Drug Detail:Tiglutik (Riluzole [ ril-ue-zole ])
Drug Class: Miscellaneous central nervous system agents
Highlights of Prescribing Information
TIGLUTIK (riluzole) oral suspension
Initial U.S. Approval: 1995
Recent Major Changes
| Dosage and Administration ( 2.1, 2.3) | 12/2019 |
Indications and Usage for Tiglutik
TIGLUTIK is indicated for the treatment of amyotrophic lateral sclerosis (ALS) ( 1)
Tiglutik 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)
Dosage Forms and Strengths
Oral suspension: 50 mg/10 mL (5 mg/mL) in 300 mL multiple-dose bottle ( 3)
Contraindications
Patients with a history of severe hypersensitivity reactions to riluzole or to any of its components ( 4)
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)
Adverse Reactions/Side Effects
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.
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)
Use In Specific Populations
- Pregnancy: Based on animal data, may cause fetal harm ( 8.1)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 3/2020
Full Prescribing Information
1. Indications and Usage for Tiglutik
TIGLUTIK is indicated for the treatment of amyotrophic lateral sclerosis (ALS).
2. Tiglutik Dosage and Administration
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.
3. Dosage Forms and Strengths
Oral suspension: 50 mg/10 mL (5 mg/mL) slightly brown, opaque, homogeneous suspension in a 300-mL multiple-dose amber bottle.
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)].
5. Warnings and Precautions
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)] .
6. Adverse Reactions/Side Effects
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)]
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.
| 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 |
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
7. Drug Interactions
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)].
8. Use In Specific Populations
8.3 Females and Males of Reproductive Potential
In rats, oral administration of riluzole resulted in decreased fertility indices and increases in embryolethality [see Nonclinical Toxicology (13.1)].
8.5 Geriatric Use
In clinical studies of riluzole, 30% of patients were 65 years and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
8.6 Hepatic Impairment
Patients with mild [Child-Pugh's (CP) score A] or moderate (CP score B) hepatic impairment had increases in AUC, compared to patients with normal hepatic function. Thus, patients with mild or moderate hepatic impairment may be at increased risk of adverse reactions. The impact of severe hepatic impairment on riluzole exposure is unknown.
Use of TIGLUTIK is not recommended in patients with baseline elevations of serum aminotransferases greater than 5 times upper limit of normal or evidence of liver dysfunction (e.g., elevated bilirubin) [see Clinical Pharmacology (12.3)].
10. Overdosage
Reported symptoms of overdose following ingestion of riluzole ranging from 1.5 to 3 grams (30 to 60 times the recommended dose) included acute toxic encephalopathy, coma, drowsiness, memory loss, and methemoglobinemia.
No specific antidote for the treatment of TIGLUTIK overdose is available. For current information on the management of poisoning or overdosage, contact a certified poison control center.
11. Tiglutik Description
Riluzole is a member of the benzothiazole class. The chemical designation for riluzole is 2-amino-6-(trifluoromethoxy)benzothiazole. Its molecular formula is C 8H 5F 3N 2OS, and its molecular weight is 234.2. The chemical structure is:
Riluzole is a white to slightly yellow powder that is very soluble in dimethylformamide, dimethylsulfoxide, and methanol; freely soluble in dichloromethane; sparingly soluble in 0.1 N HCl; and very slightly soluble in water and in 0.1 N NaOH.
TIGLUTIK (50 mg/10mL) oral suspension is a slightly brown, opaque, homogeneous suspension containing 50 mg of riluzole per 10 mL of suspension.
TIGLUTIK also contains the following inactive ingredients: magnesium aluminum silicate, noncrystallizing sorbitol solution, polyoxyl 20 cetostearyl ether, purified water, saccharin sodium, simethicone emulsion, sodium lauryl sulfate, and xanthan gum.
12. Tiglutik - Clinical Pharmacology
12.1 Mechanism of Action
The mechanism by which riluzole exerts its therapeutic effects in patients with ALS is unknown.
12.3 Pharmacokinetics
A pharmacokinetic study in healthy adult subjects who received riluzole suspension 50 mg under fasting conditions demonstrated similar pharmacokinetics following intragastric administration via feeding tubes and oral administration.
Table 2 displays the pharmacokinetic parameters of riluzole.
|
|
| Absorption | |
| Bioavailability (oral) | Approximately 60% |
| Dose Proportionality | Linear over a dose range of 25 mg to 100 mg every 12 hours (1/2 to 2 times the recommended dosage) |
| Food effect † | AUC ↓ 9% and Cmax ↓ 55% (high fat meal) |
| Time to peak plasma concentration (median) † | 0.8 hours |
| Distribution | |
| Plasma Protein Binding | 96% (Mainly to albumin and lipoproteins) |
| Elimination | |
| Elimination half-life |
|
| Accumulation | Approximately 2-fold |
| Metabolism | |
| Fraction metabolized (% dose) | At least 88% |
| Primary metabolic pathway(s) [in vitro] |
|
| Active Metabolites | Some metabolites appear pharmacologically active in vitro, but the clinical implications are not known. |
| Excretion | |
| Primary elimination pathways (% dose) |
|
14. Clinical Studies
The efficacy of TIGLUTIK is based upon bioavailability studies comparing oral riluzole tablets to TIGLUTIK oral suspension [see Clinical Pharmacology (12.3)].
The efficacy of riluzole was demonstrated in two studies (Study 1 and 2) that evaluated 50 mg riluzole oral tablets twice daily in patients with amyotrophic lateral sclerosis (ALS). Both studies included patients with either familial or sporadic ALS, disease duration of less than 5 years, and baseline forced vital capacity greater than or equal to 60% of normal.
Study 1 was a randomized, double-blind, placebo-controlled clinical study that enrolled 155 patients with ALS. Patients were randomized to receive riluzole 50 mg twice daily (n=77) or placebo (n=78) and were followed for at least 13 months (up to a maximum duration of 18 months). The clinical outcome measure was time to tracheostomy or death.
The time to tracheostomy or death was longer for patients receiving riluzole compared to placebo. There was an early increase in survival in patients receiving riluzole compared to placebo. Figure 1 displays the survival curves for time to death or tracheostomy. The vertical axis represents the proportion of individuals alive without tracheostomy at various times following treatment initiation (horizontal axis). Although these survival curves were not statistically significantly different when evaluated by the analysis specified in the study protocol (Logrank test p=0.12), the difference was found to be significant by another appropriate analysis (Wilcoxon test p=0.05). As seen in Figure 1, the study showed an early increase in survival in patients given riluzole. Among the patients in whom the endpoint of tracheostomy or death was reached during the study, the difference in median survival between the riluzole 50 mg twice daily and placebo groups was approximately 90 days.
Figure 1. Time to Tracheostomy or Death in ALS Patients in Study 1 (Kaplan-Meier Curves)
Study 2 was a randomized, double-blind, placebo-controlled clinical study that enrolled 959 patients with ALS. Patients were randomized to riluzole 50 mg twice daily (n=236) or placebo (n=242) and were followed for at least 12 months (up to a maximum duration of 18 months). The clinical outcome measure was time to tracheostomy or death.
The time to tracheostomy or death was longer for patients receiving riluzole compared to placebo. Figure 2 displays the survival curves for time to death or tracheostomy for patients randomized to either riluzole 100 mg per day or placebo. Although these survival curves were not statistically significantly different when evaluated by the analysis specified in the study protocol (Logrank test p=0.076), the difference was found to be significant by another appropriate analysis (Wilcoxon test p=0.05). Not displayed in Figure 2 are the results of riluzole 50 mg per day (one-half of the recommended daily dose), which could not be statistically distinguished from placebo, or the results of riluzole 200 mg per day (two times the recommended daily dose), which were not distinguishable from the 100 mg per day results. Among the patients in whom the endpoint of tracheostomy or death was reached during the study, the difference in median survival between riluzole and placebo was approximately 60 days.
Although riluzole improved survival in both studies, measures of muscle strength and neurological function did not show a benefit.
Figure 2. Time to Tracheostomy or Death in ALS Patients in Study 2 (Kaplan-Meier Curves)
17. Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Instructions for Use).
| TIGLUTIK
riluzole liquid |
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| Labeler - Itf Pharma, Inc. (080260470) |
| Establishment | |||
| Name | Address | ID/FEI | Business Operations |
|---|---|---|---|
| Aphena Pharma Solutions | 829739833 | manufacture(70726-0303) | |
