Zelapar Information
Zelapar (Selegiline) Description
Its empirical formula is CHN• HCl, representing a molecular weight of 223.75. Selegiline hydrochloride is a white to almost white crystalline powder that is freely soluble in water, chloroform, and methanol.
Zelapar (Selegiline) Orally Disintegrating Tablets are available for oral administration (not to be swallowed) in a strength of 1.25 mg. Each lyophilized orally disintegrating tablet contains the following inactive ingredients: gelatin, mannitol, glycine, aspartame, citric acid, yellow iron oxide, and grapefruit flavor.
Zelapar (Selegiline) Clinical Pharmacology
The mechanisms accounting for selegiline's beneficial adjunctive action in the treatment of Parkinson's disease are not fully understood. Inhibition of monoamine oxidase type B (MAO-B) activity is generally considered to be of primary importance; in addition, there is evidence that selegiline may act through other mechanisms to increase dopaminergic activity.
Selegiline is best known as an irreversible inhibitor of monoamine oxidase (MAO), an intracellular enzyme associated with the outer membrane of mitochondria. Selegiline inhibits MAO by acting as a suicide substrate for the enzyme; that is, converted by MAO to an active moiety which combines irreversibly with the active site and/or the enzyme's essential flavin adenine dinucleotide (FAD) cofactor. Because selegiline has greater affinity for type B rather than for type A active sites, it can serve as a selective inhibitor of MAO type B if it is administered at the recommended dose. However, even for "selective" MAO-B inhibitors, the selectivity for inhibiting MAO-B typically diminishes and is ultimately lost as the dose is increased beyond particular dose levels.
MAOs are widely distributed throughout the body; their concentration is especially high in liver, kidney, stomach, intestinal wall, and brain. MAOs are currently subclassified into two types, A and B, which differ in their substrate specificity and tissue distribution. In humans, intestinal MAO is predominantly type A (MAO-A), while most of that in brain is type B (MAO-B).
In CNS neurons, MAO plays an important role in the catabolism of catecholamines (dopamine, norepinephrine and epinephrine) and serotonin. MAOs are also important in the catabolism of various exogenous amines found in a variety of foods and drugs. MAO in the GI tract and liver (primarily type A), for example, is thought to provide vital protection from exogenous amines (e.g., tyramine) that have the capacity, if absorbed intact, to cause a hypertensive crisis, the so-called cheese reaction. (If large amounts of certain exogenous amines gain access to the systemic circulation - e.g., from fermented cheese, red wine, herring, over-the-counter cough/cold medications, etc. - they are taken up by adrenergic neurons and displace norepinephrine from storage sites within membrane bound vesicles. Subsequent release of the displaced norepinephrine causes the rise in systemic blood pressure, etc.)
In theory, since MAO-A of the gut is not inhibited, patients treated with Zelapar (Selegiline) at the recommended dose of 2.5 mg a day should be able to take medications containing pharmacologically active amines and consume tyramine-containing foods without risk of uncontrolled hypertension.
Although rare, a few reports of hypertensive reactions have occurred in patients receiving swallowed selegiline at the recommended dose (a dose believed to be selective for MAO-B), with tyramine-containing foods. In addition, one case of hypertensive crisis has been reported in a patient taking the recommended dose of swallowed selegiline and a sympathomimetic medication (ephedrine). The pathophysiology of the cheese reaction is complicated and, in addition to its ability to inhibit MAO-B selectively, selegiline's relative freedom from this reaction has been attributed to an ability to prevent tyramine and other indirect acting sympathomimetics from displacing norepinephrine from adrenergic neurons. However, until the pathophysiology of the cheese reaction is more completely understood, it seems prudent to assume that Zelapar (Selegiline) can ordinarily only be used safely without dietary restrictions at doses where it presumably selectively inhibits MAO-B (e.g., 2.5 mg/day). Safe use of Zelapar (Selegiline) at doses above 2.5 mg daily without dietary tyramine restrictions has not been established.
Because selegiline's inhibition of MAO-B is irreversible, it is impossible to predict the extent of MAO-B inhibition from steady state plasma levels. For the same reason, it is not possible to predict the rate of recovery of MAO-B activity as a function of plasma levels. The recovery of MAO-B activity is a function of de novo protein synthesis; however, information about the rate of de novo protein synthesis is not yet available. Although platelet MAO-B activity returns to the normal range within 5 to 7 days of selegiline discontinuation, the linkage between platelet and brain MAO-B inhibition is not fully understood nor is the relationship of MAO-B inhibition to the clinical effect established.
It is important to be aware that selegiline may have pharmacological effects unrelated to MAO-B inhibition. As noted above, there is some evidence that it may increase dopaminergic activity by other mechanisms, including interfering with dopamine re-uptake at the synapse. Effects resulting from swallowed selegiline may also be mediated through its metabolites. However, the extent to which these metabolites contribute to the effects of swallowed selegiline are unknown. Since Zelapar (Selegiline) is primarily absorbed across the buccal mucosa, thereby bypassing the significant first pass metabolism seen with swallowed selegiline, the concentrations of these metabolites (including amphetamine and methamphetamine) are negligible.
Zelapar (Selegiline) Clinical Studies
The effectiveness of Zelapar (Selegiline) as an adjunct to levodopa/carbidopa in the treatment of Parkinson's disease was established in a multicenter randomized placebo-controlled trial (n=140; 94 received Zelapar (Selegiline) , 46 received placebo) of three months' duration. Patients randomized to Zelapar (Selegiline) received a daily dose of 1.25 mg for the first 6 weeks and a daily dose of 2.5 mg for the last 6 weeks. Patients were all treated with concomitant levodopa products and could additionally have been on concomitant dopamine agonists, anticholinergics, amantadine, or any combination of these during the trial. COMT (catechol-O-methyl-transferase) inhibitors were not allowed.
Patients with idiopathic Parkinson's disease receiving levodopa were enrolled if they demonstrated an average of at least 3 hours of "OFF" time per day on weekly diaries collected during a 2-week screening period. The patients enrolled had a mean duration of Parkinson's disease of 7 years, with a range from 0.3 years to 22 years.
At selected times during the 12 week study, patients were asked to record the amount of "OFF," "ON," "ON with dyskinesia," or "sleep" time per day for two separate days during the week prior to each scheduled visit. The primary efficacy outcome was the reduction in average percentage daily "OFF" time during waking hours from baseline to the end of the trial (averaging results at Weeks 10 and 12). Both treatment groups had an average of 7 hours per day of "OFF" time at baseline. The absolute mean percent reduction of "OFF" time was 13.1% for Zelapar (Selegiline) and 5.1% for placebo. Zelapar (Selegiline) -treated patients had an average of 2.2 hours per day less "OFF" time compared to baseline. Placebo-treated patients had 0.6 hours per day less "OFF" time compared to baseline. These differences were statistically significant (p
Dosage reduction of levodopa was allowed during this study if dopaminergic side effects, including dyskinesia and hallucinations, emerged. Levodopa dosage reduction occurred in 17% of patients in the Zelapar (Selegiline) group and in 19% in the placebo group. In those patients who had levodopa dosage reduced, the dose was reduced on average by 24% in the Zelapar (Selegiline) group and by 21% in the placebo group.
No difference in effectiveness based on age (patients > 66 years old vs.
Zelapar (Selegiline) Indications And Usage
Zelapar (Selegiline) ® is indicated as an adjunct in the management of patients with Parkinson's disease being treated with levodopa/carbidopa who exhibit deterioration in the quality of their response to this therapy. There is no evidence from controlled studies that Zelapar (Selegiline) has any beneficial effect in the absence of concurrent levodopa therapy.
Zelapar (Selegiline) Contraindications
Zelapar (Selegiline) is contraindicated in patients with a known hypersensitivity to any formulation of selegiline or any of the inactive ingredients of Zelapar (Selegiline) .
Zelapar (Selegiline) is contraindicated for use with meperidine. Serious reactions have been precipitated with concomitant use of meperidine (e.g., Demerol and other tradenames) and MAO inhibitors including selective MAO-B inhibitors. These reactions have been characterized by coma, severe hypertension or hypotension, severe respiratory depression, convulsions, malignant hyperpyrexia, excitation, peripheral vascular collapse and death. At least 14 days should elapse between discontinuation of Zelapar (Selegiline) ® and initiation of treatment with meperidine. (See
For similar reasons, Zelapar (Selegiline) should not be administered with the analgesic agents tramadol, methadone, and propoxyphene.
Zelapar (Selegiline) Warnings
The selectivity of Zelapar (Selegiline) for MAO-B may not be absolute even at the recommended daily dose of 2.5 mg a day. Even for "selective" MAO-B inhibitors, the selectivity for inhibiting MAO-B typically diminishes and is ultimately lost as the dose is increased beyond particular dose levels. Rare cases of hypertensive reactions associated with ingestion of tyramine containing foods have been reported even in patients taking the recommended daily dose of swallowed selegiline, a dose which is generally believed to be selective for MAO-B. Obviously, any selectivity is further diminished with increasing daily doses. An increase in tyramine sensitivity for blood pressure responses appears to occur beginning at a 5 mg daily dose. However, the precise dose at which Zelapar (Selegiline) becomes a non-selective inhibitor of all MAO is unknown.
Zelapar (Selegiline) Precautions
Epidemiological studies have shown that patients with Parkinson's disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population.
Whether the increased risk observed was due to Parkinson's disease or other factors, such as drugs used to treat Parkinson's disease, is unclear.
For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using Zelapar (Selegiline) for indication. Ideally, periodic skin examination should be performed by appropriately qualified individuals (e.g., dermatologists).
Some patients given Zelapar (Selegiline) may experience an exacerbation of levodopa associated side effects, presumably due to the increased amounts of dopamine reacting with super sensitive, post-synaptic receptors. These effects may often be mitigated by reducing the dose of levodopa/carbidopa. For example, in the study demonstrating the efficacy of Zelapar (Selegiline) , there was an average 24% reduction in levodopa/carbidopa dosage in the 17% of patients who experienced a dose reduction during Zelapar (Selegiline) treatment.
The decision to prescribe Zelapar (Selegiline) should take into consideration that the MAO system of enzymes is complex and incompletely understood and there is only a limited amount of carefully documented clinical experience with Zelapar (Selegiline) . Consequently, the full spectrum of possible responses to Zelapar (Selegiline) may not have been observed in pre-marketing evaluation of the drug. It is advisable, therefore, to observe patients closely for atypical responses.
When used as an adjunct to levodopa, hallucinations were reported as an adverse event in approximately 4% of patients treated with Zelapar (Selegiline) and 2% of patients treated with placebo. Hallucinations led to drug discontinuation and premature withdrawal from clinical trials in about 1% of patients treated with Zelapar (Selegiline) and none of the placebo treated patients.
Patients should be cautioned of the possibility of developing hallucinations and instructed to report them to their health care provider promptly should they develop.
Patients should be advised of the possible need to reduce levodopa dosage after the initiation of Zelapar (Selegiline) therapy.
Patients (or their families if the patient is incompetent) should be advised not to exceed the daily recommended dose of 2.5 mg. The risk of using higher daily doses of Zelapar (Selegiline) should be explained, and a brief description of the hypertensive/cheese reaction provided. Rare hypertensive reactions with oral selegiline at recommended doses associated with dietary influences have been reported.
Consequently, it may be useful to inform patients (or their families) about the signs and symptoms associated with MAOI-induced hypertensive reactions. In particular, patients should be urged to report, immediately, any severe headache or other atypical or unusual symptoms not previously experienced.
Patients should be informed that hallucinations can occur.
There have been reports of patients experiencing intense urges to gamble, increased sexual urges, and other intense urges and the inability to control these urges while taking one or more of the medications that increase central dopaminergic tone, that are generally used for the treatment of Parkinson's disease, including Zelapar (Selegiline) . Although it is not proven that the medications caused these events, these urges were reported to have stopped in some cases when the dose was reduced or the medication was stopped. Prescribers should ask patients about the development of new or increased gambling urges, sexual urges or other urges while being treated with Zelapar (Selegiline) . Patients should inform their physician if they experience new or increased gambling urges, increased sexual urges or other intense urges while taking Zelapar (Selegiline) . Physicians should consider dose reduction or stopping the medication if patient develops such urges while taking Zelapar (Selegiline) .
Patients should be instructed not to remove the blister from the outer pouch until just prior to dosing. The blister pack should then be peeled open with dry hands and the orally disintegrating tablet placed on the tongue, where it will disintegrate. Patients should also avoid drinking liquids or eating food five minutes before and after taking Zelapar (Selegiline) .
Carcinogenicity studies of selegiline have not been conducted using the buccal route.
Selegiline did not induce mutations or chromosomal damage when tested in the bacterial mutation assay in and in an oral chromosomal aberration assay. While these studies provide some reassurance that selegiline is not mutagenic or clastogenic, they are not definitive because of methodological limitations. No definitive chromosomal aberration or mammalian gene mutation studies have been performed.
The effect of selegiline on fertility has not been adequately assessed.
Zelapar (Selegiline) Adverse Reactions
A total of 578 patients received Zelapar (Selegiline) in clinical trials. Because the controlled trials performed during premarketing development both used a titration design (1.25 mg per day for 6 weeks, followed by 2.5 mg per day for 6 weeks), with a resultant confounding of time and dose, it was impossible to adequately evaluate the effects of dose on the incidence of adverse events.
The most commonly observed adverse events, which were greater than placebo, reported in the double-blind, placebo-controlled trials during Zelapar (Selegiline) treatment were dizziness, nausea, pain, headache, insomnia, rhinitis, dyskinesia, back pain, stomatitis, and dyspepsia.
Of the 194 patients treated with Zelapar (Selegiline) in the double-blind, placebo-controlled trials, 5.2% discontinued due to adverse events compared to 1.0% of the 98 patients who received placebo. Events causing discontinuation of treatment included dizziness, chest pain, accidental injury, and myasthenia.
Zelapar (Selegiline) Postmarketing Reports
There have been reports of the following adverse reactions: pathological gambling, increased libido including hypersexuality, and impulse control symptoms while taking one or more of the medications that are generally used for the treatment of Parkinson's disease.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a casual relationship to drug exposure.
Zelapar (Selegiline) Overdosage
No specific information is available about clinically significant overdoses with swallowed selegiline or Zelapar (Selegiline) . However, experience gained during development of the 5 mg swallowed dosage form reveals that some individuals exposed to doses of 600 mg of d,l-selegiline suffered severe hypotension and psychomotor agitation.
Since the selective inhibition of MAO-B by Zelapar (Selegiline) is achieved only at doses in the range recommended for the treatment of Parkinson's disease (e.g., 2.5 mg/day), overdoses are likely to cause significant inhibition of both MAO-A and MAO-B. Consequently, the signs and symptoms of overdose may resemble those observed with marketed non-selective MAO inhibitors [e.g., tranylcypromine (PARNATE), isocarboxazide (MARPLAN), and phenelzine (NARDIL)].
NOTE: This section is provided for reference; it does not describe events that have actually been observed with oral selegiline or Zelapar (Selegiline) in overdose.
Characteristically, signs and symptoms of non-selective MAOI overdose may not appear immediately. Delays of up to 12 hours between ingestion of drug and the appearance of signs may occur. Importantly, the peak intensity of the syndrome may not be reached for upwards of a day following the overdose. Death has been reported following overdosage. Therefore, immediate hospitalization, with continuous patient observation and monitoring for a period of at least two days following the ingestion of such drugs in overdose, is strongly recommended.
The clinical picture of MAOI overdose varies considerably; its severity may be a function of the amount of drug consumed. The central nervous and cardiovascular systems are prominently involved.
Signs and symptoms of overdosage may include, alone or in combination, any of the following: drowsiness, dizziness, faintness, irritability, hyperactivity, agitation, severe headache, hallucinations, trismus, opisthotonos, convulsions, and coma; rapid and irregular pulse, hypertension, hypotension and vascular collapse; precordial pain, respiratory depression and failure, hyperpyrexia, diaphoresis, and cool, clammy skin.
NOTE: Because there is no recorded experience with swallowed selegiline or Zelapar (Selegiline) overdose, the following suggestions are offered based upon the assumption that such overdoses may be modeled by non-selective MAOI poisoning. In any case, up-to-date information about the treatment of overdose can often be obtained from a certified Regional Poison Control Center. Telephone numbers of certified Poison Control Centers are listed in the Physicians Desk Reference (PDR).
Treatment of overdose with non-selective MAOIs is symptomatic and supportive. Induction of emesis or gastric lavage with instillation of charcoal slurry may be helpful in early poisoning, provided the airway has been protected against aspiration. Signs and symptoms of central nervous system stimulation, including convulsions, should be treated with diazepam, given slowly intravenously. Phenothiazine derivatives and central nervous system stimulants should be avoided. Hypotension and vascular collapse should be treated with intravenous fluids and, if necessary, blood pressure titration with an intravenous infusion of a dilute pressor agent. It should be noted that adrenergic agents may produce a markedly increased pressor response.
Respiration should be supported by appropriate measures, including management of the airway, use of supplemental oxygen, and mechanical ventilatory assistance, as required.
Body temperature should be monitored closely. Intensive management of hyperpyrexia may be required. Maintenance of fluid and electrolyte balance is essential.
Zelapar (Selegiline) Dosage And Administration
Zelapar (Selegiline) is intended for administration to patients with Parkinson's disease receiving levodopa/carbidopa therapy who demonstrate a deteriorating response to this treatment.
Treatment should be initiated with 1.25 mg given once a day for at least 6 weeks. After 6 weeks, the dose may be escalated to 2.5 mg given once a day if a desired benefit has not been achieved and the patient is tolerating Zelapar (Selegiline) . There is no evidence that doses greater than 2.5 mg a day confer any additional benefit, and they should ordinarily be avoided because of the potential increased risk of adverse events.
Zelapar (Selegiline) should be taken in the morning before breakfast and without liquid.
In the controlled trial of Zelapar (Selegiline) in which Zelapar (Selegiline) was shown to be effective compared to placebo, 17% of patients in the Zelapar (Selegiline) group and 19% of patients in the placebo treatment group had a reduction in their doses of levodopa/carbidopa because of perceived dopaminergic side effects. For those patients with a dose reduction, the average reduction was 24% for Zelapar (Selegiline) and 21% for placebo.
Patients should not attempt to push Zelapar (Selegiline) through the foil backing. Patients should PEEL BACK the backing of one or two blisters (as prescribed) with dry hands, and GENTLY remove the tablet(s). Patients should IMMEDIATELY place the Zelapar (Selegiline) tablet(s) on top of the tongue where it will disintegrate in seconds. Patients should avoid ingesting food or liquids for 5 minutes before and after taking Zelapar (Selegiline) .
Zelapar (Selegiline) How Supplied
Zelapar (Selegiline) Orally Disintegrating Tablets are available containing 1.25 mg selegiline hydrochloride in a Zydis formulation. Each pale yellow tablet is imprinted with a stylized "V". Ten tablets are contained in a moisture-resistant pouch and packaged in a carton. Neither the blister card nor the pouch is child-resistant.
Zelapar (Selegiline) (selegiline hydrochloride) is available as: NDC 0187-0453-02, carton of 6 pouches (60 tablets).
Zelapar (Selegiline)
Zelapar (Selegiline) Principal Display Panel - Pouches, Tablet Carton
(selegiline HCl) Orally Disintegrating Tablets
VALEANT
