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) ( 1 )

2 DOSAGE AND ADMINISTRATION Recommended dosage: 50 mg (10 mL), twice daily, taken orally or via percutaneous endoscopic gastrostomy tubes (PEG-tubes), every 12 hours ( 2.1 ) Measure serum aminotransferases before and during treatment ( 2.2 , 5.1 ) Take at least 1 hour before or 2 hours after a meal ( 2.3 ) 2.1 Dosage 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 [see Clinical Pharmacology (12.3) ]. 2.2 Monitoring to Assess Safety Measure serum aminotransferases before and during treatment with TIGLUTIK [see Warnings and Precautions (5.1) ]. 2.3 Important 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.

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) [see Adverse Reactions (6.1) ]. Patients with a history of severe hypersensitivity reactions to riluzole or to any of its components ( 4 )

5 WARNINGS AND PRECAUTIONS 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 ( 5.1 ) Neutropenia: Advise patients to report any febrile illness ( 5.2 ) Interstitial lung disease: Discontinue TIGLUTIK if interstitial lung disease develops ( 5.3 ) 5.1 Hepatic 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 [see Clinical Studies (14) ]. 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 [see Drug Interactions (7.3) ] . 5.2 Neutropenia 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. 5.3 Interstitial Lung Disease TIGLUTIK can cause interstitial lung disease, including hypersensitivity pneumonitis. Discontinue TIGLUTIK immediately if interstitial lung disease develops.

7 DRUG INTERACTIONS Strong to moderate CYP1A2 inhibitors: Co-administration may increase TIGLUTIK-associated adverse reactions ( 7.1 ) Strong to moderate CYP1A2 inducers: Co-administration may result in decreased efficacy ( 7.2 ) Hepatotoxic drugs: TIGLUTIK-treated patients that take other hepatotoxic drugs may be at increased risk for hepatotoxicity ( 7.3 ) 7.1 Agents that may Increase Riluzole Blood Concentrations CYP1A2 Inhibitors Co-administration of riluzole (a CYP1A substrate) with CYP1A2 inhibitors was not evaluated in a clinical trial; however, in vitro findings suggest an increase in riluzole exposure is likely. The concomitant use of strong or moderate CYP1A2 inhibitors (e.g., ciprofloxacin, enoxacin, fluvoxamine, methoxsalen, mexiletine, oral contraceptives, thiabendazole, vemurafenib, zileuton) with TIGLUTIK may increase the risk of TIGLUTIK - associated adverse reactions [see Clinical Pharmacology (12.3) ]. 7.2 Agents that may Decrease Riluzole Plasma Concentrations CYP1A2 Inducers Co-administration of riluzole (a CYP1A substrate) with CYP1A2 inducers was not evaluated in a clinical trial; however, in vitro findings suggest a decrease in riluzole exposure is likely. Lower exposures may result in decreased efficacy [see Clinical Pharmacology (12.3) ] . 7.3 Hepatotoxic Drugs Clinical trials in ALS patients excluded patients on concomitant medications which were potentially hepatotoxic (e.g., allopurinol, methyldopa, sulfasalazine). TIGLUTIK-treated patients who take other hepatotoxic drugs may be at an increased risk for hepatotoxicity [see Warnings and Precautions (5.1) ].

6 ADVERSE REACTIONS The following adverse reactions are described below and elsewhere in the labeling: Hepatic Injury [see Warnings and Precautions (5.1) ] Neutropenia [see Warnings and Precautions (5.2) ] Interstitial Lung Disease [see Warnings and Precautions (5.3) ] 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 ( 6.1 ) 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. 6.1 Clinical 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 [see Clinical Studies (14) ]. 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. 6.2 Postmarketing 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 [see Warnings and Precautions (5.1) ] Renal tubular impairment Pancreatitis

8.1 Pregnancy 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 [see Data ] . 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.