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