Tiglutik

1 INDICATIONS AND USAGE TIGLUTIK is indicated for the treatment of amyotrophic lateral sclerosis (ALS). TIGLUTIK is indicated for the treatment of amyotrophic lateral sclerosis (ALS)

Recommended dosage: 50 mg (10 mL), twice daily, taken orally or via percutaneous endoscopic gastrostomy tubes (PEG-tubes), every 12 hours Measure serum aminotransferases before and during treatment ( 2.2 , 5.1 ) Take at least 1 hour before or 2 hours after a meal

2.1Dosage Information The

recommended dosage for TIGLUTIK is 50 mg (10 mL) taken orally or via Percutaneous Endoscopic Gastrostomy tubes (PEG-tubes) twice daily, every 12 hours. TIGLUTIK should be taken at least 1 hour before or 2 hours after a meal .

2.2Monitoring to Assess Safety Measure

serum aminotransferases before and during treatment with TIGLUTIK .

2.3Important Administration Instructions Gently

shake the TIGLUTIK bottle for at least 30 seconds before administration.Gently shake the TIGLUTIK bottle for at least 30 seconds before administration. TIGLUTIK can be administered by mouth or via percutaneous endoscopic gastrostomy tubes (PEG-tubes). Both silicone and polyurethane PEG tubes can be used.

See the Instructions for Use for further administration details.See the Instructions for Use for further administration details.

Hepatic injury: Use of TIGLUTIK is not recommended in patients with baseline elevations of serum aminotransferases greater than 5 times the upper limit of normal; discontinue TIGLUTIK if there is evidence of liver dysfunction Neutropenia: Advise patients to report any febrile illness Interstitial lung disease: Discontinue TIGLUTIK if interstitial lung disease develops

5.1Hepatic Injury

TIGLUTIK can cause liver injury. Cases of drug-induced liver injury, some of which were fatal, have been reported in patients taking riluzole. Asymptomatic elevations of hepatic transaminases have also been reported, and in some patients have recurred upon re-challenge with riluzole.

In clinical studies, the incidence of elevations in hepatic transaminases was greater in riluzole-treated patients than placebo-treated patients. The incidence of elevations of ALT above 5 times the upper limit of normal (ULN) was 2% in riluzole-treated patients. Maximum increases in ALT occurred within 3 months after starting riluzole.

About 50% and 8% of riluzole-treated patients in pooled controlled efficacy studies (Studies 1 and 2) had at least one elevated ALT level above ULN and above 3 times ULN, respectively . Monitor patients for signs and symptoms of hepatic injury, every month for the first 3 months of treatment, and periodically thereafter. The use of TIGLUTIK is not recommended if patients develop hepatic transaminases levels greater than 5 times the ULN. Discontinue TIGLUTIK if there is evidence of liver dysfunction (e.g., elevated bilirubin). Concomitant use with other hepatotoxic drugs may increase the risk for hepatotoxicity .

5.2Neutropenia

TIGLUTIK can cause neutropenia. Cases of severe neutropenia (absolute neutrophil count less than 500 per mm 3 ) within the first 2 months of riluzole treatment have been reported. Advise patients to report febrile illnesses.

5.3Interstitial Lung Disease

TIGLUTIK can cause interstitial lung disease, including hypersensitivity pneumonitis. Discontinue TIGLUTIK immediately if interstitial lung disease develops.

4 CONTRAINDICATIONS TIGLUTIK is contraindicated in patients with a history of severe hypersensitivity reactions to riluzole or to any of its components (anaphylaxis has occurred) . Patients with a history of severe hypersensitivity reactions to riluzole or to any of its components

8.1Pregnancy Risk Summary There

are no studies of riluzole in pregnant women, and case reports have been inadequate to inform the drug-associated risk. The background risk for major birth defects and miscarriage in patients with amyotrophic lateral sclerosis is unknown. In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

In studies in which riluzole was administered orally to pregnant animals, developmental toxicity (decreased embryofetal/offspring viability, growth, and functional development) was observed at clinically relevant doses . Based on these results, women should be advised of a possible risk to the fetus associated with use of TIGLUTIK during pregnancy. Data Animal Data Oral administration of riluzole (3, 9, or 27 mg/kg/day) to pregnant rats during the period of organogenesis resulted in decreases in fetal growth (body weight and length) at the high dose. The mid dose, a no-effect dose for embryofetal developmental toxicity, is approximately equal to the recommended human daily dose (RHDD, 100 mg) on a mg/m2 basis.

When riluzole was administered orally (3, 10, or 60 mg/kg/day) to pregnant rabbits during the period of organogenesis, embryofetal mortality was increased at the high dose and fetal body weight was decreased and morphological variations increased at all but the lowest dose tested. The no-effect dose (3 mg/kg/day) for embryofetal developmental toxicity is less than the RHDD on a mg/m2 basis. Maternal toxicity was observed at the highest dose tested in rat and rabbit.

When riluzole was orally administered (3, 8, or 15 mg/kg/day) to male and female rats prior to and during mating and to female rats throughout gestation and lactation, increased embryofetal mortality and decreased postnatal offspring viability, growth, and functional development were observed at the high dose. The mid dose, a no-effect dose for pre- and postnatal developmental toxicity, is approximately equal to the RHDD on a mg/m2 basis.

The following adverse reactions are described below and elsewhere in the labeling: Hepatic Injury Neutropenia Interstitial Lung Disease Most common adverse reactions (incidence greater than or equal to 5% and greater than placebo) were oral hypoesthesia, asthenia, nausea, decreased lung function, hypertension, and abdominal pain To report SUSPECTED ADVERSE REACTIONS, contact ITF Pharma Inc. at 1-800-664-1490 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical Trials Experience Because

clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in Controlled Clinical Trials of Riluzole Tablets In the placebo-controlled clinical trials in patients with ALS (Study 1 and 2), a total of 313 patients received riluzole 50 mg twice daily . The most common adverse reactions in riluzole-treated patients (in at least 5% of patients and more frequently than on placebo) were asthenia, nausea, decreased lung function, hypertension, and abdominal pain. The most common adverse reactions leading to discontinuation in the riluzole group were nausea, abdominal pain, constipation, and elevated ALT. There was no difference in the rate of adverse reactions leading to discontinuation between females and males.

However, the incidence of dizziness was higher in females (11%) than in males (4%). The adverse reaction profile was similar in older and younger patients. There are insufficient data to assess racial differences in the adverse reaction profile. Table 1 lists adverse reactions that occurred in at least 2% of riluzole-treated patients (50 mg twice daily) in pooled Study 1 and 2, and at a higher rate than on placebo.

Table 1. Adverse Reactions in Pooled Placebo-Controlled Trials (Studies 1 and 2) in Patients with ALS Adverse Reaction Riluzole Tablets 50 mg twice daily (N=313) % Placebo (N=320) % Asthenia 19 12 Nausea 16 11 Decreased lung function 10 9 Hypertension 5 4 Abdominal pain 5 4 Vomiting 4 2 Arthralgia 4 3 Dizziness 4 3 Dry mouth 4 3 Insomnia 4 3 Pruritus 4 3 Tachycardia 3 1 Flatulence 3 2 Increased cough 3 2 Peripheral edema 3 2 Urinary Tract Infection 3 2 Circumoral paresthesia 2 0 Somnolence 2 1 Vertigo 2 1 Eczema 2 1 Additional Adverse Reactions with TIGLUTIK In an open-label pharmacokinetic study in healthy subjects (n=36), oral hypoesthesia was observed in 29% of subjects taking TIGLUTIK, compared to 6% in patients taking riluzole tablets, under fasting conditions.

6.2Postmarketing Experience The

following adverse reactions have been identified during post-approval use of riluzole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Acute hepatitis and icteric toxic hepatitis Renal tubular impairment Pancreatitis