FDA

Zelapar

Approved 14 Jun 2006OralTablet, orally disintegrating

Indications

ZELAPAR 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 has any beneficial effect in the absence of concurrent levodopa therapy [see Clinical Studies (14 ) ]. ZELAPAR, a monoamine oxidase type B (MAO-B) inhibitor, 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 ( 1 )

Contraindications

ZELAPAR is contraindicated in patients with:

Concomitant use of opioid drugs (e.g., meperidine, tramadol, or methadone). 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) ] .
Concomitant use of other drugs in the monoamine oxidase inhibitor (MAOI) class or other drugs that are potent inhibitors of monoamine oxidase, including linezolid), because of an increased risk for hypertensive crisis [see Warnings and Precautions (5.1)]. At least 14 days should elapse between discontinuation of ZELAPAR and initiation of treatment with any MAO inhibitor.
Concomitant use of St. John’s wort or cyclobenzaprine (a tricyclic muscle relaxant).
Concomitant use of dextromethorphan, because of reported episodes of psychosis or bizarre behavior. ZELAPAR is contraindicated in patients using the following drugs: opioid drugs (e.g., meperidine, tramadol, methadone), MAO inhibitors including selective MAO-B inhibitors, dextromethorphan, St. John’s wort, and cyclobenzaprine ( 4 )

Warnings and precautions

May cause hypertension above 2.5 mg/day (5.1)
May cause serotonin syndrome when used with antidepressants (5.2)
May cause falling asleep during activities of daily living (5.3)
May cause hypotension/orthostatic hypotension (5.4)
May cause or exacerbate dyskinesia (5.5)
May cause hallucinations and psychotic-like behavior (5.6)
May cause problems with impulse control and compulsive behaviors (5.7)

At a glance

Brand name: Zelapar
Active substance: selegiline hydrochloride
Route: Oral
Dosage form: Tablet, orally disintegrating
Applicant: Bausch
Status: Prescription
FDA approval: 14 Jun 2006
Application: NDA021479-001

Indications

Contraindications

ZELAPAR is contraindicated in patients with:

Concomitant use of opioid drugs (e.g., meperidine, tramadol, or methadone). 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) ] .
Concomitant use of other drugs in the monoamine oxidase inhibitor (MAOI) class or other drugs that are potent inhibitors of monoamine oxidase, including linezolid), because of an increased risk for hypertensive crisis [see Warnings and Precautions (5.1)]. At least 14 days should elapse between discontinuation of ZELAPAR and initiation of treatment with any MAO inhibitor.
Concomitant use of St. John’s wort or cyclobenzaprine (a tricyclic muscle relaxant).
Concomitant use of dextromethorphan, because of reported episodes of psychosis or bizarre behavior. ZELAPAR is contraindicated in patients using the following drugs: opioid drugs (e.g., meperidine, tramadol, methadone), MAO inhibitors including selective MAO-B inhibitors, dextromethorphan, St. John’s wort, and cyclobenzaprine ( 4 )

Warnings and precautions

May cause hypertension above 2.5 mg/day (5.1)
May cause serotonin syndrome when used with antidepressants (5.2)
May cause falling asleep during activities of daily living (5.3)
May cause hypotension/orthostatic hypotension (5.4)
May cause or exacerbate dyskinesia (5.5)
May cause hallucinations and psychotic-like behavior (5.6)
May cause problems with impulse control and compulsive behaviors (5.7)

Interactions

7.1Opioid Drugs

Because serious, sometimes fatal reactions have been precipitated with concomitant use of opioid drugs (e.g., meperidine and its derivatives, methadone, or tramadol) and MAOIs, including selective MAO-B inhibitors, concomitant use of these drugs with ZELAPAR is contraindicated [see Contraindications (4) and Warnings and Precautions (5.2)] . At least 14 days should elapse between discontinuation of ZELAPAR and initiation of treatment with these drugs.

7.2Dextromethorphan

The combination of MAO inhibitors and dextromethorphan has been reported to cause brief episodes of psychosis or bizarre behavior. Therefore, in view of ZELAPAR’s MAO inhibitory activity, dextromethorphan should not be used concomitantly with ZELAPAR [see Contraindications (4) ].

7.3MAO Inhibitors

ZELAPAR is contraindicated for concomitant use with other drugs in the MAOI class or other drugs that are potent inhibitors of monoamine oxidase (including linezolid, an oxazolidinone antibacterial, which also has reversible nonselective MAO inhibition activity) because of the increased risk for hypertensive crisis [see Contraindications (4) and Warnings and Precautions (5.1 ) ] . At least 14 days should elapse between discontinuation of ZELAPAR and initiation of treatment with other MAOIs.

7.4Sympathomimetic Medications

Uncontrolled hypertension, including hypertensive crisis, has been reported when taking the recommended dose of swallowed selegiline and a sympathomimetic medication (ephedrine).

7.5Tyramine/Selegiline Interaction

The enzyme, monoamine oxidase (MAO) (primarily type A), in the gastrointestinal tract and liver provides protection from ingested amines (e.g., tyramine) that, if absorbed, have the capacity to cause uncontrolled hypertension (tyramine reaction). If MAO is inhibited in the gastrointestinal tract and liver, ingestion of exogenous amines contained in some foods such as fermented cheese, herring, or over-the-counter cough/cold medicines may be absorbed systemically causing release of norepinephrine and a rise in systemic blood pressure with the potential for uncontrolled hypertension.

Selective MAO-B inhibitors lose their selectivity for MAO-B when taken in doses higher than recommended . Non-selective MAO-A inhibitors or MAO-B inhibitors in higher than recommended doses may result in MAO-A inhibition in the gastrointestinal tract and liver. Results of a tyramine challenge study indicate that ZELAPAR is relatively selective for MAO-B at the recommended dose. In most cases, there is no need for dietary tyramine restriction in patients prescribed ZELAPAR [see Clinical Pharmacology (12.2) ] at the recommended dose.

Because the selectivity for inhibiting MAO-B diminishes as the dose of ZELAPAR is increased above the recommended daily dose, patients should not take more than 2.5 mg of ZELAPAR daily. Reports of hypertensive reactions have occurred in patients who ingested tyramine-containing consumables (i.e., food or drink) while receiving swallowed selegiline at the recommended dose (a dose believed to be relatively selective for MAO-B).

Hypertensive crisis has also been reported with ZELAPAR use that was not above the recommended dosing. Uncontrolled hypertension has been reported when taking the recommended dose of swallowed selegiline and a sympathomimetic medication (ephedrine).

7.6Tricyclic Antidepressants and Selective Serotonin Reuptake Inhibitors

Severe toxicity has also been reported in patients receiving the combination of tricyclic antidepressants and swallowed selegiline, or selective serotonin reuptake inhibitors and swallowed selegiline [see Warnings and Precautions (5.2) ].

7.7 Drugs that Induce CYP450 Adequate studies have not been done investigating the effect of CYP3A4 inducers on selegiline. Drugs that induce CYP3A4 (e.g., phenytoin, carbamazepine, nafcillin, phenobarbital, and rifampin) should be used with caution.

7.8Dopaminergic Antagonists

It is possible that dopamine antagonists, such as antipsychotics or metoclopramide, could diminish the effectiveness of ZELAPAR.

Adverse reactions

The following adverse reactions are discussed in more detail in the Warnings and Precautions section of labeling:

Risk for Hypertension [see Warnings and Precautions (5.1) ]
Risk of Serotonin Syndrome [see Warnings and Precautions (5.2) ]
Falling Asleep During Activities of Daily Living and Somnolence [see Warnings and Precautions (5.3) ]
Hypotension/Orthostatic Hypotension [see Warnings and Precautions (5.4) ]
Dyskinesia [see Warnings and Precautions (5.5) ]
Hallucinations/Psychotic-Like Behavior [see Warnings and Precautions (5.6) ]
Impulse Control/Compulsive Behaviors [see Warnings and Precautions (5.7) ]
Withdrawal Emergent Hyperpyrexia and Confusion [see Warnings and Precautions (5.8) ]
Irritation of the Buccal Mucosa [see Warnings and Precautions (5.9) ]
Risk for Patients with Phenylketonuria [see Warnings and Precautions (5.10) ] The most common adverse reactions (incidence at least 3% greater than on placebo) are constipation, skin disorders, vomiting, dizziness, dyskinesia, insomnia, dyspnea, myalgia, and rash (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Bausch Health US, LLC at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the incidence of adverse reactions (number of unique patients experiencing an adverse reaction per total number of patients treated) observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the incidence of adverse reactions observed in clinical practice. 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 reactions.

The most common adverse reactions (treatment difference incidence at least 3% greater than placebo incidence) reported in the double-blind, placebo-controlled trials during ZELAPAR treatment were constipation, skin disorders, vomiting, dizziness, dyskinesia, insomnia, dyspnea, myalgia, and rash (see Table 1 ). Of the 194 patients treated with ZELAPAR in the double-blind, placebo-controlled trials, 5% discontinued due to adverse reactions compared to 1% of the 98 patients who received placebo.

Most common adverse reactions causing discontinuation of treatment included dizziness, chest pain, accidental injury, and myasthenia. Incidence in Controlled Clinical Trials Table 1 lists the adverse reactions reported in the placebo-controlled trials after at least one dose of ZELAPAR (incidence 2% or greater). Table 1: Adverse Reactions Patients may have reported multiple adverse experiences during the study or at discontinuation; thus patients may be included in more than one category. in Double-Blind, Placebo-Controlled Trials with an Incidence ≥2% of Patients Treated with ZELAPAR and More Frequent than the Placebo Group Body System/ Adverse Event ZELAPAR 1.25/2.5 mg N=194 % Placebo N=98 % Body as a Whole Pain 8 7 Back Pain 5 3 Chest Pain 2 0 Cardiovascular System Hypertension 3 2 Digestive System Nausea 11 9 Stomatitis 5 4 Dyspepsia 5 3 Constipation 4 0 Vomiting 3 0 Diarrhea 2 1 Dysphagia 2 1 Flatulence 2 1 Tooth Disorder 2 1 Hemic and Lymphatic System Ecchymosis 2 0 Metabolic and Nutritional Disorders Hypokalemia 2 0 Musculoskeletal System Leg Cramps 3 1 Myalgia 3 0 Nervous System Dizziness 11 8 Headache 7 6 Insomnia 7 4 Dyskinesia 6 3 Dry Mouth 4 2 Hallucinations 4 2 Somnolence 3 2 Tremor 3 1 Ataxia 3 1 Depression 2 1 Respiratory System Pharyngitis 4 2 Rhinitis 7 6 Dyspnea 3 0 Skin and Appendages Rash 4 1 Skin Disorders Skin disorders represent any new skin abnormality that would not be characterized as rash or neoplastic lesion.

These include events such as skin ulcer, fungal dermatitis, skin hypertrophy, contact dermatitis, herpes simplex, dry skin, sweating, urticaria, and pruritus. 6 2 Certain adverse reactions were reported at a higher frequency by patients ≥65 years of age compared to patients <65 years [see Use in Specific Populations (8.5) ]. No consistent differences in the incidences of adverse reactions were observed between male and female patients.

There were insufficient data to assess the impact of race on the incidence of adverse reactions.

Zelapar

Indications

Contraindications

Warnings and precautions

At a glance

Two medicines in one question?

Zelapar

Indications

Contraindications

Warnings and precautions

At a glance

Two medicines in one question?

5.1Hypertension

5.2Serotonin Syndrome

5.4Hypotension/Orthostatic Hypotension Assessments

Interactions

7.1Opioid Drugs

7.2Dextromethorphan

7.3MAO Inhibitors

7.4Sympathomimetic Medications

7.5Tyramine/Selegiline Interaction

7.6Tricyclic Antidepressants and Selective Serotonin Reuptake Inhibitors

7.8Dopaminergic Antagonists

Adverse reactions

6.1Clinical Trials Experience

Composition

Official product information