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Azilect

Azilect

SIDE EFFECTS

Clinical Studies Experience

During the clinical development of AZILECT, 1361 Parkinson's disease patients received rasagiline as initial monotherapy or as adjunct therapy to levodopa. As these two populations differ, not only in the adjunct use of levodopa during rasagiline treatment, but also in the severity and duration of their disease, they may have differential risks for various adverse reactions. Therefore, most of the adverse reactions data in this section are presented separately for each population.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates 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 rates of adverse reactions observed in practice.

Patients Receiving AZILECT (rasagiline) as Initial Monotherapy Treatment

Adverse Reactions Leading to Discontinuation in Controlled Clinical Studies

In the double-blind, placebo-controlled trials con ducted in patients receiving AZILECT (rasagiline) as monotherapy, approximately 5% of the 149 patients treated with rasagiline discontinued treatment due to adverse reactions compared to 2% of the 151 patients who received placebo.

The only adverse reaction that led to the discontinuation of more than one patient was hallucinations.

Adverse Reaction Incidence in Controlled Clinical Studies

The most commonly observed adverse reactions were those in which the treatment difference for the incidence in AZILECT (rasagiline) -treated patients was ≥ 3 % greater than the incidence in the placebo-treated patients and included flu syndrome, arthralgia, depression, and dyspepsia. Table 1 lists treatment-emergent adverse reactions that occurred in ≥ 2% of patients receiving AZILECT (rasagiline) as monotherapy participating in the double -blind, placebo-controlled trial and were numerically more frequent than in the placebo group.

Table 1 :Treatment-Emergent* Adverse Reactions in AZILECT (rasagiline) 1 mg-Treated Monotherapy Patients

Placebo-Controlled Studies Without Levodopa Treatment AZILECT (rasagiline) 1 mg
(N=149)
% of Patients
Placebo
(N=151)
% of Patients
Headache 14 12
Arthralgia 7 4
Dyspepsia 7 4
Depression 5 2
Fall 5 3
Flu syndrome 5 1
Conjunctivitis 3 1
Fever 3 1
Gastroenteritis 3 1
Rhinitis 3 1
Arthritis 2 1
Ecchymosis 2 0
Malaise 2 0
Neck Pain 2 0
Paresthesia 2 1
Vertigo 2 1
*Incidence ≥ 2% in AZILECT 1 mg group and numerically more frequent than in placebo group

Other events of potential clinical importance reported by 1% or more of patients receiving AZILECT (rasagiline) as monotherapy, and at least as frequent as in the placebo group, in descending order of frequency include: dizziness, diarrhea, chest pain, albuminuria, allergic reaction, alopecia, angina pectoris, anorexia, asthma, hallucinations, impotence, leukopenia, libido decreased, liver function tests abnormal, skin carcinoma, syncope, vesiculobullous rash, vomiting.

There were no significant differences in the safety profile based on age or gender.

Patients Receiving AZILECT (rasagiline) as Adjunct to Levodopa Therapy

Adverse Reactions Leading to Discontinuation in Controlled Clinical Studies

In a double-blind, placebo-controlled trial (Study 1) conducted in patients treated with AZ ILECT as adjunct to levodopa therapy, approximately 9% of the 164 patients treated with AZILECT (rasagiline) 0.5 mg /day and 7% of the 149 patients treated with AZILECT (rasagiline) 1 mg/day discontinued treatment due to adverse react ions compared to 6% of the 159 patients who received placebo. The adverse reactions that led to discontinuation of more than one rasagiline-treated patient were: diarrhea, weight loss, hallucination, and rash. Adverse event reporting was considered more reliable for Study 1 than for the second controlled trial (Study 2); therefore only the adverse event data from Study 1 are presented in this section of labeling.

Adverse Reactions: Incidence in Controlled Clinical Studies

The most commonly observed adverse reactions were those in which the treatment difference for the incidence in AZILECT (rasagiline) -treated patients (n=149) was ≥ 3 % greater than the incidence in the placebo-treated patients (n=159) and included dyskinesia, accidental injury, weight loss, postural hypotension, vomiting, anorexia, arthralgia, abdominal pain, nausea, constipation, dry mouth, rash, abnormal dreams, and fall.

Table 2 lists treatment-emergent adverse reactions that occurred in ≥ 2% of patients treated with AZILECT (rasagiline) 1 mg/day as adjunct to levodopa therapy participating in the double-blind, placebo-controlled trial (Study 1) and that were numerically more frequent than t he placebo group. The table also shows the rates for the 0.5 mg group in Study 1 .

Table 2: Incidence of Treatment-Emergent* Adverse Reactions in Patients Receiving AZILECT (rasagiline) as Adjunct to Levodopa Therapy in Study 1

  AZILECT (rasagiline)
1 mg + Levodopa
(N=149)
% of patients
AZILECT (rasagiline)
0.5 mg + Levodopa
(N=164)
% of patient
Placebo
+ Levodopa
(N=159)
% of patients
Dyskinesia 18 18 10
Accidental injury 12 8 5
Nausea 12 10 8
Headache 11 8 10
Fall 11 12 8
Weight loss 9 2 3
Constipation 9 4 5
Postural hypotension 9 6 3
Arthralgia 8 6 4
Vomiting 7 4 1
Dry mouth 6 2 3
Rash 6 3 3
Somnolence 6 4 4
Abdominal pain 5 2 1
Anorexia 5 2 1
Diarrhea 5 7 4
Ecchymosis 5 2 3
Dyspepsia 5 4 4
Paresthesia 5 2 3
Abnormal dreams 4 1 1
Hallucinations 4 5 3
Ataxia 3 6 1
Dyspnea 3 5 2
Infection 3 2 2
Neck pain 3 1 1
Sweating 3 2 1
Tenosynovitis 3 1 0
Dystonia 3 2 1
Gingivitis 2 1 1
Hemorrhage 2 1 1
Hernia 2 1 1
Myasthenia 2 2 1
*Incidence ≥ 2% in AZILECT 1 mg group and numerically more frequent than in placebo group

Several of the more common adverse reactions seemed dose-related, including weight loss, postural hypotension, and dry mouth.

Other adverse reactions s of potential clinical importance reported in Study 1 by 1% or more of patients treated with rasagiline 1 mg/day as adjunct to levodopa therapy, and at least as frequent as in the placebo group, in descending order of frequency include : skin carcinoma, anemia, albuminuria, amnesia, arthritis, bursitis, cerebrovascular accident, confusion, dysphagia, epistaxis, leg cramps, pruritus, skin ulcer.

There were no significant differences in the safety profile based on age or gender.

Other Adverse Reactions Observed During All Phase 2/3 Clinical Trials

Rasagiline was administered to approximately 1361 patients during all PD phase 2/3 clinical trials. About 283 patients received rasagiline for at least one year, approximately 410 patients received rasagiline for at least two years, 116 patients received rasagiline for at least 3 years, and 245 patients received rasagiline for more than 3 years, with some patients treated for more than 5 years. The long-term safety profile was similar to that observed with shorter duration exposure.

The frequencies listed below represent the proportion of the 1361 individuals exposed to rasagiline who experienced events of the type cited.

All events that occurred at least twice (or once for serious or potentially serious events), except those already listed above, trivial events, terms too vague to be meaningful, adverse events with no plausible relation to treatment, and events that would be expected in patients of the age studied, w ere reported without regard to determination of a causal relationship to rasagiline.

Events are further classified within body system categories and enumerated in order of decreasing frequency using t he following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients, infrequent adverse events are defined as those occurring in at least 1/100 to 1/1000 patients and rare adverse events are defined as those occurring in fewer than 1/1000 patients.

Body as a whole: Frequent: asthenia Infrequent: chills, face edema, flank pain, photosensitivity reaction

Cardiovascular system: Frequent: bundle branch block Infrequent: deep thrombophlebitis, heart failure, migraine, myocardial infarct, phlebitis, ventricular tachycardia Rare: arterial thrombosis, atrial arrhythmia, AV block complete, AV block second degree, bigeminy, cerebral hemorrhage, cerebral ischemia, ventricular fibrillation

Digestive system: Frequent: gastrointestinal hemorrhage Infrequent: colitis, esophageal ulcer, esophagitis, fecal incontinence, intestinal obstruction, mouth ulceration, stomach ulcer, stomatitis, tongue edema Rare: hematemesis, hemorrhagic gastritis, intestinal perforation, intestinal stenosis, jaundice, large intestine perforation, megacolon, melena

Hemic and Lymphatic system: Infrequent: macrocytic anemia Rare: purpura, thrombocythemia

Metabolic and Nutritional disorders: Infrequent: hypocalcemia

Musculoskeletal system: Infrequent: bone necrosis, muscle atrophy Rare: arthrosis

Nervous system: Frequent: abnormal gait, anxiety, hyperkinesia, hypertonia, neuropathy, tremor Infrequent: agitation, aphasia, circumoral paresthesia, convulsion, delusions, dementia , dysarthria, dysautonomia, dysesthesia, emotional lability, facial paralysis, foot drop, hemiplegia, hypesthesia, incoordination, manic reaction, myoclonus, neuritis, neurosis, paranoid reaction, personality disorder, psychosis, wrist drop Rare: apathy, delirium, hostility, manic depressive reaction, myelitis, neuralgia, psychotic depression, stupor

Respiratory system: Frequent: cough increased Infrequent: apnea, emphysema, laryngismus, pleural effusion, pneumothorax Rare: interstitial pneumonia, larynx edema, lung fibrosis

Skin and Appendages: Infrequent: eczema, urticaria Rare: exfoliative dermatitis, leukoderma

Special senses: Infrequent: blepharitis, deafness, diplopia, eye hemorrhage, eye pain, glaucoma, keratitis, ptosis, retinal degeneration, taste perversion, visual field defect Rare: blindness, parosmia, photophobia, retinal detachment, retinal hemorrhage, strabismus, taste loss, vestibular disorder

Urogenital system: Frequent: hematuria, urinary incontinence Infrequent: acute kidney failure, dysmenorrhea, dysuria, kidney calculus, nocturia, polyuria, scrotal edema, sexual function abnormal, urinary retention, urination impaired, vaginal hemorrhage, vaginal moniliasis, vaginitis Rare: abnormal ejaculation, amenorrhea, anuria, epididymitis, gynecomastia, hydroureter, leukorrhea, priapism

Post-marketing Experience

The following adverse events not described in sections 4 and 5 have been identified during the postmarketing/post-approval use of AZILECT (rasagiline) . Because these adverse events are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency nor to establish unequivocally a causal relationship to drug exposure: Increased libido including hypersexuality, impulse control symptoms, pathological gambling [see PATIENT INFORMATION]

Read the Azilect (rasagiline) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

Meperidine

Serious, sometimes fatal reactions have been precipitated with concomitant use of meperidine (e.g., Demerol and other trade names) and MAO inhibitors including selective MAO-B inhibitors [see CONTRAINDICATIONS].

Dextromethorphan

The concomitant use of AZILECT (rasagiline) and dextromethorphan was not allowed in clinical studies. The combination of MAO inhibitors and dextromethorphan has been reported to cause brief episodes of psychosis or bizarre behavior. Therefore, in view of AZILECT (rasagiline) 's MAO inhibitory activity, dextromethorphan should not be used concomitantly with AZILECT [see CONTRAINDICATIONS].

Sympathomimetic Medications

The concomitant use of AZILECT (rasagiline) and sympathomimetic medications was not allowed in clinical studies. Severe hypertensive reactions have followed the administration of sympathomimetics and non-selective MAO inhibitors. One case of hypertensive crisis has been reported in a patient taking the recommended dose of a selective MAO-B inhibitor and a sympathomimetic medication (ephedrine). Elevated blood pressure was reported in another patient taking the recommended dose of AZILECT (rasagiline) and ophthalmic drops with a sympathomimetic medication (tetrahydrozoline).

Because AZILECT (rasagiline) is a selective MAOI, hypertensive reactions are not ordinarily expected with the concomitant use of sympathomimetic medications. Nevertheless, caution should be exercised when concomitantly using recommended doses of AZILECT (rasagiline) with any sympathomimetic medications including nasal, oral, and ophthalmic decongestants and cold remedies.

MAO Inhibitors

AZILECT (rasagiline) should not be administered along with other MAO inhibitors because of the increased risk of non-selective MAO inhibition that may lead to a hypertensive crisis [see CONTRAINDICATIONS].

Antidepressants

Concomitant use of AZILECT (rasagiline) with one of many classes of antidepressants (e.g., SSRIs, SNRIs, triazolopyridine, tricyclic or tetracyclic antidepressants) is not recommended [see WARNINGS AND PRECAUTIONS].

Levodopa/Carbidopa

[see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].

Ciprofloxacin and Other CYP1A2 Inhibitors

Rasagiline plasma concentrations may increase up to 2 fold in patients using concomitant ciprofloxacin and other CYP1A2 inhibitors. This could result in increased adverse events [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].

Theophylline

[see CLINICAL PHARMACOLOGY].

Tyramine/Rasagiline Interaction

MAO in the gastrointestinal tract and liver (primarily type A) 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 a mines (e.g., from fermented cheese, herring, over-the-counter cough/cold medications) gain access to the systemic circulation because MAO-A has been inhibited, they cause release of norepinephrine which may result in a rise in systemic blood pressure. MAOIs that selectively inhibit MAO-B are largely devoid of the potential to cause tyramine-induced hypertensive crisis.

Results of a special tyramine challenge study indicate that rasagiline is selective for M AO-B at recommended doses and can ordinarily be used without dietary tyramine restriction. However, certain foods (e.g., aged cheeses, such as Stilton cheese) may contain very high amounts (i.e., > 15 0 mg) of tyramine and could potentially cause a hypertensive cheese reaction in patients taking AZILECT (rasagiline) due to mild increased sensitivity to tyramine. Patients should be advised to avoid foods (e.g. ., aged cheese) containing a very large amount of tyramine while taking recommended doses of AZILECT (rasagiline) because of the potential for large increases in blood pressure. Selectivity for inhibiting MAO-B diminishes in a dose-related manner as the dose is progressively increased above the recommended daily doses.

There were no cases of hypertensive crisis in the clinical development program associated with 1 mg daily rasagiline treatment, in which most patients did not follow dietary tyramine restriction.

Despite the selective inhibition of MAO-B at recommended doses of AZILECT (rasagiline) , there have been postmarketing reports of patients who experienced significantly elevated blood pressure (including rare cases of hypertensive crisis) after ingestion of unknown amounts of tyramine-rich foods while taking recommended doses of AZILECT [see DOSING AND ADMINISTRATION, and WARNINGS AND PRECAUTIONS].

Drug Abuse And Dependence

Controlled Substance

AZILECT (rasagiline) is not a controlled substance.

Abuse

Studies conducted in mice and rats did not reveal any potential for drug abuse and dependence. Clinical trials have not revealed any evidence of the potential for abuse, tolerance or physical dependence; however, systematic studies in humans designed to evaluate these effects have not been performed.

Dependence

Studies conducted in mice and rats did not reveal any potential for drug abuse and dependence. Clinical trials have not revealed any evidence of the potential for abuse, tolerance or physical dependence; however, systematic studies in humans designed to evaluate these effects have not been performed.

Read the Azilect Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 12/29/2009
This monograph has been modified to include the generic and brand name in many instances.

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