A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Rilutek Warnings, Precautions, Pregnancy, Nursing, Abuse - Riluzole
Rilutek Warnings, Precautions, Pregnancy, Nursing, Abuse - Riluzole
WARNINGS
Liver Injury/Monitoring Liver Chemistries
RILUTEK should be prescribed with care in patients with current evidence
or history of abnormal liver function indicated by significant abnormalities
in serum transaminase (ALT/SGPT; AST/SGOT), bilirubin, and/or gamma-glutamate
transferase (GGT) levels (see PRECAUTIONS
and
DOSAGE ADMINISTRATION SECTIONS).
Baseline elevations of several LFTs (especially elevated bilirubin) should
preclude the use of RILUTEK.
RILUTEK, even in patients without a prior history of liver disease, causes
serum aminotransferase elevations. Experience in almost 800 ALS patients
indicates that about 50% of riluzole-treated patients will experience
at least one ALT/SGPT level above the upper limit of normal, about 8%
will have elevations > 3 X ULN, and about 2% of patients will have elevations
> 5 X ULN. A single non ALS patient with epilepsy treated with concomitant
carbamazepine and phenobarbital experienced marked, rapid elevations of
liver enzymes with jaundice (ALT 26 X ULN, AST 17 X ULN, and bilirubin
11 X ULN) four months after starting RILUTEK; these returned to normal
7 weeks after treatment discontinuation.
Maximum increases in serum ALT usually occurred within 3 months after
the start of riluzole therapy and were usually transient when < 5 times
ULN. In trials, if ALT levels were < 5 times ULN, treatment continued
and ALT levels usually returned to below 2 times ULN within 2 to 6 months.
Treatment in studies was discontinued, however, if ALT levels exceeded
5 X ULN, so that there is no experience with continued treatment of ALS
patients once ALT values exceed 5 times ULN (see PRECAUTIONS
:
Laboratory Tests). There were rare instances of jaundice. Liver chemistries
should be monitored (see PRECAUTIONS
).
Neutropenia
Among approximately 4000 patients given riluzole for ALS, there were
three cases of marked neutropenia (absolute neutrophil count less than
500/mm3), all seen within the first 2 months of riluzole treatment.
In one case, neutrophil counts rose on continued treatment. In a second
case, counts rose after therapy was stopped. A third case was more complex,
with marked anemia as well as neutropenia and the etiology of both is
uncertain. Patients should be warned to report any febrile illness to
their physicians. The report of a febrile illness should prompt treating
physicians to check white blood cell counts.
PRECAUTIONS
Use in Patients with Concomitant Disease
RILUTEK should be used with caution in patients with concomitant liver
and/or renal insufficiency (see WARNINGS
, CLINICAL
PHARMACOLOGY). In particular, in cases of RILUTEK-induced hepatic
injury manifested by elevated liver enzymes, the effect of the hepatic
injury on RILUTEK metabolism is unknown.
Special Populations
Riluzole should be used with caution in elderly patients whose hepatic
or renal functions may be compromised due to age. Also, females and Japanese
patients may possess a lower metabolic capacity to eliminate riluzole
compared to males and Caucasian subjects, respectively (see CLINICAL
PHARMACOLOGY: Special Populations).
Information for the Patient
See PATIENT INFORMATION section.
Laboratory Tests
It is recommended that serum aminotransferases including ALT levels be
measured before and during riluzole therapy. Serum ALT levels should be
evaluated every month during the first 3 months of treatment, every 3
months during the remainder of the first year, and periodically thereafter.
Serum ALT levels should be evaluated more frequently in patients who develop
elevations (see WARNINGS
).
As noted in the WARNINGS
section, there is no experience with
continued treatment of patients once ALT exceeds 5 X ULN. If a decision
is made to continue to treat these patients, frequent monitoring (at least
weekly) of complete liver function is recommended. Treatment should be
discontinued if ALT exceeds 10 X ULN or if clinical jaundice develops.
Because there is no experience with rechallenge of patients who have had
RILUTEK discontinued for ALT > 5 X ULN, no recommendations about restarting
RILUTEK can be made.
In the two controlled trials in patients with ALS, the frequency with
which values for hemoglobin, hematocrit, and erythrocyte counts fell below
the lower limit of normal was greater in RILUTEK-treated patients than
in placebo-treated patients; however, these changes were mild and transient.
The proportions of patients observed with abnormally low values for these
parameters showed a dose-response relationship. Only one patient was discontinued
from treatment because of severe anemia. The significance of this finding
is unknown.
Drug Interactions
See DRUG INTERACTIONS section.
Drug Laboratory Test Interactions: None known
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies to determine the carcinogenic potential of riluzole
have not yet been completed.
The genotoxic potential of riluzole was evaluated in the bacterial mutagenicity
(Ames) test, the mouse lymphoma mutation assay in L5178Y cells, the in
vitro chromosomal aberration assay in human lymphocytes and the in
vivo rat cytogenetic assay and in vivo mouse micronucleus assay
in bone marrow. There was no evidence of mutagenic or clastogenic potential
in the Ames test, the mouse lymphoma assay, or the in vivo assays
in the mouse and rat. There was an equivocal clastogenic response in the
in vitro lymphocyte chromosomal aberration assay.
Riluzole impaired fertility when administered to male and female rats
prior to and during mating at an oral dose of 15 mg/kg or 1.5 times the
maximum daily dose on a mg/m2 basis (see Pregnancy for
effects on fertility).
Pregnancy
Pregnancy Category C:
Oral administration of riluzole to pregnant animals during the period
of organogenesis caused embryotoxicity in rats and rabbits at doses of
27 mg/kg and 60 mg/kg, respectively, or 2.6 and 11.5 times, respectively,
the recommended maximum human daily dose on a mg/m2 basis.
Evidence of maternal toxicity was also observed at these doses.
When administered to rats prior to and during mating (males and females)
and throughout gestation and lactation (females), riluzole produced adverse
effects on pregnancy (decreased implantations, increased intrauterine
death) and offspring viability and growth at an oral dose of 15 mg/kg
or 1.5 times the maximum daily dose on a mg/m2 basis.
There are no adequate and well-controlled studies in pregnant women.
Riluzole should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus.
Nursing Women
In rat studies, 14C-riluzole was detected in maternal milk.
It is not known whether riluzole is excreted in human breast milk. Because
many drugs are excreted in human milk, and because the potential for serious
adverse reactions in nursing infants from RILUTEK® is unknown,
women should be advised not to breast feed during treatment with RILUTEK.
Use in the Elderly
Age-related compromised renal and hepatic function may cause a decrease
in clearance of riluzole (see CLINICAL
PHARMACOLOGY: Special Populations). In controlled clinical trials,
about 30% of patients were over 65. There were no differences in adverse
effects between younger and older patients.
Pediatric Use
The safety and the effectiveness of RILUTEK in pediatric patients have
not been established.
top
