt™METHADOSE Oral Concentrate (methadone hydrochloride oral concentrate USP) 10 mg per mL is supplied as a red, cherry flavored liquid concentrate.1 Liter Bottle……………NDC 0406-0527-1015 Liter Bottle..…………NDC 0406-0527-15 METHADOSE Sugar-Free Oral Concentrate (methadone hydrochloride oral concentrate USP) 10 mg per mL is supplied as a dye-free, sugar-free, unflavored liquid concentrate.1 Liter Bottle……………NDC 0406-8725-1015 Liter Bottle..…………NDC 0406-8725-15 Dispense in tight containers, protected from light. Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].Mallinckrodt, the “M” brand mark, the Mallinckrodt Pharmaceuticals logo and other brands are trademarks of a Mallinckrodt company. © 2018 Mallinckrodt.SpecGx LLCWebster Groves, MO 63119 USAMade in USA Rev 02/2018Mallinckrodt™METHADOSE Oral Concentrate (methadone hydrochloride oral concentrate USP) 10 mg per mL is supplied as a red, cherry flavored liquid concentrate.1 Liter Bottle……………NDC 0406-0527-1015 Liter Bottle..…………NDC 0406-0527-15 METHADOSE Sugar-Free Oral Concentrate (methadone hydrochloride oral concentrate USP) 10 mg per mL is supplied as a dye-free, sugar-free, unflavored liquid concentrate.1 Liter Bottle……………NDC 0406-8725-1015 Liter Bottle..…………NDC 0406-8725-15 Dispense in tight containers, protected from light. Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].Mallinckrodt, the “M” brand mark, the Mallinckrodt Pharmaceuticals logo and other brands are trademarks of a Mallinckrodt company. © 2018 Mallinckrodt.SpecGx LLCWebster Groves, MO 63119 USAMade in USA Rev 02/2018Mallinckrodt™METHADOSE Oral Concentrate (methadone hydrochloride oral concentrate USP) 10 mg per mL is supplied as a red, cherry flavored liquid concentrate.1 Liter Bottle……………NDC 0406-0527-1015 Liter Bottle..…………NDC 0406-0527-15 METHADOSE Sugar-Free Oral Concentrate (methadone hydrochloride oral concentrate USP) 10 mg per mL is supplied as a dye-free, sugar-free, unflavored liquid concentrate.1 Liter Bottle……………NDC 0406-8725-1015 Liter Bottle..…………NDC 0406-8725-15 Dispense in tight containers, protected from light. Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].Mallinckrodt, the “M” brand mark, the Mallinckrodt Pharmaceuticals logo and other brands are trademarks of a Mallinckrodt company. © 2018 Mallinckrodt.SpecGx LLCWebster Groves, MO 63119 USAMade in USA Rev 02/2018Mallinckrodt™METHADOSE Oral Concentrate (methadone hydrochloride oral concentrate USP) 10 mg per mL is supplied as a red, cherry flavored liquid concentrate.1 Liter Bottle……………NDC 0406-0527-1015 Liter Bottle..…………NDC 0406-0527-15 METHADOSE Sugar-Free Oral Concentrate (methadone hydrochloride oral concentrate USP) 10 mg per mL is supplied as a dye-free, sugar-free, unflavored liquid concentrate.1 Liter Bottle……………NDC 0406-8725-1015 Liter Bottle..…………NDC 0406-8725-15 Dispense in tight containers, protected from light. Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].Mallinckrodt, the “M” brand mark, the Mallinckrodt Pharmaceuticals logo and other brands are trademarks of a Mallinckrodt company. © 2018 Mallinckrodt.SpecGx LLCWebster Groves, MO 63119 USAMade in USA Rev 02/2018Mallinckrodt™METHADOSE Oral Concentrate (methadone hydrochloride oral concentrate USP) 10 mg per mL is supplied as a red, cherry flavored liquid concentrate.1 Liter Bottle……………NDC 0406-0527-1015 Liter Bottle..…………NDC 0406-0527-15 METHADOSE Sugar-Free Oral Concentrate (methadone hydrochloride oral concentrate USP) 10 mg per mL is supplied as a dye-free, sugar-free, unflavored liquid concentrate.1 Liter Bottle……………NDC 0406-8725-1015 Liter Bottle..…………NDC 0406-8725-15 Dispense in tight containers, protected from light. Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].Mallinckrodt, the “M” brand mark, the Mallinckrodt Pharmaceuticals logo and other brands are trademarks of a Mallinckrodt company. © 2018 Mallinckrodt.SpecGx LLCWebster Groves, MO 63119 USAMade in USA Rev 02/2018Mallinckrodt™METHADOSE Oral Concentrate (methadone hydrochloride oral concentrate USP) 10 mg per mL is supplied as a red, cherry flavored liquid concentrate.1 Liter Bottle……………NDC 0406-0527-1015 Liter Bottle..…………NDC 0406-0527-15 METHADOSE Sugar-Free Oral Concentrate (methadone hydrochloride oral concentrate USP) 10 mg per mL is supplied as a dye-free, sugar-free, unflavored liquid concentrate.1 Liter Bottle……………NDC 0406-8725-1015 Liter Bottle..…………NDC 0406-8725-15 Dispense in tight containers, protected from light. Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].Mallinckrodt, the “M” brand mark, the Mallinckrodt Pharmaceuticals logo and other brands are trademarks of a Mallinckrodt company. © 2018 Mallinckrodt.SpecGx LLCWebster Groves, MO 63119 USAMade in USA Rev 02/2018Mallinckrodt™METHADOSE Oral Concentrate (methadone hydrochloride oral concentrate USP) 10 mg per mL is supplied as a red, cherry flavored liquid concentrate.1 Liter Bottle……………NDC 0406-0527-1015 Liter Bottle..…………NDC 0406-0527-15 METHADOSE Sugar-Free Oral Concentrate (methadone hydrochloride oral concentrate USP) 10 mg per mL is supplied as a dye-free, sugar-free, unflavored liquid concentrate.1 Liter Bottle……………NDC 0406-8725-1015 Liter Bottle..…………NDC 0406-8725-15 Dispense in tight containers, protected from light. Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].Mallinckrodt, the “M” brand mark, the Mallinckrodt Pharmaceuticals logo and other brands are trademarks of a Mallinckrodt company. © 2018 Mallinckrodt.SpecGx LLCWebster Groves, MO 63119 USAMade in USA Rev 02/2018Mallinckrodt™METHADOSE Oral Concentrate (methadone hydrochloride oral concentrate USP) 10 mg per mL is supplied as a red, cherry flavored liquid concentrate.1 Liter Bottle……………NDC 0406-0527-1015 Liter Bottle..…………NDC 0406-0527-15 METHADOSE Sugar-Free Oral Concentrate (methadone hydrochloride oral concentrate USP) 10 mg per mL is supplied as a dye-free, sugar-free, unflavored liquid concentrate.1 Liter Bottle……………NDC 0406-8725-1015 Liter Bottle..…………NDC 0406-8725-15 Dispense in tight containers, protected from light. Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].Mallinckrodt, the “M” brand mark, the Mallinckrodt Pharmaceuticals logo and other brands are trademarks of a Mallinckrodt company. © 2018 Mallinckrodt.SpecGx LLCWebster Groves, MO 63119 USAMade in USA Rev 02/2018Mallinckrodt™METHADOSE Oral Concentrate (methadone hydrochloride oral concentrate USP) 10 mg per mL is supplied as a red, cherry flavored liquid concentrate.1 Liter Bottle……………NDC 0406-0527-1015 Liter Bottle..…………NDC 0406-0527-15 METHADOSE Sugar-Free Oral Concentrate (methadone hydrochloride oral concentrate USP) 10 mg per mL is supplied as a dye-free, sugar-free, unflavored liquid concentrate.1 Liter Bottle……………NDC 0406-8725-1015 Liter Bottle..…………NDC 0406-8725-15 Dispense in tight containers, protected from light. Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].Mallinckrodt, the “M” brand mark, the Mallinckrodt Pharmaceuticals logo and other brands are trademarks of a Mallinckrodt company. © 2018 Mallinckrodt.SpecGx LLCWebster Groves, MO 63119 USAMade in USA Rev 02/2018Mallinckrodt™

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Clinical Information

Chemical Structure

No Image found

Clinical Pharmacology

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.

Non-Clinical Toxicology

METHADOSE is contraindicated in patients with:

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 ( ).

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of METHADOSE, 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 METHADOSE 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 ( ). 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:

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 ).

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 laboratory studies, and methadone has been shown to inhibit cardiac potassium channels in 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 METHADOSE 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 METHADOSE 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 METHADOSE, especially by children, can result in respiratory depression and death due to an overdose. Keep METHADOSE out of reach of children to prevent accidental ingestion.

Misuse, Abuse, and Diversion of Opioids

METHADOSE 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 ( ).

Advise pregnant women receiving opioid addiction treatment with METHADOSE 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 METHADOSE 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 METHADOSE is achieved. Similarly, discontinuation of concomitant CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers in METHADOSE-treated patients may increase methadone plasma concentrations resulting in fatal respiratory depression. Consider dosage reduction of METHADOSE 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 METHADOSE may decrease methadone plasma concentrations, reducing efficacy or, and may, lead to a withdrawal symptoms in patients physically dependent on methadone. When using METHADOSE 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 METHADOSE dosage as needed.

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

The use of METHADOSE 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

–

see

Elderly, Cachectic, or Debilitated Patients

see

Monitor such patients closely, particularly when initiating and titrating METHADOSE and when METHADOSE 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 METHADOSE 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) ( ). 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 METHADOSE 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 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) ( ). Monitor these patients for signs of hypotension after initiating or titrating the dosage of METHADOSE. In patients with circulatory shock, METHADOSE may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of METHADOSE 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) METHADOSE 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

METHADOSE is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The methadone in METHADOSE 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 METHADOSE 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 METHADOSE. In these patients, mixed agonists/antagonist and partial agonist analgesics may precipitate withdrawal symptoms ( ).

When discontinuing METHADOSE, gradually taper the dosage ( ). Do not abruptly discontinue METHADOSE.

Use in Ambulatory Patients

Driving or Operating Heavy Machinery

Inform patients that METHADOSE 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 ( ).

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.

No specific drug interaction studies have been conducted with Promethazine HCl and Codeine Phosphate Oral Solution.

Information for Patients

Life-Threatening Respiratory Depression

Discuss the risk of respiratory depression with patients, explaining that the risk is greatest when starting METHADOSE or when the dose is increased ( ). 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 additive effects may occur if METHADOSE 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 ( ).

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 METHADOSE ( ).

Accidental Ingestion

Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death ( ). Instruct patients to take steps to store METHADOSE securely. Advise patients to dispose of unused METHADOSE by flushing down the toilet.

Abuse Potential

Inform patients that METHADOSE contain methadone, a Schedule II controlled substance that is subject to abuse ( ). Instruct patients not to share METHADOSE with others and to take steps to protect METHADOSE from theft or misuse.

Important Administration Instructions

Instruct patients how to properly take METHADOSE, including the following:

Serotonin Syndrome

Inform patients that METHADOSE 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 ( ).

MAOI Interaction

Inform patients to avoid taking METHADOSE while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking METHADOSE ( ).

Adrenal Insufficiency

Inform patients that METHADOSE 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 ( ).

Anaphylaxis

Inform patients that anaphylaxis has been reported with ingredients contained in METHADOSE. Advise patients how to recognize such a reaction and when to seek medical attention ( ).

Neonatal Opioid Withdrawal

Advise women that if they are pregnant while being treated with METHADOSE, the baby may have signs of withdrawal at birth and that withdrawal is treatable ( ).

Lactation

Instruct nursing mothers using METHADOSE 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) ( ).

Constipation

Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention ( ).

Drug Interactions

Drug Interactions

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 METHADOSE and could precipitate a withdrawal syndrome. Monitor patients receiving METHADOSE any of these anti-retroviral therapies closely for evidence of withdrawal effects and adjust the METHADOSE dose accordingly.

Effects of Methadone on Antiretroviral Agents

Didanosine and Stavudine

–

Zidovudine

–

Desipramine

–

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis –

Mutagenesis –

Drosophila

in vivo

in vivo

E. coli

Neurospora crassa

Impairment of Fertility –

Pregnancy

Pregnancy Category C.

see

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 ( ). 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 METHADOSE.

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 ( ).

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 ( ). 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.

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

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Cardiovascular

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Digestive

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Hematologic and Lymphatic

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Metabolic and Nutritional

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Nervous

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Respiratory

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Skin and Appendages

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Special Senses

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Urogenital –

Postmarketing Experience

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

Serotonin syndrome

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see

and

Adrenal insufficiency

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Anaphylaxis

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Androgen deficiency

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Reference

This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"

While we update our database periodically, we cannot guarantee it is always updated to the latest version.

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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72

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Interactions

A total of 440 drugs (1549 brand and generic names) are known to interact with Imbruvica (ibrutinib). 228 major drug interactions (854 brand and generic names) 210 moderate drug interactions (691 brand and generic names) 2 minor drug interactions (4 brand and generic names) Show all medications in the database that may interact with Imbruvica (ibrutinib).

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METHADOSE

Overview

What is METHADOSE?

What does METHADOSE look like?

What are the available doses of METHADOSE?

What should I talk to my health care provider before I take METHADOSE?

How should I use METHADOSE?

What interacts with METHADOSE?

What are the warnings of METHADOSE?

What are the precautions of METHADOSE?

What are the side effects of METHADOSE?

What should I look out for while using METHADOSE?

What might happen if I take too much METHADOSE?

How should I store and handle METHADOSE?

Clinical Information

Chemical Structure

Clinical Pharmacology

Non-Clinical Toxicology

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