Zelapar

If you take too much this medication, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

If this medication is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• a light-headed feeling, like you might pass out;

• trouble breathing;

• confusion, hallucinations, unusual thoughts or behavior;

• increased tremors or uncontrolled muscle movements;

• worsening side effects of your other medications;

• high levels of serotonin in the body (when taken with an antidepressant)--agitation, fever, fast heart rate, overactive reflexes, nausea, vomiting, diarrhea, loss of coordination, fainting; or

• dangerously high blood pressure--severe headache, blurred vision, pounding in your neck or ears, anxiety, nausea, vomiting, severe chest pain, shortness of breath, pounding heartbeats, or seizure (convulsions).

You may have increased sexual urges, unusual urges to gamble, or other intense urges while taking this medicine. Talk with your doctor if this occurs.

Common side effects may include:

• dizziness;

• nausea, stomach pain, constipation;

• skin rash or other irritation;

• sleep problems (insomnia); or

• mouth sores or ulcers, pain with swallowing (while using selegiline orally disintegrating tablets).

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Many drugs can interact with selegiline, and some drugs should not be used together. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide. Tell your doctor about all medicines you use, and those you start or stop using during your treatment with selegiline. Give a list of all your medicines to any healthcare provider who treats you.

• It is used to treat Parkinson's disease.

Zelapar is contraindicated in patients using meperidine, tramadol, methadone, or propoxyphene. Serotonin syndrome, a potentially serious condition, which can result in death, has been reported with concomitant use of meperidine (e.g., Demerol and other trade names). At least 14 days should elapse between discontinuation of Zelapar and initiation of treatment with these medications [see Warnings and Precautions (5.2)].

Zelapar is contraindicated in patients on any other MAO inhibitor (selective or non-selective), because of an increased risk for hypertensive crisis. At least 14 days should elapse between discontinuation of Zelapar and initiation of treatment with any MAO inhibitor.

Zelapar is contraindicated in patients using St. John’s wort, or cyclobenzaprine (a tricyclic muscle relaxant).

Zelapar is contraindicated in patients using dextromethorphan, because of reported episodes of psychosis or bizarre behavior.

Selegiline

No specific information is available about clinically significant overdoses with swallowed selegiline or Zelapar. 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 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®), isocarboxazid (MARPLAN®), and phenelzine (NARDIL®)]. For this reason, in cases of overdose with selegiline, dietary tyramine restriction should be observed for several weeks to avoid the risk of a hypertensive reaction.

Overdose with Non-Selective MAO Inhibitors

NOTE: The following description of presenting symptoms and clinical course is based upon overdose descriptions of nonselective MAO inhibitors and does not include information from patients who have overdosed on oral selegiline or Zelapar.

Characteristically, signs and symptoms of non-selective MAO inhibitor 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 MAO inhibitor 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.

Treatment or Management of Overdose

Treatment of overdose with non-selective MAO inhibitors 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.

Support respiration, 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 Orally Disintegrating Tablets contain selegiline hydrochloride, a levorotatory acetylenic derivative of phenethylamine. Selegiline hydrochloride is described chemically as: (-)-(R)-N, α-dimethyl-N-2-propynylphenethylamine hydrochloride and its structural formula is:

Its empirical formula is C13H17N∙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 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.

Mechanism of Action

Selegiline is an irreversible inhibitor of monoamine oxidase (MAO), which regulates the metabolic degradation of catecholamines and serotonin in the central nervous system and peripheral tissues. At recommended doses, selegiline is selective for MAO type B (MAO-B), the major form in the brain. Inhibition of MAO-B activity, by blocking the catabolism of dopamine, may result in increased dopamine levels; however, there is evidence that selegiline may act through other mechanisms to increase dopaminergic activity.

Pharmacodynamics

A pharmacodynamic study investigating daily Zelapar doses of 2.5 mg, 5 mg, and 10 mg for tyramine sensitivity showed that increased tyramine sensitivity resulting in increased blood pressure (because of MAO-A inhibition and decreased selectivity for MAO-B) occurred with dosing above the recommended level (2.5 mg daily). An increase in tyramine sensitivity for blood pressure responses appears to begin at a dose of 5 mg Zelapar daily [see Warnings and Precautions (5.1)].

Pharmacokinetics

Absorption

Zelapar disintegrates within seconds after placement on the tongue and is rapidly absorbed. Detectable levels of selegiline from Zelapar have been measured at 5 minutes after administration, the earliest time point examined.

Selegiline is more rapidly absorbed from the 1.25 or 2.5 mg dose of Zelapar (Tmax range: 10-15 minutes) than from the swallowed 5 mg selegiline tablet (Tmax range: 40-90 minutes). Mean (SD) maximum plasma concentrations of 3.34 (1.68) and 4.47 (2.56) ng/mL are reached after single dose of 1.25 and 2.5 mg Zelapar compared to 1.12 ng/mL (1.48) for the swallowed 5 mg selegiline tablets (given as 5 mg bid). On a dose-normalized basis, the relative bioavailability of selegiline from Zelapar is greater than from the swallowed formulation.

The pre-gastric absorption from Zelapar and the avoidance of first-pass metabolism results in higher concentrations of selegiline and lower concentrations of the metabolites compared to the 5 mg swallowed selegiline tablet.

Plasma Cmax and AUC of Zelapar were dose proportional at doses between 2.5 and 10 mg daily.

When Zelapar is taken with food, the Cmax and AUC of selegiline are about 60% of those seen when Zelapar is taken in the fasted state. Since Zelapar is placed on the tongue and absorbed through the oral mucosa, the intake of food and liquid should be avoided 5 minutes before and after Zelapar administration [see Dosage and Administration (2.1)].

Up to 85% of plasma selegiline is reversibly bound to proteins.

Following a single dose, the median elimination half-life of selegiline was 1.3 hours at the 1.25 mg dose. Under steady-state conditions, the median elimination half-life increases to 10 hours. Upon repeat dosing, accumulation in the plasma concentration of selegiline is observed both with Zelapar and the swallowed 5 mg tablet. Steady state is achieved after 8 days.

Selegiline is metabolized in vivo to l-methamphetamine and N-desmethylselegiline and subsequently to l-amphetamine; which in turn are further metabolized to their hydroxymetabolites.

Zelapar also produces a smaller fraction of the administered dose recoverable as the metabolites than the conventional, swallowed formulation of selegiline.

In vitro metabolism studies indicate that CYP2B6 and CYP3A4 are involved in the metabolism of selegiline. CYP2A6 may play a minor role in the metabolism.

Following metabolism in the liver, selegiline is excreted primarily in the urine as metabolites (mainly as l-methamphetamine) and as a small amount in the feces.

Age:

The effect of age on the pharmacokinetics of selegiline following Zelapar administration has not been adequately characterized.

Gender:

There are no differences between male and female subjects in overall (AUC∞), time to maximum exposure (Tmax), and elimination half-life (t½) after administration of Zelapar. Female subjects have an approximate 25% decrease in Cmax compared to male subjects. However, since the overall exposure (AUC∞) is not different between the genders, this pharmacokinetic difference is not likely to be clinically relevant.

Race:

No studies have been conducted to evaluate the effects of race on the pharmacokinetics of Zelapar.

Renal Impairment:

Following once-daily dosing of Zelapar 2.5 mg to selegiline steady-state (10 days) in 6 subjects with mild renal impairment (CLcr >50 to 89 mL/min) and in 6 subjects with moderate renal impairment (CLcr >30 to 50 mL/min), AUC and Cmax of selegiline and desmethylselegiline were not substantially different from healthy subjects; however, methamphetamine and amphetamine exposures were increased by 34-67% in subjects with moderate renal impairment. Following once-daily dosing of Zelapar 1.25 mg to steady-state (10 days) in 6 end-stage renal disease patients, off dialysis, selegiline exposure was not substantially different from that in healthy subjects, however methamphetamine and amphetamine exposures were increased approximately 4-fold compared to healthy subjects [see Dosage and Administration (2.3) and Use in Specific Populations (8.7)].

Hepatic Impairment:

Subjects with mild hepatic impairment (Child-Pugh score 5 to 6), received once-daily dosing of Zelapar 2.5 mg to selegiline until they attained steady-state (10 days). The AUC and Cmax of selegiline were 1.5-fold higher and the AUC and Cmax of the metabolite desmethylselegiline were 1.4-fold and 1.2-fold higher. In subjects with moderate hepatic impairment (Child-Pugh score 7 to 9), the AUC of selegiline and desmethylselegiline increased 1.5-fold and 1.8-fold, respectively, whereas the Cmax of selegiline and demethylselegiline were comparable to healthy subjects. Patients with severe hepatic impairment (Child-Pugh score >9) had a 4-fold increased AUC of selegiline, 3-fold increased Cmax of selegiline, a 1.25-fold increased AUC of desmethylselegeline and 50% reduced Cmax of desmethylselegiline. Methamphetamine and amphetamine metabolite AUC values were not affected by liver dysfunction [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)].

Drug Interactions:

No studies have been conducted to evaluate drug interactions on the pharmacokinetics of Zelapar.

Effect of CYP3A inhibitor itraconazole: Itraconazole (200 mg QD) did not affect the pharmacokinetics of selegiline (single 10 mg oral, swallowed dose).

Although adequate studies to investigate the effect of CYP3A4-inducers on selegiline have not been performed, drugs that induce CYP3A4 (e.g., phenytoin, carbamazepine, nafcillin, phenobarbital, and rifampin) should be used with caution.

No drug interaction studies have been conducted to evaluate the effects of other drugs on the pharmacokinetics of Zelapar or the effect of selegiline on other drugs. In vitro studies have demonstrated that selegiline is not an inhibitor of CYP450 enzymes. Selegiline and two of its metabolites, methamphetamine and desmethylselegiline, have little or no potential to induce CYP1A2 and CYP3A4/5 under clinical conditions.

Serious drug interactions can occur when certain medicines are used together with Zelapar. Tell each of your healthcare providers about all medicines you use now, and any medicine you start or stop using.

You should not use Zelapar if you are allergic to selegiline, or if you have taken fluoxetine (Prozac, Sarafem and others) within the past 5 weeks.

Some medicines can cause unwanted or dangerous effects when used with Zelapar. Your doctor may need to change your treatment plan if you use any of the following drugs:

• cough medicine that contains dextromethorphan;

• cyclobenzaprine (Flexeril);

• meperidine (Demerol) or other narcotic (opioid) pain medicine;

• methadone;

• St. John's wort;

• tramadol (Ultram, Ultracet);

• an antidepressant - citalopram, desvenlafaxine, duloxetine, escitalopram, fluvoxamine, levomilnacipran, milnacipran, mirtazapine, nefazodone, paroxetine, venlafaxine, vilazodone, vortioxetine, and others; or

• an MAO inhibitor - isocarboxazid, linezolid, methylene blue injection, phenelzine, rasagiline, selegiline, tranylcypromine, and others.

After you stop taking Zelapar, you must wait at least 14 days before taking any of the medications listed above.

To make sure Zelapar is safe for you, tell your doctor if you have:

• liver or kidney disease;

• high blood pressure; or

• phenylketonuria (Zelapar orally disintegrating tablets may contain phenylalanine).

People with Parkinson's disease may have a higher risk of skin cancer (melanoma). Talk to your doctor about this risk and what skin symptoms to watch for.

It is not known whether Zelapar will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

It is not known whether selegiline passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

Take Zelapar exactly as it was prescribed for you. Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not use this medicine in larger or smaller amounts or for longer than recommended. Do not change your doses or medication schedule without your doctor's advice.

Zelapar disintegrating tablet should be taken once a day before breakfast and without any liquid.

While you are using Zelapar and for 14 days after you stop, you must not eat foods listed in the "What should I avoid while using Zelapar?" section of this leaflet. Eating these foods while you are using Zelapar can raise your blood pressure to dangerous levels.

Foods that you MAY eat include:

• fresh meat, poultry, or fish (including lunch meat, hot dogs, breakfast sausage, and cooked sliced ham);

• any vegetables except broad bean pods (fava beans);

• processed cheese, mozzarella, ricotta, cottage cheese;

• pizza made with cheeses low in tyramine;

• soy milk, yogurt; or

• Brewer's or baker's yeast.

To take Zelaparorally disintegrating tablets:p>

• Keep the tablet in its blister pack until you are ready to take the medicine. Open the package and peel back the foil from the tablet blister. Do not push a tablet through the foil or you may damage the tablet.

• Using dry hands, remove the tablet and place it on your tongue. It will begin to dissolve right away. Do not swallow the tablet whole. Allow it to dissolve in your mouth without chewing. Swallow several times as the tablet dissolves.

• Do not drink or eat anything for at least 5 minutes after taking a Zelapar orally disintegrating tablet.

Do not stop taking Zelapar suddenly or you may have harmful side effects. For best results, keep taking the medicine as prescribed.

Store this medicine at room temperature away from moisture and heat.

Keep each Zelapar tablet in the foil blister pack until you are ready to take it. Throw away any tablets not used within 3 months after you have opened the pouch containing the blister pack.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include severe headache, hallucinations, vision problems, sweating, cool or clammy skin, fast or uneven heart rate, feeling light-headed, fainting, or seizure (convulsions).