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Concentrated solution. Do not dispense the medicine to the patient in this bottle. The solution should be diluted by the pharmacist to the requested concentration and volume into a new bottle, according to the physician’s instructions. For oral administration only. The preparation must not be injected.
For oral use only. Methadone differs from many other opioid agonists in several important ways. Methadone’s pharmacokinetic properties, coupled with high interpatient variability in its absorption, metabolism, and relative analgesic potency, necessitate a cautious and highly individualized approach to prescribing.
Particular vigilance is necessary during treatment initiation, during conversion from one opioid to another and during dose titration. While methadone’s duration of analgesic action (typically 4 to 8 hours) in the setting of single-dose studies approximates that of morphine, methadone’s plasma elimination half-life is substantially longer than that of morphine (typically 8 to 59 hours vs. 1 to 5 hours). Methadone’s peak respiratory depressant effects typically occur later and persist longer than its peak analgesic effects. Also, with repeated dosing, methadone may be retained in the liver and then slowly released, prolonging the duration of action despite low plasma concentrations. For these reasons steady-state plasma concentrations and full analgesic effects are usually not attained until 3 to 5 days of dosing. Additionally, incomplete cross-tolerance between mu-opioid agonists makes determination of dosing during opioid conversion complex. The complexities associated with methadone dosing can contribute to cases of iatrogenic overdose, particularly during treatment initiation and dose titration. A high degree of “opioid tolerance” does not eliminate the possibility of methadone overdose, iatrogenic or otherwise. Deaths have been reported during conversion to methadone from chronic, high-dose treatment with other opioid agonists and during initiation of methadone treatment of addiction in subjects previously abusing high doses of other agonists.
Treatment of Pain: Optimal methadone initiation and dose titration strategies for the treatment of pain have not been determined. Published equianalgesic conversion ratios between methadone and other opioids are imprecise, providing at best, only population averages that cannot be applied consistently to all patients. It should be noted that many commonly cited equianalgesia tables only present relative analgesic potencies of single opioid doses in non-tolerant patients, thus greatly underestimating methadone’s analgesic potency and its potential for adverse effects in repeated-dose settings. Regardless of the dose determination strategy employed, methadone is most safely initiated and titrated using small initial doses and gradual dose adjustments. As with all opioid drugs, it is necessary to adjust the dosing regimen for each patient individually, taking into account the patient’s prior analgesic treatment experience. The following dosing recommendations should only be considered as suggested approaches to what is actually a series of clinical decisions over time in the management of the pain of each individual patient. Prescribers should always follow appropriate pain management principles of careful assessment and ongoing monitoring. In the selection of an initial dose of methadone, attention should be given to the following:
– The total daily dose, potency and specific characteristics of the opioid the patient had been taking previously, if any.
– The relative potency estimate used to calculate an equianalgesic starting methadone dose, in particular, whether it is intended for use in acute or chronic methadone dosing.
– The patient’s degree of opioid tolerance.
– The age, general condition and medical status of the patient.
– Concurrent medications, particularly other CNS and respiratory depressants.
– The type, severity and expected duration of the patient’s pain.
– The acceptable balance between pain control and adverse side effects.
Initiation of Therapy in Opioid Non-Tolerant Patients: When oral methadone is used as the first analgesic in patients who are not already being treated with, and tolerant to, opioids, the usual oral methadone starting dose is 2.5 mg to 10 mg every 8 to 12 hours, slowly titrated to effect. More frequent administration may be required during methadone initiation in order to maintain adequate analgesia, and extreme caution is necessary to avoid overdose, taking into account methadone’s long elimination half-life.
Conversion from Parenteral Methadone to Oral Methadone: Conversion from parenteral methadone to oral methadone should initially use a 1:2 dose ratio (e.g., 5 mg parenteral methadone to 10 mg oral methadone).
Switching Patients to Methadone from other Chronic Opioids: Switching a patient from another chronically administered opioid to methadone requires caution due to the uncertainty of dose conversion ratios and incomplete cross-tolerance. Deaths have occurred in opioid tolerant patients during conversion to methadone. Conversion ratios in many commonly used equianalgesic dosing tables do not apply in the setting of repeated methadone dosing. Although with single-dose administration the onset and duration of analgesic action, as well as the analgesic potency of methadone and morphine, are similar methadone’s potency increases over time with repeated dosing. Furthermore, the conversion ratio between methadone and other opiates varies dramatically depending on baseline opiate (morphine equivalent) use as shown in the table below. The dose conversion scheme below is derived from various consensus guidelines for converting chronic pain patients to methadone from morphine. Clinicians should consult published conversion guidelines to determine the equivalent morphine dose for patients converting from other opioids.
Gastro-intestinal spasms, renal, biliary colic, neuralgia, gynaecological pains, withdrawal treatment of morphine and pethidine addiction, relief of severe pain.
Known hypersensitivity to methadone or to any other ingredient in this preparation. Methadone is contraindicated in any situation where opioids are contraindicated such as: patients with respiratory depression (in the absence of resuscitative equipment or in unmonitored settings), and in patients with acute bronchial asthma or hypercarbia. Methadone is contraindicated in any patient who has or is suspected of having a paralytic ileus.
NOTE: Concentrated solution. Do not dispense the medicine to the patient in this bottle. The solution should be diluted by the pharmacist to the requested concentration and volume into a new bottle, according to the physician’s instructions. For oral administration only. The preparation must not be injected.
Respiratory depression: Respiratory depression is the chief hazard associated with methadone hydrochloride administration. Methadone’s peak respiratory depressant effects typically occur later, and persist longer than its peak analgesic effects, particularly during the initial dosing period. These characteristics can contribute to cases of iatrogenic overdose, particularly during treatment initiation or dose titration. Respiratory depression is of particular concern in elderly or debilitated patients as well as in those suffering from conditions accompanied by hypoxia or hypercapnia when even moderate therapeutic doses may dangerously decrease pulmonary ventilation. Methadone should be used with extreme caution in patients with conditions accompanied by hypoxia, hypercapnia, or decreased respiratory reserve such as asthma, chronic obstructive pulmonary disease or cor pulmonale, severe obesity, sleep apnea syndrome, myxedema, kyphoscoliosis, and CNS depression or coma. In these patients even usual therapeutic doses of methadone may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea. Alternative, non-opioid analgesics should be considered, and Methadone should be used at the lowest effective dose and only under careful medical supervision. Incomplete Cross-tolerance between Methadone and other Opioids 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 who are being converted to treatment with methadone, thus making determination of dosing during opioid treatment conversion complex. Deaths have been reported during conversion from chronic, high-dose treatment with other opioid agonists. Therefore, it is critical to understand the pharmacokinetics of methadone when converting patients from other opioids. A high dose of “opioid tolerance” does not eliminate the possibility of methadone overdose, iatrogenic or otherwise.
WARNING: RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death.
Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
Limit dosages and durations to the minimum required.
Follow patients for signs and symptoms of respiratory depression and sedation.
Deaths, cardiac and respiratory, have been reported during initiation and conversion of pain patients to methadone treatment from treatment with other opioid agonists and during initiation of methadone treatment for opioid dependence. In some cases, drug interactions with other drugs, both licit and illicit, have been suspected. However, in other cases, deaths appear to have occurred due to the respiratory or cardiac effects of methadone and too-rapid titration without appreciation for the accumulation of methadone over time. It is critical to understand the pharmacokinetics of methadone when converting patients from other opioids. Particular vigilance is necessary during treatment initiation, during conversion from one opioid to another, and during dose titration. Patients must also be strongly cautioned against self-medicating with CNS depressants during initiation of methadone treatment. Respiratory depression is the chief hazard associated with methadone hydrochloride administration. Methadone’s peak respiratory depressant effects typically occur later, and persist longer than its peak analgesic effects, particularly in the early dosing period. These characteristics can contribute to cases of iatrogenic overdose, particularly during treatment initiation and dose titration. In addition, cases of QT interval prolongation and serious arrhythmia (torsades de pointes) have been observed during treatment with methadone. Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. Methadone treatment for analgesic therapy in patients with acute or chronic pain should only be initiated if the potential analgesic or palliative care benefit of treatment with methadone is considered and outweighs the risks.
Acute abdominal conditions (diagnosis or clinical course) may be obscured by narcotics. Exercise caution in elderly and debilitated patients and in patients sensitive to CNS depressants, including those with cardiovascular disease, myxedema, acute alcoholism, delirium tremens, cerebral arteriosclerosis, fever, kyphoscoliosis, Addison’s disease, prostatic hypertrophy or urethral stricture, toxic psychosis, severe CNS depression or coma. Renal and hepatic dysfunction may cause a prolonged duration of action and cumulative effects. Use with caution in atrial flutter and other supraventricular tachycardias, because vagolytic action may produce an increase in the ventricular response rate. If dosage is substantially increased because of tolerance to the drug, seizures may be aggravated or occur in individuals without a history of convulsive disorders. Cough reflex is suppressed. Exercise caution when using postoperatively and in patients with pulmonary disease. Methadone may cause drowsiness or dizziness. Patients should be cautioned against engaging in potentially hazardous activities requiring mental or physical alertness, such as driving a car or operating machinery. Should be used with extreme caution in patients with acute asthma, chronic obstructive pulmonary disease or respiratory reserve, pregnancy and lactation, elderly and debilitated patients, pediatrics, sensitive to CNS depressants, cardiovascular disease, myxedema, acute alcoholism, delirium tremens, cerebral arteriosclerosis, fever, kyphoscoliosis, Addison’s disease, prostatic hypertrophy or urethral stricture, severe CNS depression or coma, atrial flutter and other supraventricular tachycardias, cough reflex is suppressed, driving a car or operating machinery.
Pediatric Use: Safety and effectiveness in pediatric patients below the age of 18 years have not been established. Accidental or deliberate ingestion by a child may cause respiratory depression that can result in death. Patients and caregivers should be instructed to keep methadone in a secure place out of the reach of children and to discard unused methadone in such a way that individuals other than the patient for whom it was originally prescribed will not come in contact with the drug.
Heroin Withdrawal: During the induction phase of methadone maintenance treatment, patients are being withdrawn from heroin and may therefore 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.
Initial Administration: The initial methadone dose should be carefully titrated to the individual. Too rapid titration for the patient’s sensitivity is more likely to produce adverse effects.
Major Hazards: Respiratory depression, apnea, and to a lesser degree, systemic hypotension, circulatory depression, respiratory arrest, shock and cardiac arrest, and death have occurred.
Most Frequent: Lightheadedness, dizziness, sedation, nausea, vomiting, and sweating. These effects are more prominent in ambulatory patients and in those not experiencing severe pain. They can be alleviated by lowering the dosage.
Allergic: Pruritis, urticaria, other skin rashes, diaphoresis, laryngospasm, edema, and rarely, haemorrhagic urticaria.
Central Nervous System: Euphoria, dysphoria, delirium, weakness, headache, edema, drowsiness, miosis, coma, insomnia, agitation, tremor, seizures, impairment of mental and physical performance, lethargy, anxiety, fear, psychic dependence, mood changes, hallucinations, disorientation, confusion, and visual disturbances. Choreic movements have been induced by methadone.
Cardiovascular: Facial flushing, peripheral circulatory collapse, arrhythmias, bigeminal rhythms, cardiomyopathy, ECG abnormalities, extrasystoles, heart failure, phlebitis, QT interval prolongation, T-wave inversion, torsade de pointes, tachycardia, bradycardia, palpitations, hypotension, syncope, ventricular fibrillation.
Gastrointestinal: Dry mouth, glossitis, abdominal pain, anorexia, constipation, and biliary tract spasm. Patients with chronic ulcerative colitis may experience increased colonic motility and toxic dilation. Concomitant administration of laxatives may counteract narcotic-induced constipation.
Genitourinary: Ureteral spasm and spasm of vesical sphincters, urinary retention or hesitancy, oliguria, antidiuretic effect, reduced libido or potency, amenorrhea.
Haematologic and Lymphatic: Reversible thrombocytopenia has been described in opioid addicts with chronic hepatitis.
Metabolic and Nutritional: Hypokalemia, hypomagnesemia, weight gain.
Respiratory: Pulmonary edema, respiratory depression.
Other: Muscular rigidity.
Maintenance on a stabilized dose – during prolonged administration of methadone, as in a methadone maintenance treatment program, there is usually a gradual, yet progressive, disappearance of side effects over a period of several weeks. However, constipation and sweating often persist. Respiratory depression, circulatory depression, shock and cardiac arrest, lightheadedness, dizziness, sedation, nausea, vomiting and sweating, euphoria, dysphoria, delirium, headache, drowsiness, miosis, insomnia, agitation, tremor, impairment of mental and physical performance, lethargy, anxiety, fear, psychic dependence, mood changes, hallucinations, disorientation, confusion and visual disturbances, choreic movements, gastrointestinal changes, cardiovascular changes, ureteral, vesical sphincters spasm, allergic reactions, muscular rigidity.
Methadone/Alcohol/General Anesthetics/Tricyclic Antidepressants/CNS Depressants: Concomitant use may result in increased CNS depression, respiratory depression, and hypotensive effects. Caution is recommended, and the dosage of one or both agents should be reduced. Deaths have been reported when methadone has been abused in conjunction with benzodiazepines. In addition, some phenothiazines increase, while others decrease, methadone-induced analgesia.
Methadone/Anticholinergics: Concomitant use may result in increased risk of severe constipation and/or urinary retention.
Abacavir, amprenavir, efavirenz, nelfinavir, nevirapine, ritonavir, lopinavir + ritonavir combination: Concomitant use of these anti retroviral agents resulted in increased clearance or decreased plasma levels of methadone. Methadone-maintained patients beginning treatment with these anti-retroviral drugs should be monitored for evidence of withdrawal effects and methadone dose should be adjusted accordingly.
Didanosine and Stavudine: Experimental evidence demonstrated that methadone decreased the 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/Cytochrome P450: In vitro results suggest that methadone undergoes hepatic N-demethylation by cytochrome P450 enzymes, principally CYP3A4, CYP2B6, CYP2C19 and to a lesser extent by CYP2C9 and CYP2D6. Coadministration of methadone with CYP inducers of these enzymes may result in a more rapidmetabolism and potential for decreased effects of methadone, whereas administration with CYP inhibitors may reduce metabolism and potentiate methadone’s effects. Although antiretroviral drugs such as efavirenz, nelfinavir, nevirapine, ritonavir, lopinavir + ritonavir combination are known to inhibit CYPs, they are shown to reduce the plasma levels of methadone, possibly due to their CYP induction activity. Therefore, drugs administered concomitantly with methadone should be evaluated for interaction potential; clinicians are advised to evaluate individual response to drug therapy.
Pregnancy and Lactation
Use in Pregnancy: Safety of use in pregnancy has not been established. The placental transfer of narcotics is very rapid. Maternal addiction with subsequent neonatal withdrawal is well documented following illicit use. Withdrawal symptoms include irritability, excessive crying, yawning, sneezing, increased respiratory rate, tremors, hyperreflexia, fever, vomiting, increased stools and diarrhea. Symptoms usually appear during the first days of life.
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.
Nursing Mothers: Methadone is secreted into human milk. The safety of breastfeeding while taking oral methadone is controversial. At maternal oral doses of 10 to 80 mg/day, methadone concentrations from 50 to 570 mcg/L in milk have been reported, which, in the majority of samples, were lower than maternal serum drug concentrations at steady state. Peak methadone levels in milk occur approximately 4 to 5 hours after an oral dose. Based on an average milk consumption of 150 mL/kg/day, an infant would consume approximately 17.4 mcg/kg/day which is approximately 2 to 3% of the oral maternal dose. Methadone has been detected in very low plasma concentrations in some infants whose mothers were taking methadone. Caution should be exercised when methadone is administered to a nursing woman. There have been rare cases of sedation and respiratory depression in infants exposed to methadone through breast milk. Mothers using methadone should receive specific information about how to identify respiratory depression and sedation in their babies. They should know when to contact their healthcare provider or seek immediate medical care. A healthcare provider should weigh the benefits of breastfeeding against the risks of infant exposure to methadone and possible exposure to other medicines. Women on high dose methadone maintenance, who are already breast feeding, should be counseled to wean breast-feeding gradually in order to prevent neonatal abstinence syndrome. Methadone-treated mothers considering nursing an opioid-naïve infant should be counseled regarding the presence of methadone in breast milk. Because of the potential for serious adverse reactions in nursing infants from methadone, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. In patients being treated for opioid dependence, this should include weighing the risk of methadone against the risk of maternal illicit drug use.
Manifestations: In severe overdose, apnea, circulatory collapse, convulsions, cardiopulmonary arrest and even death may occur. The less severely poisoned patient often presents the triad of central nervous system depression, miosis and respiratory depression.
Serious overdose is characterized by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, constricted pupils, skeletal muscle flaccidity, and cold and clammy skin. Hypotension, bradycardia, hypothermia, pulmonary edema, pneumonia or shock occurs in up to 40% of patients.
Treatment: Primary attention should be given to the maintenance of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. If depressed respiration is associated with muscular rigidity, an intravenous neuromuscular blocking agent may be required. After assessing the pulmonary status of the patient, administer a narcotic antagonist (naloxone is the antagonist of choice). Narcotic antagonists are specific antidotes for overdose. The physician must remember, however, that methadone is a long-acting depressant (36 to 48 hours), where opioid antagonist act for much shorter periods (one to three hours).
Since the duration of action of most narcotics exceeds that of narcotic antagonists, administration of the antagonist should be repeated to maintain adequate respiration and the patient should be kept under surveillance. Do not administer an antagonist in the absence of clinically-significant respiratory or cardiovascular depression. In an individual physically dependent on opioids, the administration of the usual dose of an opioid antagonist may precipitate an acute withdrawal syndrome. The severity of this syndrome will depend on the degree of physical dependence and the dose of the antagonist administered. If antagonists must be used to treat serious respiratory depression in the physically dependent patient, the antagonist should be administered with extreme care and by titration with smaller than usual doses of the antagonist. Intravenously administered naloxone or nalmefene may be used to reverse signs of intoxication. Because of the relatively short half-life of naloxone as compared with methadone, repeated injections may be required until the status of the patient remains satisfactory. Naloxone may also be administered by continuous intravenous infusion. Employ oxygen, intravenous fluids, vasopressors and other supportive measures as indicated. In cases of oral overdose, and where treatment can be instituted within 2 hours following ingestion, evacuate the stomach by emesis or gastric lavage. Closely observe the patient for a rise in temperature or pulmonary complications that may require institution of antibiotic therapy.