ZAVESCA100,,,
(miglustat) capsules
Incidence of Adverse Reaction
Study 1
(starting dose of
100 mg T101
ZAVESCA® [miglustat] Capsules, 100mg
Patients Entered in Study (n)
Body System—Preferred Term
Brief Summary: Please see package insert for full prescribing
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
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. ZAVESCAD 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/benefit of ZAVESCAtherapy 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`t 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°.
Carcinogenesis, 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 5 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 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.
16
May 18 2006
Metro
Adverse Reactions in 6% of Patients in Two Open-Label,
Uncontrolled Monotherapy Trials of ZAVESCA°
Study 2
150 mg TID)
28
% of patients
18
reporting
reporting
29
18
14
- 4
0
7
7
89
44
50
22
11
6
0
0
0
6
39
67
21
11
0
22
11
11
4
11
7
0
0
6
0
17
0
11
7
6
0
6
89
-
ART
% of patients
•
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 are
presented in the following table.
Adverse Reactions in 5°/o of Patients in Open-Label
Active-Controlled Study
Incidence of Adverse Reaction
ZAVESCA'
Cerezyme
ZAVESCA
alone
alone
+ Cerezyme
Patients Entered
in Study (n)
Body System •-•
Preferred Term
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 _
12
% of patients
reporting
12
% of patients
reporting
12
% of patients
reporting
100
67
50
8
8
8
0
0
0
0
0
0
83
58
42
25
8
0
0
0
0
8
0
8
0
0
0
8
0
8
8
8
8
8
0
8
0
8
0
0
0
0
8
0
67
0
42
17
8
8
8
0
0
0
0
0
0
0
0
33
25
0
0
8
0
0
0
8
8
0
0
0
8
0
0
8
0
0
8
17
Tani Shtull-Leber of
the Jewish Academy
of Metropolitan
Detroit tied for first
place with his
drawing.
Talented
Young
Artists
.
S
0
0
8
8
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.
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 m2) 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.
Erica Kelman placed
third from Yeshivat
Akiva with this
painting.
tudents in grades 4-6 from Hillel Day
School of Metropolitan Detroit, Yeshivat
Akiva in Southfield and the Jewish
Academy of Metropolitan Detroit submitted more
than 120 works of art in a contest themed to
Passover.
Though the holiday has passed, it's not too late
to look at 20 pieces of artwork depicting Haggadah
covers, including all the win-
ners, in the lobby of the Max
M. Fisher Federation Building
in Bloomfield Township. These
pieces are complemented
by 20 pieces of art on the
same theme from students
in Federation's Partnership
2000 region in Israel's Central
Galilee. More than 800 sub-
missions came from the Israeli
students. The artwork will be
up until May 26.
Local winners from Akiva
were Josh Sider, first place;
Rachel Spitzer, second place; and Erica Kelman,
third place. Hillel winners were Madeline Gonte,
first place; Alexis Darmon, second place; and
Rachel Kahan, third place. JAMD winners were Tani
Shtull-Leber and Melissa Gildenberg, who tied for
first place. All winners received gift certificates to
Borders.
— Keri Guten Cohen,
ACTU ZAV JA 004 0506
ACTEL10N
00
1117500
story development editor