rirriNTIr Adverse Reactions in .5°A, of Patients in Two Open-Label, ZAVESCA Metro Uncontrolled Monotherapy Trials of ZAVESCA' Incidence of Adverse Reaction (miglustat) capsules Study 1 (stoning dose of 100 mg TIM ZAVESCA® [miglustat] Capsules, 100mg Brief Summary: Please one 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 Diarrhea 89 89 Flatulence 29 44 Abdominal_pain 18 50 Nausea 14 22 Vomiting 4 Bloating 0 6 0 6 39 67 Headache 21 Tremor 11 22 11 0 11 4 11 7 0 Anorexia WARNINGS: Cases of peripheral neuropathy have been reported in Weight decrease 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/benefit of ZAVESCA' therapy and cessation of treatment may be considered. Central and Peripheral Nervous System PRECAUTIONS: Tremor: Approximately 30% of patients have reported Paresthesia 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'. studies in animals to evaluate the carcinogenic potential of miglustat have not been conducted. Miglustat was not mutagenic or dints- 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. Giving Back Dyspepsia Epigastric pain not food related Metabolic and Nutritional Disorders Dizziness Cramps legs - Migraine Heart recipient's family gives back through local organ donor group. 0 Shelli Liebman Dorfman Vision Disorders 0 Visual disturbance 17 Staff Writer Musculoskeletal Disorders L 0 Cramps Platelet. Bleeding, and Clotting Disorders Thrombocytopenia Reproductive Disorders. •Female 0 Menstrual disorder 6 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 .6°10 of Patients in Open-Label Active-Controlled Study Incidence of Adverse Reaction ZAVESCA' alone Patients Entered in Study (n) Body System - Preferred Term Cerezyme alone ZAVESCA' + Cerezyme 12 12 12 % of patients reporting % of patients reporting % of patients reporting 83 Diarrhea 100 0 Abdominal pain 67 0 58 Flatulence 50 0 42 Constipon 8 0 25 Nausea 8 0 8 Mouth dry 8 0 0 Influenza-like symptoms 0 0 8 Pain 0 8 8 Pain legs 0 0 Weakness generalized 17 Abdominal distension 8 0 8 Back pain 8 0 0 0 Abdominal distension gaseous 8 8 0 0 0 8 8 0 0 67 0 42 17 33 Gait unsteady 8 0 0 Numbness localized 0 0 8 Shaking 0 0 8 Chills Heaviness in limbs Metabolic and Nt tuonal Disorders Weight decrease Lisa and Shay Ziff at last year's Central and Peripheral Nervous System Tremor Gift of Life walk 25 Dizziness _ Cramps legs loving parents," said Adam Ziff of West 0 Psychiatric Disorders Appetite absent 0 0 studies of miglustat in pregnant women. ZAVESCA• should not be used during pregnancy. Jitteriness 0 0 8 8 Memory loss 8 0 0 SPECIAL POPULATIONS: Labor and Delivery Studies in pregnant rats Vision Disorders 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. Eye abnormality 0 0 8 Visual disturbance 0 0 8 0 0 8 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 1], 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 ?.5%, are presented in the following table. Reproductive Disorders, Female Menstrual irregularity OVERDOSAGE In the clinical development program fo 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. 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 mUmin/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 mUmin/1.73 in') 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 (59uF to 86°F) permitted (see USP Controlled Room Temperature). CO 2006 Actelion Pharmaceuticals US, Inc. All rights reserved. ACTU ZAV JA 004 0506 ACTELION 17500 18 July 13 • 2006 JIM 7.= Body as a Whole Pregnancy: Category X. There are no adequate and well-controlled ADVERSE REACTIONS: The safety and tolerability of ZAVESCA' have isa and Adam Ziff understand better than most the monu- mental impact of organ dona- tion, having experienced firsthand how a transplanted heart saved the life of their daughter, Shay. As an infant, Shay was diagnosed with restrictive cardiomyopathy, and her name was placed on an organ donor list. "Shay's gift (would) be the result of pain and anguish of other Gastrointestinal System i o Carcinogenesis, Mutagenesis, and Impairment of Fertility: Long - term 18 % of patients reporting Gastrointestinal System 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. 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' it 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. 28 % of patients reporting Patients Entered in Study (n) Body System—Preferred Term Study 2 150 mg TM) Bloomfield. . Shay received a life-saving heart transplant when she w as 4 months old. At the time, Adam expressed immense gratitude "to the family that decided, in their time of tremendous grief, to think of others . in need. Their kind act will give our daughter, Shay, a second - chance at life." Two years later, the Ziffs continue to promote organ donor awareness. They will participate in the 9:30 a.m. Saturday, July 22, Gift of Life Minority Organ Tissue Transplant Education Program (MOTTEP) LIFE Walk at Belle Isle Park in Detroit. The family walked last year, too, recruiting friends and family to join them. This is the first time they have organized "Shay's Team," a group that has grown to 50 members. Proceeeds from the walk benefit public education about organ, tissue, eye, blood and hone marrow donation in Michigan. "This walk is important because it helps to raise awareness in minority communities — including the Jewish community — about the importance of organ donation , ) ' Lisa said. "One person who makes that choice can potentially save or improve the lives of 50 people. There are too many people, including children, waiting for precious organs to be donated so they can have a second chance at life." She emphasized the importance of signing up as an organ donor on the Michigan organ donor registry (www.giftoflifemichigan.org ). "Signing the back of your driver's license is not enough ) ) she said. Registration also can be made through the International Association for Organ Donation Web site (www.IAOEorg) or with forms available at Michigan Secretary of State offices. "Shay is doing really well': Lisa said. "We still face many challenges but we continue to persevere. She continues to amaze us day after day with her resil- ience and determination. If it wasn't for the selfless act of a family we have never met, our little angel, Shay, would not be here today" E Donor information: • For donor registration informa- tion, call IAOD at (313) 745-0844 or contact the United Network for Organ Sharing at (804) 782-4800 or www.unos.org . • More than 90,000 Americans are waiting for life-saving transplants. • Approximately 18 people die daily waiting for transplants. • An estimated 10,000-14,000 people who die each year meet the criteria for organ donation, but less than -half become organ donors. • There is no cost to donor's families • The body is not disfigured from donation. • Successful donations may come from unrelated donors and donors over 65 years of age. The 9:30 a.m. Saturday, July 22, MOTTEP LIFE Walk is a 5K walk- run (with an optional 1-mile route), with registration beginning at 8:30 a.m. The walk takes plate at Belle Isle Park in Detroit in the Belle Isle Casino area. Cost: $25, For infor- mation, call (800) 482-4881 or access the Web site at www.motteplifewalk.org .