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 .