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Rilutek

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Rilutek

Rilutek

WARNINGS

Liver Injury/ Monitoring Liver Chemistries

RILUTEK (riluzole) 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 AND ADMINISTRATION sections). Baseline elevations of several LFTs (especially elevated bilirubin) should preclude the use of RILUTEK (riluzole) .

RILUTEK (riluzole) , even in patients without a prior history of liver disease, causes serum aminotransferase elevations. Treatment should be discontinued if ALT levels are ≥ 5 X ULN or if clinical jaundice develops.

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 (riluzole) ; 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. There were rare instances of jaundice. There is limited experience with rechallenge of patients who have had RILUTEK (riluzole) discontinued for ALT > 5 X ULN, but there is the possibility of increased ALT values reoccurring (see PRECAUTIONS: Laboratory Tests). Therefore, rechallenge is not recommended.

In postmarketing experience, cases of clinical hepatitis associated with riluzole have been reported, including one with fatal outcome.

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 (riluzole) should be used with caution in patients with concomitant liver insufficiency (see WARNINGS, CLINICAL PHARMACOLOGY). In particular, in cases of RILUTEK (riluzole) -induced hepatic injury manifested by elevated liver enzymes, the effect of the hepatic injury on RILUTEK (riluzole) metabolism is unknown.

Special Populations

Riluzole should be used with caution in elderly patients whose hepatic function may be compromised due to age. Also, female patients may possess a lower metabolic capacity to eliminate riluzole compared to males (see CLINICAL PHARMACOLOGY: Special Populations).

Laboratory Tests

Serum aminotransferases including ALT levels should 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. Treatment should be discontinued if ALT levels are ≥ 5 X ULN or if clinical jaundice develops. There is limited experience with rechallenge of patients who have had RILUTEK (riluzole) discontinued for ALT > 5 X ULN, but there is the possibility of increased ALT values reoccurring. Therefore, rechallenge is not recommended.

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 (riluzole) -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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Riluzole was not carcinogenic in mice or rats when administered for 2 years at daily oral doses up to 20 mg/kg and 10 mg/kg, respectively, which are approximately equivalent to the maximum human dose on a mg/m2 basis.

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 human lymphocyte chromosomal aberration assay, which was not reproduced in a second assay performed at equal or higher concentrations; riluzole was therefore considered non-clastogenic in the human lymphocyte assay.

N-hydroxyriluzole, the major active metabolite of riluzole, caused chromosomal damage in the in vitro mammalian mouse lymphoma assay and in the in vitro micronucleus assay that used the same mouse lymphoma cell line, L5178Y. N-hydroxyriluzole was not mutagenic in this cell line when tested in the HPRT gene mutation assay, and was negative in the Ames bacterial gene mutation assay (with and without rat or hamster S9), the in vitro UDS assay in rat hepatocytes, the chromosomal aberration test in human lymphocytes, and the in vivo mouse bone marrow micronucleus test.

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 PRECAUTIONS: “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® (riluzole) is unknown, women should be advised not to breast-feed during treatment with RILUTEK (riluzole) .

Geriatric Use

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 (riluzole) in pediatric patients have not been established.

Last reviewed on RxList: 8/4/2009
This monograph has been modified to include the generic and brand name in many instances.

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