"A deeper dive into data from the Trial Evaluating Cardiovascular Outcomes With Sitagliptin (TECOS) with the type 2 diabetes drug sitagliptin (Januvia, Merck), confirming that the dipeptidyl peptidase-4 (DPP-4) is not associated with any "...
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LAAM is a synthetic opioid agonist with actions qualitatively similar to morphine (a prototypic mu agonist) and affecting the central nervous system (CNS) and smooth muscle. Principal actions include analgesia and sedation. Tolerance to these effects develops with repeated use. An abstinence syndrome generally occurs upon cessation of chronic administration similar to that observed with other opiates, but with slower onset, more prolonged course, and less severe symptoms.
LAAM exerts its clinical effects in the treatment of opiate abuse through two mechanisms. First, LAAM cross-substitutes for opiates of the morphine-type, suppressing symptoms of withdrawal in opiate-dependent individuals. Second, chronic oral administration of LAAM can produce sufficient tolerance to block the subjective "high" of usual doses of parenterally administered opiates.
LAAM is metabolized by N-demethylation to nor-LAAM and dinor-LAAM, which are also opioid agonists. These metabolites are more potent than the parent drug. The opioid effect which occurs when LAAM is administered is slower in onset and longer in duration (72 hours) than that of methadone (24 hours). This extended duration of action allows three-times-weekly administration (see CLINICAL TRIALS ).
The duration of action of a single dose of LAAM is due to the sum of the opioid activity of the parent drug and its metabolites. A single dose of orally administered LAAM has an onset of opioid effects averaging 2 to 4 hours after ingestion and a duration of action of 48 to 72 hours (as measured by pupillary constriction and suppression of abstinence signs). LAAM cross-substitutes for opiates like morphine in opiate-dependent individuals, suppressing symptoms of withdrawal from these compounds. Single oral doses of 30 to 60 mg of LAAM eliminate signs of abstinence for 24 to 48 hours in individuals maintained on high doses of morphine who are abruptly withdrawn. At higher doses (80 mg and above), suppression of withdrawal can increase to 48 to 72 hours in most individuals.
Repeated oral administration of LAAM can produce sufficient tolerance to block the effects of parenterally administered opiates. Chronic oral administration of 70 to 100 mg of LAAM three times weekly produces tolerance which blocks the "high" of a 25 mg dose of intravenously administered heroin for up to 72 hours; maintenance on lower doses (50 mg) of LAAM produces only partial blockage for the same period.
LAAM is rapidly absorbed from an oral solution. Plasma levels are detectable within 15 to 30 minutes after ingestion and reach their peak within 1.5 to 2 hours at steady-state. LAAM undergoes first-pass metabolism to its demethylated metabolite nor-LAAM, which is sequentially N-demethylated to dinor-LAAM. Both metabolites are active and contribute to the extent and duration of ORLAAM (levomethadyl acetate) 's clinical activity (see PHARMACODYNAMICS ).
The steady-state pharmacokinetics of LAAM were modeled from a study in 25 healthy adult addicts using three-times-a-week dosing over a 15-day observation period. LAAM and its metabolites were found to follow a multi-compartment model with extensive tissue distribution (Vd ~ 20 L/kg). LAAM had a clearance of about 0.22 L/kg/hr, mostly by conversion to nor-LAAM. Kinetic studies of the pure metabolites in man have not yet provided accurate estimates of their clearance in the absence of the precursor, but the half-lives observed in this study were 2.6 days for LAAM, approximately 2 days for nor-LAAM, and approximately 4 days for dinor-LAAM.
The pharmacokinetic model used to estimate steady-state plasma levels for each subject in this study assumed a common 3 mg/kg/wk dosage regimen (0.94 mg/kg on Mon. and Wed., 1.125 mg/kg on Fri.). The estimates (which fit the observed data with a correlation of better than 0.95) revealed a large inter-patient variability. There was at least a 5-fold range in peak plasma concentrations for LAAM and its metabolites across the 25 subjects over the 72-hour interval from Friday to Monday on a 3-times-a-week dosage regimen. Table 1 contains these estimates of peak and trough plasma concentrations of LAAM, nor-LAAM, and dinor-LAAM.
|204 (34%)||173 (34%)||114 (28%)|
|36 (62%)||85 (58%)||96 (34%)|
|*Following Friday Morning Dose|
|**Prior to Monday Morning Dose|
Metabolism and Elimination
The cyctochrome P450 isoform, CYP3A4, plays a major role in the metabolism of LAAM. As noted above, the formation of nor-LAAM and dinor-LAAM is by sequential demethylation, such that dinor-LAAM is formed from nor-LAAM, not directly from LAAM. While N-demethylation is the primary route of metabolism, minor pathways of elimination include direct excretion and deacetylation to methadol, nor-methadol, and dinor-methadol.
Gender An analysis of the data from the above study showed some difference in the plasma clearance of LAAM in 8 females versus 17 males. Males showed a trend toward a slower conversion of LAAM to nor-LAAM, which may alter the plasma concentration profile of LAAM and its active opioid metabolites. Although this effect was much smaller than the observed inter-individual differences, physicians should be alert to a possible gender difference (see INDIVIDUALIZATION OF DOSAGE ).
Hepatic and Renal Disease At the present time no pharmacokinetics studies have been carried out in subjects with clinically significant hepatic insufficiency or serious renal impairment. Since both the pharmacokinetics and pharmacodynamics of opiate agonists may be altered in these subjects, and any additional risks of ORLAAM (levomethadyl acetate) therapy are not well understood in such patients, physicians may choose to manage such patients with methadone due to its simpler metabolic profile.
ORLAAM (levomethadyl acetate) has been studied in 2666 street addicts and 3319 methadone maintenance patients, including 5697 males and 288 females. During the course of 27 studies, 4610 patients received orally administered ORLAAM (levomethadyl acetate) for up to three years in thrice-weekly doses ranging from 10 to 140 mg. Twenty-one studies provide the primary evidence upon which the dosing recommendations for ORLAAM (levomethadyl acetate) are based.
The vast majority of patients who received ORLAAM (levomethadyl acetate) were treated on a thrice-weekly basis, typically on Mondays, Wednesdays and Fridays (Mon./Wed./Fri.), although every-other-day dosing schedules were used in some settings. Most of the sites dosing patients with LAAM on a 3-times-a-week (Mon./Wed./Fri. or Tues./Thurs./Sat.) schedule increased the dose prior to the 72-hour inter-dose interval by 20 to 40% to obtain coverage for the full 72 hours.
In controlled clinical trials, treatment with ORLAAM (levomethadyl acetate) was found to be comparable to treatment with methadone with respect to reduction in use of illicit opioids. ORLAAM (levomethadyl acetate) doses in the range of 60 to 100 mg 3-times-a-week reduced the average frequency of urine samples positive for opiates to 15-20%, as did therapy with 50 to 100 mg a day of methadone. There was a trend for more patients to drop out of ORLAAM (levomethadyl acetate) therapy than methadone therapy in the first 4 weeks of treatment (16% dropouts for ORLAAM (levomethadyl acetate) v. 12% for methadone), but the dropout rates for both treatments rapidly declined and both were in the range of 1 to 2% per week for the remaining patients by the third month of the studies. Global ratings of patient acceptability and response to treatment were similar for both LAAM and methadone.
In the Phase III studies, ORLAAM (levomethadyl acetate) tended to be more effective in patients perceived by staff to benefit from a reduced frequency of clinic visits and less effective in patients perceived as needing the added support of daily clinic visits.
Four independent studies were concerned with other research objectives, including induction regimens, methadone-to-ORLAAM (levomethadyl acetate) (and ORLAAM (levomethadyl acetate) -to-methadone) crossover ratios, and detoxification. This research involved 800 adults (including 11 females), approximately 440 of whom were methadone maintenance patients. The results of these studies, as well as the results of a nationwide Phase III usage study of 623 patients (including 204 females) in 25 representative clinics across the country, are reflected in the dosing recommendations.
INDIVIDUALIZATION OF DOSAGE
ORLAAM (levomethadyl acetate) is intended for use as part of a comprehensive treatment plan for narcotic dependence of the opioid type. Supplying narcotic drugs to narcotic addicts for the treatment of addiction without appropriate medical evaluation, treatment planning, and counseling has not been shown to be effective, and is a violation of the law except in special circumstances.
The therapeutic goal early in treatment with ORLAAM (levomethadyl acetate) is to reduce illicit opioid use. The dose of ORLAAM (levomethadyl acetate) should be chosen and adjusted as needed to provide a dose that is high enough to suppress drug withdrawal, illicit drug seeking and usage, and related high-risk behavior. If opioid side effects persist once illicit drug use is controlled, the dose of ORLAAM (levomethadyl acetate) may require further adjustment later in treatment to minimize adverse effects.
Physicians should be alert to patient differences in levels of opioid tolerance and inter-patient variability in the absorption, distribution and metabolism of both ORLAAM (levomethadyl acetate) and its metabolites. As with methadone, an important contribution to continued abuse of illicit drugs is an inadequate dose of the treatment medication.
Initial dosage adjustment with ORLAAM (levomethadyl acetate) is complex due to its delayed onset of action. If the starting dose is too high or if the dose is escalated too rapidly for the patient's level of tolerance, symptoms characteristic of excessive opioid effect may occur, i.e., poor concentration, sedation, and orthostatic hypotension. Patients should be watched for such symptoms, and the dose should be lowered if they appear. In rare instances, serious symptoms of narcotic overdosage may occur, leading to profound CNS and respiratory depression.
ORLAAM (levomethadyl acetate) and its metabolites quickly accumulate to toxic levels if the doses intended for 3-times-a-week dosing are given too frequently. The recommended doses are intended for every-other-day or 3-times-a-week dosing and should not be given daily.
The recommended initial dose for patients with low or unknown tolerance to opioids is 20 to 40 mg three-times-a-week or every-other-day. Successive doses may be increased by 5 to 10 mg. At least two weeks are needed to achieve a clinical plateau after a dosage adjustment. Adjustment to a dosing schedule is dependent upon the rate at which an individual develops tolerance to the increasing level of ORLAAM (levomethadyl acetate) (and its metabolites) as well as the time required for ORLAAM (levomethadyl acetate) and its metabolites to accumulate to steady-state levels.
The goal of dosage titration is to suppress narcotic withdrawal while avoiding excessive opioid effects due to the build-up of long-acting metabolites. It may be safer to provide extra counseling and support rather than to attempt to completely suppress a patient's withdrawal or narcotic hunger during the first week or two of therapy. On the other hand, there is the ever-present danger that patients who receive sub-therapeutic starting doses will supplement with street drugs, resulting in overdose. Patients should be strongly warned against this practice. Later in the titration process, dosage adjustments are better made on a weekly basis whenever possible.
For patients on methadone maintenance whose level of tolerance is known, the recommended initial dose of ORLAAM (levomethadyl acetate) is 1.2 to 1.3 times the patient's daily dose of methadone, not to exceed 120 mg. Care should be taken not to adjust the dose too frequently thereafter (usually 5 to 10 mg changes every second or third dose) since increasing the dose too rapidly may result in oversedation.
One major advantage of ORLAAM (levomethadyl acetate) therapy is reduction in need for daily clinic visits and for take-home medication. In some patients, ORLAAM (levomethadyl acetate) may not provide adequate suppression of withdrawal for a full 72 hours. For such individuals, several therapeutic options are available: (1) extra support and an explanation of reasons for the effect, (2) increasing the dose given prior to the 72-hour interval, (3) switching to an every-other-day dosing schedule, (4) dispensing a supplemental methadone dose.
Most patients do not experience withdrawal during the 72-hour inter-dose interval after reaching pharmacological steady-state with or without adjustment of the Friday dose. If additional opioids are required, and the patient is not eligible or appropriate for take home doses of ORLAAM (levomethadyl acetate) , small doses of supplemental methadone should be given rather than giving ORLAAM (levomethadyl acetate) on two consecutive days. Take-home doses of ORLAAM (levomethadyl acetate) and methadone always pose a risk in this setting and physicians should carefully weigh the potential therapeutic benefit against the risk of diversion (see DOSAGE AND ADMINISTRATION ).
Patients should receive extra support and counseling and be warned against supplementing with street drugs as they make the switch from methadone to ORLAAM (levomethadyl acetate) . The variability in the clearance of LAAM, nor-LAAM, and dinor-LAAM and clinical experience suggest that there will be a small number of patients who require either lower or higher doses than those recommended.
DURATION OF ORLAAM (levomethadyl acetate) THERAPY
There is no information from controlled clinical trials as to the appropriate duration of ORLAAM (levomethadyl acetate) therapy. There are reports from investigators that some patients on ORLAAM (levomethadyl acetate) may experience less variation in opioid effects and have less drug craving than with methadone, so ORLAAM (levomethadyl acetate) should be considered for patients who need long-term maintenance during social and vocational rehabilitation.
When a patient has eliminated illicit drug use, achieved social and occupational stability, and made lifestyle changes to reduce the risk of relapse, consideration may be given to discontinuation of ORLAAM (levomethadyl acetate) therapy. Such a decision should be carefully considered as part of an individualized treatment plan. Stable long-term ORLAAM (levomethadyl acetate) therapy is preferable to repeated cycles of premature discontinuation of medication followed by relapse to uncontrolled addiction.
A patient is most likely to remain abstinent if discontinuation of medication is attempted after the achievement of behavioral objectives and is accompanied by appropriate non-pharmacological support. The rate of dose reduction should vary according to patient's response. Discontinuation of ORLAAM (levomethadyl acetate) therapy for administrative reasons or because of adverse reactions to the drug should be managed as described below under DOSAGE AND ADMINISTRATION .
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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