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Orlaam

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Orlaam

Discontinued Warning IconPlease Note: This Brand Name drug is no longer available in the US.
(Generic versions may still be available.)

WARNINGS

Due to its potential for serious and possibly life-threatening, proarrhythmic effects, LAAM should be reserved for use in the treatment of opiate-addicted patients who fail to show an acceptable response to other adequate treatments for opiate addiction, either because of insufficient effectiveness or the inability to achieve effective dose due to intolerable adverse effects from those drugs (see

WARNINGS

and Contraindications ).

Cases of QT prolongation and serious arrhythmia (torsade de pointes) have been observed during post-marketing treatment with ORLAAM (levomethadyl acetate) . Based on these reports, all patients should undergo a 12-lead ECG prior to administration of ORLAAM (levomethadyl acetate) to determine if a prolonged QT interval (QTc greater than 430 [male] or 450 [female] ms) is present. If there is a prolonged QT interval, ORLAAM (levomethadyl acetate) should NOT be administered. For patients in whom the potential benefit of ORLAAM (levomethadyl acetate) treatment is felt to outweigh the risks of potentially serious arrhythmias, an ECG should be performed prior to treatment, 12-14 days after initiating treatment, and periodically thereafter, to rule out any alterations in the QT interval.

ORLAAM (levomethadyl acetate) should be administered with extreme caution to patients who may be at risk for development of prolonged QT syndrome (e.g., congestive heart failure, bradycardia, use of a diurectic, cardiac hypertrophy, hypokalemia, or hypomagnesemia).

ORLAAM (levomethadyl acetate) is metabolized to active metabolites by the cytochrome P450 isoform, CYP3A4. Therefore, the addition of drugs that induce this enzyme (such as rifampin, phenobarbital, and phenytoin) or inhibit this enzyme (such as ketoconazole, erythromycin, and saquinavir) could increase the levels of parent drug or its active metabolites in a patient that was previously at steady-state, and this could potentially precipitate serious arrhythmias, including torsade de pointes (see

PRECAUTIONS

, Drug Interactions ).

CONDITIONS FOR DISTRIBUTION AND USE OF ORLAAM (levomethadyl acetate) (42 CFR Part 8)

ORLAAM (levomethadyl acetate) , used for the treatment of opiate addiction, shall be dispensed only by Opioid Treatment Programs (OTPs) certified by SAMHSA under 42 CFR Part 8, and registered by the Drug Enforcement Administration under 21. U.S.C. 823(g)(1). This does not preclude the maintenance or detoxification treatment of a patient who is hospitalized for medical conditions other than opiate addiction and who requires temporary maintenance for concurrent opiate addiction during the critical period of the patients hospitalization. Failure to abide by these requirements may result in injunction precluding operation of the program, revocation of the program approval, and possible criminal prosecution.

ORLAAM (levomethadyl acetate) has no recommended uses outside of the treatment of opiate addiction.

 

Administration of ORLAAM (levomethadyl acetate) on a daily basis has led to excessive drug accumulation and risk of fatal overdose.

ORLAAM (levomethadyl acetate) has only been studied on a thrice-weekly or every-other-day dosing regimen.

Any decision to administer ORLAAM (levomethadyl acetate) more frequently than every other day for any reason should be approached with extreme caution. Even then only very small doses (5 to 10 mg) should be considered.

Risk of Overdose

Analysis of some of the deaths from overdose observed in the development of ORLAAM (levomethadyl acetate) has shown that when ORLAAM (levomethadyl acetate) is diverted into channels of abuse, the uninformed addict can become impatient with the slow onset of ORLAAM (levomethadyl acetate) (2 to 4 hours) and take illicit drugs, resulting in a potentially lethal combined overdose when the peak ORLAAM (levomethadyl acetate) effect develops. Due to these risks of diversion and accidental death, ORLAAM (levomethadyl acetate) has been approved for use only when dispensed by a licensed facility.

Effects on Cardiac Conduction

ORLAAM (levomethadyl acetate) has been shown to prolong the ST segment of the electrocardiogram in beagle dogs dosed five days a week, and to inhibit the rapidly-activating delayed rectifier current I Kr in isolated myocytes in vitro . Serial EKGs performed in a human pharmacokinetics study showed a prolongation of the QTc interval in some patients which was not associated with dose.

Cases of QT prolongation and severe arrhythmias (torsade de pointes) have been observed during post-marketing treatment with ORLAAM (levomethadyl acetate) . Based on these reports, all patients should undergo a 12-lead ECG prior to administration of ORLAAM (levomethadyl acetate) to determine if a prolonged QT interval (QTc greater than 430 [male] or 450 [female] ms) is present. If there is a prolonged QT interval, ORLAAM (levomethadyl acetate) should NOT be administered. For patients in whom the potential benefit of ORLAAM (levomethadyl acetate) treatment is felt to outweigh the risks of potentially severe arrhythmias, an ECG should be performed prior to treatment and 12-14 days after initiating treatment, and periodically thereafter to rule out any alterations in the QT interval.

ORLAAM (levomethadyl acetate) should be administered with extreme caution to patients who may be at risk for development of prolonged QT syndrome (e.g., congestive heart failure, bradycardia, use of a diuretic, cardiac hypertrophy, hypokalemia, or hypomagnesemia).

ORLAAM (levomethadyl acetate) is metabolized to active metabolites by the cytochrome P450 isoform, CYP3A4. Therefore the addition of drugs that induce this enzyme (such as rifampin, phenobarbital, and phenytoin) or inhibit this enzyme (such as ketoconazole, erythromycin, and saquinavir) could increase the levels of parent drug or its active metabolites in a patient that was previously at steady-state, and this could potentially precipitate severe arrhythmias, including torsade de pointes (see

PRECAUTIONS

, Drug Interactions ).

Use of Narcotic Antagonists

In an individual receiving ORLAAM (levomethadyl acetate) , the administration of the usual dose of a narcotic antagonist may precipitate an acute withdrawal syndrome. The severity of this syndrome depends on the dose of the antagonist administered and the patient's level of physical dependence. Narcotic antagonists should be used in patients receiving ORLAAM (levomethadyl acetate) only if needed. If a narcotic antagonist is used to treat respiratory depression in the physically dependent patient, it should be administered with care and titration should begin with much smaller-than-usual doses (0.1 to 0.2 mg recommended). If the desired effect is not achieved, escalating doses may be administered every 2 to 3 minutes. If a cumulative dose of 10 mg of naloxone has been given without effect, further administration is unlikely to be of benefit (see OVERDOSAGE ).

If the patient does respond to narcotic antagonists, physicians should remember that naloxone has a much shorter duration of action than ORLAAM (levomethadyl acetate) . Such patients should remain under prolonged observation rather than being allowed to leave emergency treatment, since ORLAAM (levomethadyl acetate) 's action will outlast naloxone-induced reversal, putting the unsupervised patient at risk of relapse, a return of respiratory depression and possible death if continuing medical attention is not available. Use of other parenteral opioid antagonists may be appropriate in some cases, but only if the dosage of such drugs can be readily titrated. Oral naltrexone would not be appropriate for the treatment of ORLAAM (levomethadyl acetate) overdose, as it has been associated with the precipitation of prolonged opioid withdrawal symptoms when used in overdose settings.

Warnings to Patients

Patients must be warned that the peak activity of ORLAAM (levomethadyl acetate) is not immediate, and that use or abuse of other psychoactive drugs, including alcohol, may result in fatal overdose, especially with the first few doses of ORLAAM (levomethadyl acetate) , either during initiation of treatment or after a lapse in treatment.

Cases of QT prolongation and serious arrhythmia (torsade de pointes) have been observed during post-marketing treatment with ORLAAM (levomethadyl acetate) . If a patient taking ORLAAM (levomethadyl acetate) experiences symptoms suggestive of an arrhythmia (such as palpitations, dizziness, lightheadedness, syncope, or seizures), that patient should seek medical attention immediately.

Use in High Risk Patients

Suicide attempts with opiates, especially in combination with tricyclic antidepressants, alcohol, and other CNS active agents, are part of the clinical pattern of addiction. Although outpatient therapy with ORLAAM (levomethadyl acetate) and other drugs of this class is usually associated with a reduction in the risk of suicide, such risk is not eliminated. Individualized evaluation and treatment planning, including hospitalization, should be considered for patients who continue to exhibit uncontrolled drug use and persistent high-risk behavior despite adequate pharmacotherapy.

 

PRECAUTIONS

Initial Administration and Dosage Adjustment

Due to the long half-lives of ORLAAM (levomethadyl acetate) and its metabolites, patients will not feel the full effects of the medication for at least several days. Consequently, extra care is needed when starting patients on ORLAAM (levomethadyl acetate) and when making initial dosage adjustments (see INDIVIDUALIZATION OF DOSAGE and DOSAGE AND ADMINISTRATION ).

Use in Ambulatory Patients

Initiation of therapy or excessive doses of ORLAAM (levomethadyl acetate) may impair the mental and/or physical abilities required for performance of potentially hazardous tasks, such as driving a car or operating machinery. Patients should be warned not to engage in such activities if their alertness and behavior are affected. Most patients show no detectable impairment of ordinary tasks on ORLAAM (levomethadyl acetate) therapy.

Head Injury and Increased Intracranial Pressure

The respiratory depressant effects of narcotics and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of increased intracranial pressure. Furthermore, narcotics produce side effects that may make it difficult to evaluate the clinical course of patients with head injuries. In view of LAAM's profile as a mu agonist, it should be used with extreme caution and only if deemed essential in such patients.

Asthma and Other Respiratory Conditions

ORLAAM (levomethadyl acetate) , as with other opioids, should be used with caution in patients with asthma, in those with chronic obstructive pulmonary disease or cor pulmonale, and in individuals with a substantially decreased respiratory reserve, preexisting respiratory depression, hypoxia, or hypercapnea. In such patients, even usual therapeutic doses of narcotics may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea.

Special Risk Patients

Opioids should be given with caution and at reduced initial dose in certain patients, such as the elderly or debilitated and those with significant hepatic or renal dysfunction, hypothyroidism, Addison's Disease, prostatic hypertrophy, or urethral stricture.

Acute Abdominal Conditions

As with other mu agonists, treatment with ORLAAM (levomethadyl acetate) may obscure the diagnosis or clinical course in patients with acute abdominal conditions.

 

Drug Interactions

No interaction studies have been performed in humans. ORLAAM (levomethadyl acetate) is metabolized by the cytochrome P450 isoform, CYP3A4. The addition of drugs that induce this enzyme could increase the levels of active metabolites in a patient that was previously at steady-state.

Potentially Arrhythmogenic Agents Any drug known to have the potential to prolong the QT interval should not be used together with ORLAAM (levomethadyl acetate) . Possible pharmacodynamic interactions can occur between ORLAAM (levomethadyl acetate) and potentially arrhythmogenic agents such as class I or III antiarrhythmics, antihistamines that prolong the QT interval, antimalarials, calcium channel blockers, neuroleptics that prolong the QT interval, and antidepressants

Caution should be used when prescribing concomitant drugs known to induce hypokalemia or hypomagnesemia as they may precipitate QT prolongation and interact with ORLAAM (levomethadyl acetate) . These would include diuretics, laxatives and supraphysiological use of steroid hormones with mineralocorticoid potential.

Polydrug and Alcohol Abusers Patients who are known to abuse sedatives, tranquilizers, propoxyphene, antidepres-sants, benzodiazepines, and alcohol should be warned of the risk of serious overdose if these substances are taken while on ORLAAM (levomethadyl acetate) maintenance.

Interaction with Narcotic Antagonists, Mixed Agonists/Antago-nists, Partial Agonists, and Pure Agonists As with other mu agonists, patients maintained on ORLAAM (levomethadyl acetate) may experience withdrawal symptoms when administered pure narcotic antagonists, such as naloxone, naltrexone, and nalmefene, or when administered mixed agonists/antagonists or partial agonists such as pentazocine, nalbuphine, butorphanol, and buprenorphine.

In addition, agonists such as meperidine and propoxyphene, which are N-demethylated to long-acting, excitatory metabolites, should not be used by patients taking ORLAAM (levomethadyl acetate) because they would be ineffective unless given in such high doses that the risk of toxic effects of the metabolites becomes unacceptable.

Anesthesia and Analgesia Patients receiving ORLAAM (levomethadyl acetate) will develop a similar level of tolerance for opioids as patients receiving methadone. Anesthetists and other practitioners should be prepared to adjust their management of these patients accordingly.

Other Drug Interactions The anti-tuberculosis drug rifampin has been found to produce a marked (50%) reduction in serum methadone levels, leading to the appearance of symptoms of withdrawal in well-stabilized methadone maintenance patients. Similar effects on serum methadone levels have been observed for carbamazepine, phenobarbital, and phenytoin. The presumed mechanism for this effect is the induction of methadone metabolizing enzymes. Since ORLAAM (levomethadyl acetate) is metabolized into a more active metabolite, nor-LAAM, administration of these drugs may increase ORLAAM (levomethadyl acetate) 's peak activity and/or shorten its duration of action.

Conversely, drugs like erythromycin, cimetidine, and anti-fungal drugs like ketoconazole that inhibit hepatic metabolism, may slow the onset, lower the activity, and/or increase the duration of action of ORLAAM (levomethadyl acetate) . Caution and close observation of patients receiving these drugs are advised to allow early detection of any need to adjust the dose or dosing interval.

Information for Patients

Patients should be provided the patient package insert for ORLAAM (levomethadyl acetate) if they are new to the drug, and in addition should be advised that:

ORLAAM (levomethadyl acetate) , unlike methadone, is not to be taken daily, and daily use of the usual doses will lead to serious overdose.

If a patient taking ORLAAM (levomethadyl acetate) experiences symptoms suggestive of an arrhythmia (such as palpitations, dizziness, light-headedness, syncope, or seizures), that patient should seek medical attention immediately.

ORLAAM (levomethadyl acetate) is slow acting and patients should be alerted to the risk of abusing any psychoactive drug, including alcohol, while on ORLAAM (levomethadyl acetate) therapy. This is particularly important during the first 7 to 10 days of treatment, before ORLAAM (levomethadyl acetate) has had time to exert its full pharmacologic effect.

In addition to being warned of the delay in onset of ORLAAM (levomethadyl acetate) , patients who are transferring from ORLAAM (levomethadyl acetate) to methadone should be informed that they should wait 48 hours after the last dose of ORLAAM (levomethadyl acetate) before ingesting their first dose of methadone or other narcotic (see DOSAGE AND ADMINISTRATION ).

Patients should inform their adult family members that, in the event of overdose, the treating physician or emergency room staff should be told that the patient is being treated with ORLAAM (levomethadyl acetate) , a long-acting opioid which is likely to outlast naloxone-induced reversal and which requires prolonged observation and careful monitoring. In addition, the treating physician or emergency room staff should be informed that the patient is physically dependent on narcotics and that naloxone should be administered with care so as to minimize any precipitated abstinence syndrome.

As with most mu agonists, ORLAAM (levomethadyl acetate) may interact with other CNS depressants and should be used with caution, and in reduced dosage, in patients concurrently receiving other narcotic analgesics, antihistamines, benzodiazepines, phenothiazines or other major tranquilizers, anxiolytics, sedative-hypnotics, tricyclic antidepressants, and other CNS depressants, including alcohol. Patients should be warned of the importance of reporting the use of any of these compounds to their physicians, as serious side effects could result, including respiratory depression, hypotension, profound sedation or coma.

Carcinogenesis, Mutagenesis and Impairment of Fertility

Two-year carcinogenicity studies with LAAM in rats at 13 mg/kg (77 mg/m 2 ) and in mice at 30 mg/kg (90 mg/m 2 ) given orally in the diet did not show carcinogenic changes. LAAM is not mutagenic in the Ames test, the unscheduled DNA synthesis and repair test, mouse lymphoma cells in vitro, or chromosomal aberration tests in rats in vivo. LAAM tested positive in the forward mutation assay in N. crassa at 150 µg/mL in vitro and in the heritable translocation assay in mice at 21 mg/kg (63 mg/m 2 ). The clinical significance of these findings is not known.

Chronic treatment with LAAM at 80 mg three times a week did not produce chromosomal aberrations in peripheral human lymphocytes. Effects of LAAM on fertility in animals has not been fully evaluated.

Use in Pregnancy: Pregnancy Category C

Animal reproduction studies are not complete and there are no clinical data on the safety of ORLAAM (levomethadyl acetate) in pregnancy. For these reasons, ORLAAM (levomethadyl acetate) is not recommended for use in pregnancy. Women who may become pregnant should be advised of the risks of ORLAAM (levomethadyl acetate) therapy and of the desirability of discontinuing ORLAAM (levomethadyl acetate) prior to a planned pregnancy.

If a female patient becomes pregnant on ORLAAM (levomethadyl acetate) despite these precautions, it is recommended she be transferred to methadone for the remainder of the pregnancy (see TRANSFER FROM ORLAAM TO METHADONE , in DOSAGE AND ADMINISTRATION ). If it appears wiser to continue a specific patient on ORLAAM (levomethadyl acetate) , the physician should be alert to possible respiratory depression of the newborn and other perinatal complications (see Labor and Delivery ).

Labor and Delivery

The effects of ORLAAM (levomethadyl acetate) on labor and delivery are not known. Like other mu agonist opioids, however, ORLAAM (levomethadyl acetate) is expected to produce respiratory depression and a possible neonatal dependence syndrome with a delayed emergence of withdrawal symptoms. Use of ORLAAM (levomethadyl acetate) in labor and delivery is not recommended unless, in the opinion of the treating physician, the potential benefits outweigh the possible hazards.

Nursing Mothers

The effects of LAAM on infants of nursing mothers have not been studied. It is not known if LAAM is excreted in human milk in sufficient concentration to affect an infant. Use of ORLAAM (levomethadyl acetate) in nursing mothers is not recommended unless, in the opinion of the treating physician, the potential benefits outweigh the possible hazards.

Pediatric Use

The use of ORLAAM (levomethadyl acetate) in addicts under 18 years of age has not been studied. Its use is not recommended.

Last reviewed on RxList: 12/8/2004
This monograph has been modified to include the generic and brand name in many instances.

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