Methadone Powder

Methadone Hydrochloride Powder, an opioid agonist, is for oral administration only and is used in the preparation of a liquid by dissolving the powder in an appropriate vehicle. This product is for prescription drug compounding only.

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. 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:

Mechanism of Action

Methadone hydrochloride is a mu-agonist; a synthetic opioid analgesic with multiple actions quantitatively similar to those of morphine, the most prominent of which involve the central nervous system and organs composed of smooth muscle. The principal actions of therapeutic value are analgesia and detoxification or maintenance 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.

When administered orally, methadone is approximately one-half as potent as when given parenterally. Oral administration results in a delay of the onset, a lowering of the peak, and an increase in the duration of analgesic effect.

Pharmacodynamics

Effects on the Central Nervous System
Methadone produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.

Methadone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

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

Effects on the Gastrointestinal Tract and Other Smooth Muscle
Methadone causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone is increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

Effects on the Cardiovascular System
Methadone produces peripheral vasodilation, which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.

Effects on the Endocrine System
Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date. 

Effects on the Immune System
Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown.  Overall, the effects of opioids appear to be modestly immunosuppressive.

Concentration–Adverse Reaction Relationships
There is a relationship between increasing [drug substance] plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions.

Pharmacokinetics

Absorption
Following oral administration the bioavailability of methadone ranges between 36 to 100% and peak plasma concentrations are achieved between 1 and 7.5 hours. Dose proportionality of methadone pharmacokinetics is not known. However, after administration of daily oral doses ranging from 10 to 225 mg, the steady-state plasma concentrations ranged between 65 to 630 ng/mL and the peak concentrations ranged between 124 to 1255 ng/mL. Effect of food on the bioavailability of methadone has not been evaluated.

Distribution
Methadone is a lipophilic drug and the steady-state volume of distribution ranges between 1.0 to 8.0 L/kg. In plasma, methadone is predominantly bound to α1-acid glycoprotein (85% to 90%). Methadone is secreted in saliva, breast milk, amniotic fluid and umbilical cord plasma.

Metabolism
Methadone is primarily metabolized by N-demethylation to an inactive metabolite, 2-ethylidene-1, 5-dimethyl-3,3-diphenylpyrrolidene (EDDP). Cytochrome P450 enzymes, primarily CYP3A4, CYP2B6, CYP2C19, CYP2C9 and CYP2D6, are responsible for conversion of methadone to EDDP and other inactive metabolites, which are excreted mainly in the urine.

Excretion
The elimination of methadone is mediated by extensive biotransformation, followed by renal and fecal excretion. Published reports indicate that after multiple dose administration the apparent plasma clearance of methadone ranged between 1.4 and 126 L/h, and the terminal half-life (T1/2) was highly variable and ranged between 8 and 59 hours in different studies. Since methadone is lipophilic, it has been known to persist in the liver and other tissues. The slow release from the liver and other tissues may prolong the duration of methadone action despite low plasma concentrations.

Specific Populations
Use During Pregnancy
The disposition of oral methadone has been studied in approximately 30 pregnant patients in the second and third trimesters. Elimination of methadone was significantly changed in pregnancy. Total body clearance of methadone was increased in pregnant patients compared to the same patients postpartum or to non-pregnant opioid-dependent women. The terminal half-life of methadone is decreased during second and third trimesters. The decrease in plasma half-life and increased clearance of methadone resulting in lower methadone trough levels during pregnancy can lead to withdrawal symptoms in some pregnant patients. The dosage may need to be increased or the dosing interval decreased in pregnant patients receiving methadone (see PRECAUTIONS, Pregnancy, Labor and Delivery, and DOSAGE AND ADMINISTRATION).

Hepatic Impairment
Methadone has not been extensively evaluated in patients with hepatic insufficiency. Methadone is metabolized by hepatic pathways, therefore patients with liver impairment may be at risk of accumulating methadone after multiple dosing.

Renal Impairment
Methadone pharmacokinetics have not been extensively evaluated in patients with renal insufficiency. Unmetabolized methadone and its metabolites are excreted in urine to a variable degree. Methadone is a basic (pKa=9.2) compound and the pH of the urinary tract can alter its disposition in plasma. Urine acidification has been shown to increase renal elimination of methadone. Forced diuresis, peritoneal dialysis, hemodialysis, or charcoal hemoperfusion have not been established as beneficial for increasing the elimination of methadone or its metabolites.

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

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

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

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

Drug Interaction Studies

Cytochrome P450 Interactions
Methadone undergoes hepatic N-demethylation by cytochrome P450 isoforms, principally CYP3A4, CYP2B6, CYP2C19, CYP2C9 and CYP2D6. Coadministration of methadone with inducers of these enzymes may result in more rapid methadone metabolism, and potentially, decreased effects of methadone. Conversely, administration with CYP inhibitors may reduce metabolism and potentiate methadone’s effects. Pharmacokinetics of methadone may be unpredictable when coadministered with drugs that are known to both induce and inhibit CYP enzymes. Although anti-retroviral drugs such as efavirenz, nelfinavir, nevirapine, ritonavir, lopinavir+ritonavir combination are known to inhibit some CYPs, they are shown to reduce the plasma levels of methadone, possibly due to their CYP induction activity.

Cytochrome P450 Inducers
The following drug interactions were reported following coadministration of methadone with inducers of cytochrome P450 enzymes:

Rifampin: In patients well-stabilized on methadone, concomitant administration of rifampin resulted in a marked reduction in serum methadone levels and a concurrent appearance of withdrawal symptoms.

Phenytoin: In a pharmacokinetic study with patients on methadone maintenance therapy, phenytoin administration (250 mg b.i.d. initially for 1 day followed by 300 mg QD for 3 to 4 days) resulted in an approximately 50% reduction in methadone exposure and withdrawal symptoms occurred concurrently. Upon discontinuation of phenytoin, the incidence of withdrawal symptoms decreased and methadone exposure increased to a level comparable to that prior to phenytoin administration.

St. John’s Wort, Phenobarbital, Carbamazepine: Administration of methadone with other CYP3A4 inducers may result in withdrawal symptoms.

Cytochrome P450 Inhibitors
Voriconazole: Voriconazole can inhibit the activity of CYP3A4, CYP2C9 and CYP2C19. Repeat dose administration of oral voriconazole (400 mg Q12h for 1 day, then 200 mg Q12h for 4 days) increased the Cmax and AUC of (R)-methadone by 31% and 47%, respectively, in subjects receiving a methadone maintenance dose (30 to 100 mg QD). The Cmax and AUC of (S)-methadone increased by 65% and 103%, respectively. Increased plasma concentrations of methadone have been associated with toxicity, including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed.

Anti-retroviral Agents
Although anti-retroviral drugs such as efavirenz, nelfinavir, nevirapine, ritonavir, and lopinavir+ritonavir combination are known to inhibit CYPs, they are shown to reduce the plasma levels of methadone, possibly due to their CYP induction activity.

Abacavir, amprenavir, efavirenz, nelfinavir, nevirapine, ritonavir, lopinavir+ritonavir combination: Coadministration of these anti-retroviral agents resulted in increased clearance or decreased plasma levels of methadone.

Didanosine and Stavudine: Experimental evidence demonstrated that methadone decreased the area under the concentration-time curve (AUC) and peak levels for didanosine and stavudine, with a more significant decrease for didanosine. Methadone disposition was not substantially altered.

Zidovudine: Experimental evidence demonstrated that methadone increased the AUC of zidovudine which could result in toxic effects.

Methadone Hydrochloride Powder is contraindicated in patients with:

• Significant respiratory depression 
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment 
• Known or suspected gastrointestinal obstruction, including paralytic ileus
• Hypersensitivity (e.g., anaphylaxis) to methadone or any other ingredient in Methadone Hydrochloride Powder

Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression has been reported with the use of methadone, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with a “sighing” pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status (see OVERDOSAGE).

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Methadone Hydrochloride, the risk is greatest during the initiation of therapy or following a dose increase. The peak respiratory depressant effect of methadone occurs later, and persists longer than the peak pharmacologic effect, especially during the initial dosing period. Monitor patients closely for respiratory depression, when initiating therapy with Methadone Hydrochloride and following dose increases.

Instruct patients against use by individuals other than the patient for whom methadone was prescribed and to keep methadone out of the reach of children, as such inappropriate use may result in fatal respiratory depression.

To reduce the risk of respiratory depression, proper dosing and titration of methadone are essential (see DOSAGE AND ADMINISTRATION). Overestimating the methadone dosage when initiating treatment can result in fatal overdose with the first dose. 

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

• Patients tolerant to other opioids may be incompletely tolerant to methadone. Incomplete cross-tolerance is of particular concern for patients tolerant to other mu-opioid agonists. Deaths have been reported during conversion from chronic, high-dose treatment with other opioid agonists. Follow induction directions closely to avoid inadvertent overdose (see DOSAGE AND ADMINISTRATION).
• Proper dosing and titration are essential and methadone should be overseen only by healthcare professionals who are knowledgeable in the pharmacokinetics and pharmacodynamics of methadone. 

Life-Threatening QT Prolongation
Cases of QT interval prolongation and serious arrhythmia (torsades de pointes) have been observed during treatment with methadone. These cases appear to be more commonly associated with, but not limited to, higher dose treatment (> 200 mg/day). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. In most patients on the lower doses typically used for maintenance, concomitant medications and/or clinical conditions such as hypokalemia were noted as contributing factors. However, the evidence strongly suggests that methadone possesses the potential for adverse cardiac conduction effects in some patients. The effects of methadone on the QT interval have been confirmed in in vivo laboratory studies, and methadone has been shown to inhibit cardiac potassium channels in in vitro studies.

Closely monitor patients with risk factors for development of prolonged QT interval (e.g., cardiac hypertrophy, concomitant diuretic use, hypokalemia, hypomagnesemia), a history of cardiac conduction abnormalities, and those taking medications affecting cardiac conduction. QT prolongation has also been reported in patients with no prior cardiac history who have received high doses of methadone.

Evaluate patients developing QT prolongation while on Methadone Hydrochloride treatment for the presence of modifiable risk factors, such as concomitant medications with cardiac effects, drugs which might cause electrolyte abnormalities, and drugs which might act as inhibitors of methadone metabolism.

Only initiate therapy with Methadone Hydrochloride in patients for whom the anticipated benefit outweighs the risk of QT prolongation and development of dysrhythmias that have been reported with high doses of methadone. The use of methadone in patients already known to have a prolonged QT interval has not been systematically studied.

Accidental Ingestion
Accidental ingestion of even one dose of Methadone Hydrochloride, especially by children, can result in respiratory depression and death due to an overdose. Keep Methadone Hydrochloride out of reach of children to prevent accidental ingestion.

Misuse, Abuse, and Diversion of Opioids
Methadone Hydrochloride contains methadone, an opioid agonist and a Schedule II controlled substance. Methadone can be abused in a manner similar to other opioid agonists, legal or illicit. Opioid agonists are sought by drug abusers and people with addiction disorders and are subject to criminal diversion.

Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

Neonatal Opioid Withdrawal Syndrome
Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy, whether that use is medically-authorized or illicit. Unlike opioid withdrawal syndrome in adults, NOWS may be life-threatening if not recognized and treated in the neonate. Healthcare professionals should observe newborns for signs of NOWS and manage accordingly (see PRECAUTIONS, Pregnancy).

Advise pregnant women receiving opioid addiction treatment with Methadone Hydrochloride of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available (see PRECAUTIONS, Pregnancy). This risk must be balanced against the risk of untreated opioid addiction which often results in continued or relapsing illicit opioid use and is associated with poor pregnancy outcomes. Therefore, prescribers should discuss the importance and benefits of management of opioid addiction throughout pregnancy.

Risks of Concomitant Use of Cytochrome P450 3A4, 2B6, 2C19, 2C9, or 2D6 Inhibitors or Discontinuation P450 3A4, 2B6, 2C19, or 2C9 Inducers
Concomitant use of Methadone Hydrochloride with CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors, may increase plasma concentrations of methadone, prolong opioid adverse reactions, and may cause potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of Methadone Hydrochloride is achieved. Similarly, discontinuation of concomitant CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers in Methadone Hydrochloride-treated patients may increase methadone plasma concentrations resulting in fatal respiratory depression. Consider dosage reduction of Methadone Hydrochloride when using concomitant CYP3A4, CYP2B6, CYP2C19, CYP2C9 or CYP2D6 inhibitors or discontinuing CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers in methadone-treated patients, and follow patients closely at frequent intervals for signs and symptoms of respiratory depression and sedation.

Addition  of  CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers or discontinuation of a CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors in patients treated with Methadone Hydrochloride may decrease methadone plasma concentrations, reducing efficacy or, and may, lead to a withdrawal symptoms in patients physically dependent on methadone. When using Methadone Hydrochloride with CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers or discontinuing CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors, follow patients for signs or symptoms of opioid withdrawal and consider increasing the Methadone Hydrochloride dosage as needed.

Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients
The use of Methadone Hydrochloride in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.
 
Patients with Chronic Pulmonary Disease: Methadone Hydrochloride-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of Methadone Hydrochloride (see WARNINGS, Life-Threatening Respiratory Depression).

Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients (see WARNINGS, Life-Threatening Respiratory Depression).
 
Monitor such patients closely, particularly when initiating and titrating Methadone Hydrochloride and when Methadone Hydrochloride is given concomitantly with other drugs that depress respiration (see WARNINGS, Risks Due to Interactions Concomitant Use with CNS Depressants and Illicit Drugs).

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

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

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

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue Methadone Hydrochloride 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) (see PRECAUTIONS, Drug Interactions). Monitor these patients for signs of hypotension after initiating or titrating the dosage of Methadone Hydrochloride. In patients with circulatory shock, Methadone Hydrochloride may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Methadone Hydrochloride in patients with circulatory shock.

Risks of Use in Patients with Increased Cranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness
In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors). Methadone Hydrochloride may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with methadone. 

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

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

Risks of Use in Patients with Gastrointestinal Conditions
Methadone Hydrochloride is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The methadone in Methadone Hydrochloride may cause spasm of the sphincter of Oddi. Opioids may cause increases in the serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

Increased Risks of Seizure in Patients with Seizure Disorders
Methadone may increase frequency of seizures in patients with seizure disorders, and increase the risks of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during Methadone Hydrochloride therapy.

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

When discontinuing Methadone Hydrochloride, gradually taper the dosage (see DOSAGE AND ADMINISTRATION). Do not abruptly discontinue Methadone Hydrochloride.

Risks of Driving or Operating Heavy Machinery
Methadone Hydrochloride may impair the ability to perform potentially hazardous activities such as driving or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication (see PRECAUTIONS, Information for Patients).

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

The major hazards of methadone, are respiratory depression and, to a lesser degree, systemic hypotension, circulatory depression. Respiratory arrest, shock, cardiac arrest, and death have occurred.

The most frequently observed adverse reactions include lightheadedness, dizziness, sedation, nausea, vomiting, and sweating. These effects seem to be more prominent in ambulatory patients and in those who are not suffering severe pain. In such individuals, lower doses are advisable.

Other adverse reactions include the following:

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

Cardiovascular – arrhythmias, bigeminal rhythms, bradycardia, cardiomyopathy, ECG abnormalities, extrasystoles, flushing, heart failure, hypotension, palpitations, phlebitis, QT interval prolongation, syncope, T-wave inversion, tachycardia, torsade de pointes, ventricular fibrillation, ventricular tachycardia

Central Nervous System – Euphoria, dysphoria, weakness, headache, insomnia, agitation, disorientation, and visual disturbances.

Gastro-Intestinal – Dry mouth, anorexia, constipation, and biliary tract spasm.

Skin and Appendages – Pruritus, urticaria, other skin rashes, edema, and, rarely, hemorrhagic urticaria.

Urogenital – Urinary retention or hesitancy, antidiuretic effect, and reduced libido and/or potency.

Postmarketing Experience

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

Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs (see WARNINGS and PRECAUTIONS, Drug Interactions).

Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use (see WARNINGS).

Anaphylaxis: Anaphylactic reaction has been reported with ingredients contained in Methadone Hydrochloride Powder (see CONTRAINDICATIONS).

Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids (see CLINICAL PHARMACOLOGY).

Important Dosage and Administration Information

Methadone Hydrochloride Powder MUST BE DISSOLVED IN AN APPROPRIATE LIQUID VEHICLE BEFORE ORAL ADMINISTRATION.

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

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

• A high degree of opioid tolerance does not eliminate the possibility of methadone overdose, iatrogenic or otherwise. Deaths have been reported during conversion to methadone from chronic, high-dose treatment with other opioid agonists and during initiation of methadone treatment of addiction in subjects previously abusing high doses of other opioid agonists.

• There is high interpatient variability in absorption, metabolism, and relative analgesic potency.  Population-based conversion ratios between methadone and other opioids are not accurate when applied to individuals.

• With repeated dosing, methadone is retained in the liver and then slowly released, prolonging the duration of potential toxicity.

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

• Methadone has a narrow therapeutic index, especially when combined with other drugs.

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
THE DRUG SHALL BE ADMINISTERED DAILY UNDER CLOSE SUPERVISION AS FOLLOWS:

A detoxification treatment course shall not exceed twenty-one days and may not be repeated earlier than four weeks after completion of the preceding course.

In detoxification, the patient may receive methadone when there are significant symptoms of withdrawal. The dosage schedules indicated below are recommended but could be varied in accordance with clinical judgment. Initially, a single oral dose of 15 to 20 mg. of methadone will often be sufficient to suppress withdrawal symptoms. Additional methadone may be provided if withdrawal symptoms are not suppressed or if symptoms reappear. When patients are physically dependent on high doses, it may be necessary to exceed these levels. Forty mg per day in single or divided doses will usually constitute an adequate stabilizing dosage level. Stabilization can be continued for two to three days, and then the amount of methadone normally will be gradually decreased. The rate at which methadone is decreased will be determined separately for each patient. The dose of methadone can be decreased on a daily basis or at two-day intervals, but the amount of intake shall always be sufficient to keep withdrawal symptoms at a tolerable level. In hospitalized patients, a daily reduction of 20 percent of the total daily dose may be tolerated and may cause little discomfort. In ambulatory patients, a somewhat slower schedule may be needed. If methadone is administered for more than three weeks, the procedure is considered to have progressed from detoxification or treatment of the acute withdrawal syndrome to maintenance treatment, even though the goal and intent may be eventual total withdrawal.

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.

The patient will initially ingest the drug under observation daily, or at least six days a week, for the first three months. After demonstrating satisfactory adherence to the program regulations for at least three months, the patient may be permitted to reduce to three times weekly the occasions for ingestion of the drug under observation. No more than a two-day take-home supply should be provided. With continuing adherence to the program’s requirements for at least two years, patients may then be permitted twice-weekly visits to the program for drug ingestion under observation with a three-day take-home supply. A regular review of dosage level should be made by the responsible physician, with careful consideration given to reduction of dosage as indicated on an individual basis. A new dosage level is only a test level until stability is achieved.

Medically Supervised Withdrawal After a Period of Maintenance Treatment

There is considerable variability in the appropriate rate of methadone taper in patients choosing medically supervised withdrawal from methadone treatment. It is generally suggested that dose reductions should be less than 10% of the established tolerance or maintenance dose, and that 10 to 14-day intervals should elapse between dose reductions. Apprise patients of the high risk of relapse to illicit drug use associated with discontinuation of methadone maintenance treatment.

Risk of Relapse in Patients on Methadone Maintenance Treatment of Opioid Addiction

Abrupt opioid discontinuation can lead to development of opioid withdrawal symptoms (see DRUG ABUSE AND DEPENDENCE). Opioid withdrawal symptoms have been associated with an increased risk of relapse to illicit drug use in susceptible patients.

Considerations for Management of Acute Pain During Methadone Maintenance Treatment

Patients in methadone maintenance treatment for opioid dependence who experience physical trauma, postoperative pain or other acute pain cannot be expected to derive analgesia from their existing dose of methadone. Such patients should be administered analgesics, including opioids, in doses that would otherwise be indicated for 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 (see CLINICAL PHARMACOLOGY, Pharmacokinetics, Specific Populations, and PRECAUTIONS, Pregnancy).

Special Limitations

Treatment of Patients Under Age Eighteen

1. The safety and effectiveness of methadone for use in the treatment of adolescents have not been proven by adequate clinical study. Special procedures are therefore necessary to assure that patients under age sixteen will not be admitted to a program and that patients between sixteen and eighteen years of age will be admitted to maintenance treatment only under limited conditions.

2. Patients between sixteen and eighteen years of age who were enrolled and under treatment in approved programs on December 15, 1972, may continue in maintenance treatment. No new patients between sixteen and eighteen years of age may be admitted to a maintenance treatment program after March 15, 1973, unless a parent, legal guardian, or responsible adult designated by the state authority completes and signs Form FD 2635, “Consent for Methadone Treatment.”

   Methadone treatment of new patients between the ages of sixteen and eighteen years will be permitted after December 15, 1972, only with a documented history of two or more unsuccessful attempts at detoxification and a documented history of dependence on heroin or other morphine-like drugs beginning two years or more prior to application for treatment. No patient under age sixteen may be continued or started on methadone treatment after December 15, 1972, but these patients may be detoxified and retained in the program in a drug-free state for follow-up and aftercare.

3. Patients under age eighteen who are not placed on maintenance treatment may be detoxified. Detoxification may not exceed three weeks. A repeat episode of detoxification may not be initiated until four weeks after the completion of the previous detoxification.