ZAVESCA,:- Adverse Reactions in 25% of Patients in Two Open-Label, Uncontrolled Monotherapy Trials of ZAVESCA' Incidence of Adverse Reaction Study 1 Study 2 (starting dose of (50 mg 11D) (miglustat) capsules Middle East 100 mg TID) ZAVESCA® [miglustat] Capsules, 100mg Brief Summary: Please see package insert for full prescribing informatiOn. INDICATION AND USAGE: ZAVESCA' is indicated for the treatment of adult patients with mild to moderate type 1 Gaucher disease for whom enzyme replacement therapy is not a therapeutic option (e.g., due to constraints such as allergy, hypersensitivity, or poor venous access). CONTRAINDICATIONS: ZAVESCA" is contraindicated in patients who have demonstrated hypersensitivity to the active substance or any of the excipients. Pregnancy Category X. Miglustat may cause fetal harm when administered to a pregnant woman. ZAVESCA' is contraindicated in women who are or may become pregnant. If this drug is administered to a woman with reproductive potential, the patient should be apprised of the potential hazard to a fetus. WARNINGS:. Cases of peripheral neuropathy have been reported in patients treated with ZAVESCA". All patients undergoing ZAVESCA' treatment should undergo baseline and repeat neurological evaluations at approximately 6-month intervals. Patients who develop symptoms such as numbness and tingling should have a careful re-assessment of the risk/benefrt of ZAVESCA' therapy and cessation of treatment may be considered. PRECAUTIONS: Tremor. Approximately 30% of patients have reported tremor or exacerbation of existing tremor on treatment. Tremor usually began within the first month of therapy and in many cases resolved between 1 to 3 months during treatment Dose reduction may amelio- rate the tremor usually within days but discontinuation of treatment may sometimes be required. Diarrhea and Weight Loss: Diarrhea and weight loss were common in clinical studies of patients treated with ZAVESCA", approximately 85% and up to 65% of treated patients, respectively, reporting these conditions. Diarrhea appears to be the result of the disaccharidase inhibitory activity of ZAVESCA", with a resultant osmotic diarrhea. It is unclear if weight loss results from the diarrhea and associated gastrointestinal complaints, a decrease in food intake, or a combination of these or other factors. The incidence of diarrhea was noted to decrease over time with continued ZAVESCA' treatment, and was noted to result in an increase in the use of anti-diarrheal medications, most commonly loperamide. Patients may be instructed to avoid high carbohydrate content foods during treatment with ZAVESCA" if they present with diarrhea. The incidence of weight loss was most evident in the first 12 months of treatment Male Fertility: Male patients should maintain reliable contraceptive methods while taking ZAVESCA". Studies in the rat have shown that miglustat adversely affects spermatogenesis and sperm parameters, thereby reducing fertility. Until further information is available, it is advised that before seeking to conceive, male patients should cease ZAVESCA" and maintain reliable contraceptive methods for 3 months thereafter. Information for patients: Patients are advised to consult the ZAVESCA' Patient Information section in the full prescribing informa- tion on the safe use of ZAVESCA'. Patients should be informed of the potential risks and benefits of ZAVESCA' and of alternative modes of therapy. Patients should be advised that diarrhea, gastrointestinal complaints, and weight loss are common Side effects of ZAVESCA' therapy, and to adhere to dietary instructions. Patients should also be advised to promptly report any numbness, pain, or burning in the hands and feet, and the development of tremor or worsening in an existing tremor. Drug Interactions: While co-administration of ZAVESCA' appeared to increase the clearance of Cerezyme' (imiglucerase) by 70%, these results are not conclusive because of the small number of subjects studied and because patients took variable doses of Cerezyme. Combination therapy with Cerezyme and ZAVESCA' is not indicated. Miglustat does not inhibit or induce various substrates of CYP450 enzymes; consequently significant interactions are unlikely with drugs that are substrates of CYP450 enzymes. Concomitant therapy with lop- eramide during clinical trials did not appear to significantly alter the pharmacokinetics of ZAVESCA". Garcinogenesis, Mutagenesis, and Impairment of Fertility: Long-term studies in animals to evaluate the carcinogenic potential of miglustat have not been conducted. Miglustat was not mutagenic or clasto- genic in a battery of in vitro and in vivo assays including the bacterial reverse mutation (Ames), chromosomal aberration (in human lympho- cytes), gene mutation in mammalian cells (Chinese hamster ovary), and mouse micronucleus assays. Male rats, given 20 mg/kg/day miglustat by oral gavage 14 days prior to mating, had decreased sper- matogenesis with altered sperm morphology and motility and decreased fertility. Decreased spermatogenesis was reversible fol- lowing 6 weeks of drug withdraWal. A higher dose of 60 mg/kg/day resulted in seminiferous tubule and testicular atrophy/degeneration Female rats were given oral gavage doses of 20, 60, 180 mg/kg/day beginning 14 days before mating and continuing through gestation. Effects observed at 20 mg/kg/day included decreased corpora lutea, increased post implantation loss, and decreased live births. Pregnancy: Category X. There are no adequate and well-controlled studies of miglustat in pregnant women. ZAVESCA" should not be used during pregnancy. SPECIAL POPULATIONS: Labor and Delivery. Studies in pregnant rats exposed to ZAVESCA' during gestation through lactation are associ- ated with dystocia and delayed parturition at systemic exposure 2 times the human therapeutic systemic exposure, based on body sur- face area comparisons. Nursing Mothers: It is not known whether miglustat is excreted in human milk. ZAVESCA" should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. A decision should be made whether to discontinue nurs- ing or discontinue the drug, taking into account the importance of the drug to the lactating woman. Pediatric Use: The safety and effective- ness of ZAVESCA" have not been evaluated in patients under the age of 18. The effects of ZAVESCA' on growth and development in children have not been evaluated. Geriatric Use: Clinical studies of ZAVESCA'. did not include sufficient numbers of patients aged 65 and over. Other reported clinical experience has not identified differences in respons- es between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, and cardiac function and of concomitant disease or other drug therapy. Renal Impairment Miglustat is known to be sub- stantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. As a result of this, dose reductions are recommended for those patients with mild to moderate renal impairment, the reduction being depend- ent upon the level of their creatinine clearance adjustment For those patients with severe renal impairment, treatment with miglustat is not recommended. Since elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. ADVERSE REACTIONS: The safety and tolerability of ZAVESCA" have been evaluated in 80 adult type 1 Gaucher disease patients in two open-label uncontrolled and one open-label active controlled trials. All 80 patients in the combined dataset from the clinical studies reported at least one adverse event during their treatment period. Open-Label Uncontrolled Monotherapy Trials: In two trials in adult type 1 Gaucher disease patients treated with ZAVESCA' at a starting dose of 100 mg three times daily for 12 months in 28 patients [Study II, or at a dose of 50 mg three times daily for 6 months in 18 patients [Study 2), gastroin- testinal events were observed in more than 80% of patients either at the outset of treatment, or intermittently during treatment. Diarrhea was observed in approximately 85% of patients. Weight loss has been observed in up to 65% of patients. In the two open-label, uncontrolled monotherapy trials, the Adverse Reactions by WHO body system and preferred term occurring with an incidence of 25%, are presented in the following table. Patients Entered in Study (n) Body System—Preferred Term 28 % of patients 18 % of patients reporting reporting Gastrointestinal System Diarrhea Flatulence Abdominal pain Nausea Vomiting Bloating Anorexia Dyspepsia Epigastric pain not food related Metabolic and Nutritional Disorders Weight decrease Central and Peripheral Nervous System Headache Tremor Dizziness Cramps legs Paresthesia Migraine Vision Disorders Visual disturbance Musculoskeletal Disorders Cramps Platelet, Bleeding, and Clotting Disorders Thrombocytopenia Reproductive Disorders, Female Menstrual disorder 89 29 18 14 4 0 7 7 89 44 50 22 11 6 • 0 0 0 6 39- 67 21 11 0 4 7 0 22 11 11 11 0 6 0 17 0 11 7 6 0 6 Israeli Scouts perform at Temple Open-Label Active-Controlled Study: In an open-label, active-controlled study, 36 adult type 1 Gaucher disease patients were treated with ZAVESCA", Cerezyme, or ZAVESCA + Cerezyme (Study 3). Gastrointestinal adverse events and weight loss were commonly seen in patients exposed to ZAVESCA". The Adverse Reactions by WHO body system and preferred term occurring with an incidence of ?.5%, are presented in the following table. Adverse Reactions in .5°/o of Patients in Open-Label Active-Controlled Study Incidence of Adverse Reaction ZAVESCA' alone Cerezyme alone ZAVESCA' ÷ Cerezyme Patients Entered in Study (n) Body System – Preferred Term 12 % of patients 12 12 reporting % of patients reporting % of patients reporting 100 67 50 8 8 8 0 0 0 0 0 0 83 58 42 25 8 0 0 0 0 17 8 8 0 8 0 0 0 0 8 8 8 0 8 0 8 0 0 0 0 8 0 67 0 17 8 8 8 0 0 0 0 0 0 0 0 0 0 8 0 0 0 0 0 0 0 8 8 0 0 8 Gastrointestinal System Diarrhea Abdominal pain Flatulence Constipation Nausea Mouth dry Body as a Whole Influenza-like symptoms Pain Pain legs Weakness generalized Abdominal distension Back pain Abdominal distension gaseous Chills Heaviness in limbs Metabolic and Nutritional Disorders Weight decrease Central and Peripheral Nervous System Tremor Dizziness Cramps legs Gait unsteady Numbness localized Shaking Psychiatric Disorders Appetite absent Jitteriness Memory loss , Vision Disorders Eye abnormality Visual disturbance Reproductive Disorders, Female Menstrual irregularity - • 8 8 - .., .42 ' 33 25 - 0 ' 0 8 8 . 8 8 .0 OVERDOSAGE: In the clinical development program for ZAVESCA", no patient experienced an overdose of study drug. However, ZAVESCA" has been administered at doses of up to 3000 mg/day (approximately 10 times the recommended starting dose administered to Gaucher patients) for up to six months in HIV-positive patients. Adverse events observed in the HIV studies included granulocytopenia, dizziness, and paresthesia. Leukopenia and neutropenia have also been observed in a similar group of patients receiving 800 mg/day or above. July 27 - 2006 Making Connections Scout Caravan shows spirit of Israel. Keri Guten Cohen Story Development Editor M embers of the Tzofim Friendship Caravan 2006 played to their biggest Midwest crowd Friday night when they performed for 1,850 people at outdoor Shabbat services at Temple Israel in West Bloomfield. The summer outdoor services regularly draw more than 1,000 wor- shippers, but this mega-crowd was definitely a show of support for Israel in time of trouble. And what better way to show that support than to revel in some of Israel's finest young repre- sentatives? Chosen from a field of 2,000 appli- cants — not so much for their musi- cal talent but their outgoing personali- ties and their ability to act as links between Israeli and American Jews — the 10 Scouts are part of a three- caravan group of 30 touring the U.S. DOSAGE AND ADMINISTRATION: Therapy should be directed by physi- cians who are knowledgeable in the management of Gaucher disease. The recommended dose for the treatment of adult patients with type 1 Gaucher disease is one 100 mg capsule administered orally three times a day at regular intervals. It may be necessary to reduce the dose to one 100 mg capsule once or twice a day in some patients for adverse effects, such as diarrhea or tremor. In patients with mild renal impair- ment (adjusted creatinine clearance 50-70 mL/min/1.73 m 2 ), ZAVESCA' administration should commence at a dose of 100 mg twice per day. In patients with moderate renal impairment (adjusted creatinine clear- ance of 30-50 ml/min/1.73 m 2), ZAVESCA' administration should com- mence at a dose of one 100 mg capsule per day. Use of ZAVESCA' in patients with severe renal impairment (creatinine clearance of <30 mL/min/1.73 m') is not recommended. HOW SUPPLIED: ZAVESCA' is supplied in hard gelatin capsules con- taining 100 mg miglustat ZAVESCA' 100 mg capsules are white opaque with "OGT 918 " printed in black on the cap and "100 " printed in black on the body, ZAVESCA' 100 mg capsules are packed in blister cards. Five blister cards of 18 capsules are supplied in each carton. NDC 66215-201-90: carton containing 90 capsules. NDC 66215-201-18: blister card containing 18 capsules. Rx only STORAGE: Store at 20°C to 25°C (68°F to 77°F). Brief exposure to 15°C to 30°C (59°F to 86°F) permitted (see USP Controlled Room Temperature). © 2006 Actelion Pharmaceuticals US, Inc. All rights reserved. ACTU ZAV JA 004 0506 Mic el Ivianhaim, 17, 4LAlfei Men•lphe )onakes a ctinpection wh Mary:Silverman of Southfield during theioncert at Temple Israel. fiCTELION 1117500 22 Israel as part of the Tzofim Friendship Caravan. this summer. "We're all about making connec- tions, bringing a piece of Israel:' says Scout Lior Ashkenazi, 17, of Ramat Gan. "Were the future of Israel." For 35 years, the Tzofim have been sending troupes to North America to put on a show that gives a taste of Israel — its history and its current state, its people and culture, its hope and aspirations, and its everyday life and special occasions. For the last five years, Andi Roisman of Beverly Hills has coor- dinated the Scouts' Metro Detroit performances and finds them home hospitality while they are in the area, performing at Charlotte Rothstein Park in Oak Park, in Ann Arbor and at Temple Israel. Few know that her roots go back to the origins of the Tzofim Caravan. "In 1972, in our living room in Cleveland, my father and Dan Korin, who was head of the Scouts, came