WARNINGS
Need for Restriction of Dietary Tyramine and Amines Contained in Medications
AZILECT treatment at any dose may be associated with a hypertensive crisis/"cheese reaction" if the patient ingests tyramine-rich foods, beverages, or dietary supplements or amines (from over-the-counter medications). Hypertensive crisis, which in some cases may be fatal, consists of marked systemic blood pressure elevation and requires immediate treatment/hospitalization.
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 significant amounts of certain exogenous amines gain access to the systemic circulation — e.g., tyramine from fermented cheese, red wine, herring, or amines contained in over-the-counter cough/cold medications — they can cause release of norepinephrine, which may significantly increase systemic blood pressure. MAO inhibitors that selectively inhibit MAO-B are generally devoid of the potential to cause a hypertensive crisis/"cheese reaction" at defined relatively low doses at which tyramine sensitivity has been characterized. The selectivity of rasagiline for inhibiting MAO-B (and not MAO-A) in humans has not been sufficiently characterized to permit rasagiline treatment without restriction of dietary tyramine or amines contained in medications. 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.
Patients receiving rasagiline should be instructed about the tyramine content of foods and beverages (see table below ) and amine containing medications that should be avoided. Sympathomimetic amines found in over-the-counter medicines to be avoided include pseudoephedrine, phenylephrine, phenylpropanolamine, and ephedrine.
It is also necessary to maintain this dietary tyramine restriction and avoidance of exogenous amines contained in medications for 2 weeks following discontinuation of rasagiline because of the irreversible inhibition of the MAO enzyme and the need for new MAO enzyme synthesis.
Patients should also be instructed about the signs and symptoms of marked blood pressure elevation that could represent a hypertensive emergency requiring immediate treatment/hospitalization. These include severe headache, blurred vision/visual disturbances, difficulty thinking, stupor/coma, seizures, chest pain, unexplained nausea or vomiting, or signs or symptoms of a stroke.
Patients should be told to immediately contact a medical provider to report any severe headache or other atypical or unusual symptoms not previously experienced that could be due to a hypertensive crisis. (See PRECAUTIONS-Information for Patients , OVERDOSE , DOSAGE AND ADMINISTRATION).
| Class of Food or | Tyramine-rich Foods and Beverages to | Acceptable Foods, Containing No or |
| Beverage | Avoid | Little Tyramine |
| Adapted from K. I. Shulman, S.E. Walker, Psychiatric Annals 2001; 31:378-384 |
| Meat, Poultry and Fish | Air dried, aged and fermented meats, sausages and salamis (including cacciatore, hard salami and mortadella); pickled herring; and any spoiled or improperly stored meat, poultry and fish (e.g., foods that have undergone changes in coloration, odor, or become moldy); spoiled or improperly stored animal livers | Fresh meat, poultry and fish, including fresh processed meats (e.g. lunch meats, hot dogs, breakfast sausage, and cooked sliced ham) |
| Vegetables | Broad bean pods (fava bean pods) | All other vegetables |
| Dairy | Aged cheeses | Processed cheeses, mozzarella, ricotta cheese, cottage cheese and yogurt |
| Beverages | All varieties of tap beer and beers that have not been pasteurized so as to allow for ongoing fermentation, red wines | Bottled and canned beers and white wines contain little or no tyramine |
| Miscellaneous | Concentrated yeast extract (e.g., Marmite), sauerkraut, most soybean products (including soy sauce and tofu), OTC supplements containing tyramine | Brewer's yeast, baker's yeast, soy milk, commercial chain restaurant pizzas prepared with cheeses low in tyramine |
Coadministration with Antidepressants
Severe CNS toxicity associated with hyperpyrexia and death has been reported with the combination of tricyclic antidepressants and non-selective MAOIs (e.g., Nardil, Parnate) or a selective MAO-B inhibitor, selegiline (Eldepryl). These adverse events have included behavioral and mental status changes, diaphoresis, muscular rigidity, hypertension, syncope and death.
Serious, sometimes fatal, reactions with signs and symptoms including hyperthermia, rigidity, myoclonus, autonomic instability with rapid vital sign fluctuations, and mental status changes progressing to extreme agitation, delirium, and coma have been reported in patients receiving a combination of selective serotonin reuptake inhibitors (SSRIs), including fluoxetine (Prozac), fluvoxamine (Luvox), sertraline (Zoloft), and paroxetine (Paxil) and non-selective MAOIs or the selective MAO-B inhibitor selegiline. Similar reactions have been reported with serotonin-norepinephrine reuptake inhibitors (SNRIs) and non-selective MAOIs or the selective MAO-B inhibitor selegiline.
AZILECT clinical trials did not allow concomitant use of fluoxetine or fluvoxamine with AZILECT, but the following antidepressants and doses were allowed in the AZILECT trials: amitriptyline ≤ 50 mg/daily, trazodone ≤ 100 mg/daily, citalopram ≤ 20 mg/daily, sertraline ≤ 100 mg/daily and paroxetine ≤ 30 mg/daily.
Although a small number of rasagiline-treated patients were concomitantly exposed to antidepressants (tricyclics n= 115; SSRIs n= 141), the exposure, both in dose and number of subjects, was not adequate to rule out the possibility of an untoward reaction from combining these agents. Furthermore, because the mechanisms of these reactions are not fully understood, it seems prudent, in general, to avoid the combination of AZILECT with tricyclic, SSRI, or SNRI (serotonin-norepinephrine reuptake inhibitor) antidepressants. At least 14 days should elapse between discontinuation of AZILECT and initiation of treatment with a tricyclic, SSRI, or SNRI antidepressant. Because of the long half lives of fluoxetine and its active metabolite, at least five weeks (perhaps longer, especially if fluoxetine has been prescribed chronically and/or at higher doses) should elapse between discontinuation of fluoxetine and initiation of AZILECT. (See PRECAUTIONS, Drug Interactions, Selective Serotonin Reuptake Inhibitors (SSRIs), Tricyclic and Tetracyclic Antidepressants ).
Ciprofloxacin and Other CYP1A2 Inhibitors
Rasagiline plasma concentrations may increase up to 2 fold in patients using concomitant ciprofloxacin and other CYP1A2 inhibitors. (See CLINICAL PHARMACOLOGY, Drug-Drug Interactions and DOSAGE AND ADMINISTRATION, Patients Taking Ciprofloxacin and Other CYP1A2 Inhibitors).
Hepatic Insufficiency
Rasagiline plasma concentration may increase in patients with mild (up to 2 fold, Child-Pugh score 5-6), moderate (up to 7 fold, Child-Pugh score 7-9), and severe (Child-Pugh score 10-15) hepatic impairment. Patients with mild hepatic impairment should be given the dose of 0.5 mg/day. AZILECT should not be used in patients with moderate or severe hepatic impairment. (See CLINICAL PHARMACOLOGY, Special Populations).
PRECAUTIONS
General
Melanoma
Comparison of the rates of melanoma in the AZILECT development program with rates in age- and sex-matched populations from two epidemiologic data bases (Surveillance, Epidemiology, and End Results Registry of the National Cancer Institute and the American Academy of Dermatology Skin Cancer Screening Program) showed a risk of melanoma that was greater in patients treated with rasagiline than in the general population. Some epidemiological studies, however, have shown that patients with Parkinson's disease have a higher risk (perhaps 2- to 4-fold higher) of developing melanoma than the general population, although it was unclear whether the observed increased risk was due to Parkinson's disease itself or to drugs used to treat Parkinson's disease. The increased incidence of melanoma in the AZILECT development program was comparable to the increased risk observed in the Parkinson's disease populations examined in these epidemiological studies.
For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).
Dyskinesia Due to Levodopa Treatment
When used as an adjunct to levodopa, AZILECT may potentiate dopaminergic side effects and exacerbate pre-existing dyskinesia (treatment-emergent dyskinesia occurred in about 18% of patients treated with 0.5 mg or 1 mg rasagiline as an adjunct to levodopa, and 10% of patients who received placebo as an adjunct to levodopa). Decreasing the dose of levodopa may ameliorate this side effect.
Postural Hypotension
When used as monotherapy, postural hypotension was reported in approximately 3% of patients treated with 1 mg rasagiline and 5% of patients treated with placebo. In the monotherapy trial, postural hypotension did not lead to drug discontinuation and premature withdrawal in the rasagiline or placebo-treated patients.
When used as an adjunct to levodopa, postural hypotension was reported in approximately 6% of patients treated with 0.5 mg rasagiline, 9% of patients treated with 1 mg rasagiline and 3% of patients treated with placebo. Postural hypotension led to drug discontinuation and premature withdrawal from clinical trials in one (0.7%) patient treated with rasagiline 1 mg/day, no patients treated with rasagiline 0.5 mg/day and no placebo-treated patients.
Clinical trial data suggest that postural hypotension occurs most frequently in the first two months of rasagiline treatment and tends to decrease over time.
Hallucinations
In the monotherapy study, hallucinations were reported as an adverse event in 1.3% of patients treated with 1 mg rasagiline and in 0.7% of patients treated with placebo. In the monotherapy trial, hallucinations led to drug discontinuation and premature withdrawal from clinical trials in 1.3% of the 1 mg rasagiline-treated patients and in none of the placebo-treated patients.
When used as an adjunct to levodopa, hallucinations were reported as an adverse event in approximately 5% of patients treated with 0.5 mg/day, 4% of patients treated with 1 mg/day rasagiline and 3% of patients treated with placebo. Hallucinations led to drug discontinuation and premature withdrawal from clinical trials in about 1% of patients treated with 0.5 mg/day or 1 mg/day 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.
Information for Patients
Patients and caregivers should be informed about which foods and beverages to avoid because of high tyramine content. They should be informed that a hypertensive crisis could occur after ingestion of certain foods (e.g., aged cheeses, pickled herring, yeast extract) or beverages (e.g., some red wines and certain beers) containing significant amounts of tyramine, or amines contained in some medications including some over-the-counter cough/cold medications. Foods high in tyramine content include those that have undergone protein change by aging, fermentation, pickling, or smoking to improve flavor such as aged cheeses, air-dried meats, sauerkraut, soy sauce, tap/draft beers and red wines. The tyramine content of any protein-rich food may be increased if stored for long periods or improperly refrigerated.
Patients and caregivers should be informed of the signs and symptoms associated with hypertensive crisis, including severe headache, blurred vision, difficulty thinking, seizures, chest pain, unexplained nausea or vomiting, or signs or symptoms of a stroke. Patients and caregivers should seek immediate medical attention for patients who develop any severe headache or other atypical or unusual symptoms not previously experienced. (See WARNINGS).
Patients should inform their physician if they are taking, or planning to take, any prescription or over-the-counter drugs, especially antidepressants and over-the-counter cold medications, since there is a potential for interaction with AZILECT. Patients should not use meperidine with AZILECT.
Patients taking AZILECT as adjunct to levodopa should be advised there is the possibility of increased dyskinesia and postural hypotension.
Patients are advised to monitor for melanomas frequently and on a regular basis. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).
Patients should be instructed to take AZILECT as prescribed. If a dose is missed, the patient should not double-up the dose of AZILECT. The next dose should be taken at the usual time on the following day.
Drug Interactions
Meperidine
Serious, sometimes fatal reactions have been precipitated with concomitant use of meperidine (e.g., Demerol and other tradenames) and MAO inhibitors including selective MAO-B inhibitors. (See CONTRAINDICATIONS).
Dextromethorphan
The concomitant use of AZILECT 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's MAO inhibitory activity, dextromethorphan should not be used concomitantly with AZILECT. (See CONTRAINDICATIONS).
Sympathomimetic Medications
The concomitant use of AZILECT 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 doses of a selective MAO-B inhibitor and a sympathomimetic medication (ephedrine). Therefore, in view of AZILECT's MAO inhibitory activity, AZILECT should not be used concomitantly with sympathomimetics including nasal and oral decongestants and cold remedies. (See CONTRAINDICATIONS and WARNINGS, Need for Restriction of Dietary Tyramine and Amines Contained in Medications).
MAO Inhibitors
AZILECT 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).
Selective Serotonin Reuptake Inhibitors (SSRIs), Tricyclic and Tetracyclic Antidepressants
Concomitant use of SSRI, tricyclic, and tetracyclic antidepressants with AZILECT is not recommended. (See WARNINGS).
Levodopa/carbidopa
(See CLINICAL PHARMACOLOGY, Drug-Drug Interactions ; PRECAUTIONS, General, Dyskinesias Due to Levodopa Treatment).
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 CLINICAL PHARMACOLOGY, Drug-Drug Interactions and WARNINGS, Ciprofloxacin and Other CYP1A2 Inhibitors).
Theophylline
(See CLINICAL PHARMACOLOGY, Drug-Drug Interactions).
Laboratory Tests
No specific laboratory tests are required for the treatment of patients on AZILECT.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Two year carcinogenicity studies were conducted in CD-1 mice at oral (gavage) doses of 1, 15, and 45 mg/kg and in Sprague-Dawley rats at oral (gavage) doses of 0.3, 1, and 3 mg/kg (males) or 0.5, 2, 5, and 17 mg/kg (females). In rats, there was no increase in tumors at any dose tested. Plasma exposures at the highest dose tested were approximately 33 and 260 times, in male and female rats, respectively, the expected plasma exposures in humans at the maximum recommended dose (MRD) of 1 mg/day.
In mice, there was an increase in lung tumors (combined adenomas/carcinomas) at 15 and 45 mg/kg males and females. Plasma exposures associated with the no-effect dose (1 mg/kg) were approximately 5 times those expected in humans at the MRD.
The carcinogenic potential of rasagiline administered in combination with levodopa/carbidopa has not been examined.
Mutagenesis
Rasagiline was reproducibly clastogenic in in vitro chromosomal aberration assays in human lymphocytes in the presence of metabolic activation and was mutagenic and clastogenic in the in vitro mouse lymphoma tk assay in the absence and presence of metabolic activation. Rasagiline was negative in the in vitro bacterial reverse mutation (Ames) assay, the in vivo unscheduled DNA synthesis assay, and the in vivo micronucleus assay in CD-1 mice. Rasagiline was also negative in the in vivo micronucleus assay in CD-1 mice when administered in combination with levodopa/carbidopa.
Impairment of Fertility
Rasagiline had no effect on mating performance or fertility in male rats treated prior to and throughout the mating period, or in female rats treated from prior to mating through day 17 of gestation at oral doses up to 3 mg/kg/day (approximately 30 times the expected plasma rasagiline exposure (AUC) at the maximum recommended human dose [1 mg/day]). The effect of rasagiline administered in combination with levodopa/carbidopa on mating and fertility has not been examined.
Pregnancy Category C
No effect on embryo-fetal development was observed in a combined mating/fertility and embryo-fetal development study in female rats at doses up to 3 mg/kg/day (approximately 30 times the expected plasma rasagiline exposure (AUC) at the maximum recommended human dose [MRHD, 1 mg/day]). Effects on embryo-fetal development in rabbit have not been adequately assessed.
In a study in which pregnant rats were dosed with rasagiline (0.1, 0.3, 1 mg/kg/day) orally, from the beginning of organogenesis to day 20 post-partum, offspring survival was decreased and offspring body weight was reduced at doses of 0.3 mg/kg/day and 1 mg/kg/day (10 and 16 times the expected plasma rasagiline exposure [AUC] at the MRHD). No plasma data were available at the no-effect dose (0.1 mg/kg); however, that dose is 1 times the MRHD on a mg/m2 basis. Rasagiline's effect on physical and behavioral development was not adequately assessed in this study.
Rasagiline may be given as an adjunct therapy to levodopa/carbidopa treatment. In a study in which pregnant rats were dosed with rasagiline (0.1, 0.3, 1 mg/kg/day) and levodopa/carbidopa (80/20 mg/kg/day) (alone and in combination) throughout the period of organogenesis, there was an increased incidence of wavy ribs in fetuses from rats treated with rasagiline in combination with levodopa/carbidopa at 1/80/20 mg/kg/day (approximately 8 times the plasma AUC expected in humans at the MRHD and 1/1 times the MRHD of levodopa/carbidopa [800/200 mg/day] on a mg/m2 basis). In a study in which pregnant rabbits were dosed throughout the period of organogenesis with rasagiline alone (3 mg/kg) or in combination with levodopa/carbidopa (rasagiline: 0.1, 0.6, 1.2 mg/kg, levodopa/carbidopa: 80/20 mg/kg/day), an increase in embryo-fetal death was noted at rasagiline doses of 0.6 and 1.2 mg/kg/day when administered in combination with levodopa/carbidopa (approximately 7 and 13 times, respectively, the plasma rasagiline AUC at the MRHD). There was an increase in cardiovascular abnormalities with levodopa/carbidopa alone (1/1 times the MRHD on a mg/m2 basis) and to a greater extent when rasagiline (at all doses; 1-13 times the plasma rasagiline AUC at the MRHD) was administered in combination with levodopa/carbidopa.
There are no adequate and well-controlled studies of rasagiline in pregnant women. Therefore, AZILECT should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
In rats rasagiline was shown to inhibit prolactin secretion and it may inhibit milk secretion in females.
It is not known whether rasagiline is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when AZILECT is administered to a nursing woman.
Pediatric Use
The safety and effectiveness of AZILECT in the pediatric population have not been studied.
Geriatric Use
Approximately half of patients in clinical trials were 65 years and over. There were no significant differences in the safety profile of the geriatric and non-geriatric patients.
|
