RILUTEK 50 MG ( RILUZOLE ) 56 FILM-COATED TABLETS

Dosing & Uses
Adult
Dosage Forms & Strengths

tablet
50mg
oral suspension
5mg/mL (300-mL multidose bottle)
oral film
50mg

• Amyotrophic Lateral Sclerosis

50 mg PO q12hr

Also see Administration

Dosage Modifications
Hepatic impairment

• Mild or moderate (Child-Pugh A or B): Patients had increases in AUC; thus, may be at increased risk of adverse reactions
• Severe (Child-Pugh C): Unknown
• Not recommended for patients with baseline serum aminotransferases (AST/ALTs) >5x ULN or evidence of liver dysfunction (eg, elevated bilirubin)

Dosing Considerations
Measure serum AST/ALTs before and during treatment

• Huntington Disease (Orphan)

Orphan indication sponsor
Rhone-Poulenc Rorer Pharmaceuticals, Inc; 500 Arcola Road, PO Box 5096; Collegeville, PA 19426-0800

• Ataxia (Orphan)
• Orphan designation for treatment of spinocelebellar ataxia

Sponsor
Biohaven Pharmaceutical Holding Company, Ltd; 234 Church Street, Suite 304; New Haven, Connecticut 06511

• Amyotrophic Lateral Sclerosis (Orphan)

Oral suspension (Teglutik [brand name]): Orphan designation for amyotrophic lateral sclerosis (ALS)

Sponsor
Italfarmaco SpA; 54 Via dei Lavoratori; Cinisello Balsamo, Italy

Interactions

Contraindicated (0)
Serious (2)
givosiran
leniolisib

Monitor Closely (17)
bupivacaine implant
cannabidiol
ciprofloxacin
dichlorphenamide
elranatamab
enasidenib
epcoritamab
fexinidazole
fluvoxamine
glofitamab
pefloxacin
ritlecitinib
rucaparib
stiripentol
talquetamab
teriflunomide
viloxazine

Minor (19)
amobarbital
armodafinil
butabarbital
butalbital
carbamazepine
cigarette smoking
cimetidine
food
mexiletine
peginterferon alfa 2a
pentobarbital
phenobarbital
pipemidic acid
primidone
rifampin
smoking
tobacco use
verapamil
zileuton

Adverse Effects
>10%
Oral hypoesthesia (29%)

Asthenia (19%)

Nausea (16%)

1-10%

Decreased lung function (10%)

Hypertension (5%)

Abdominal pain (5%)

Vomiting (4%)

Arthralgia (4%)

Dizziness (4%)

Dry mouth (4%)

Insomnia (4%)

Pruritus (4%)

Tachycardia (3%)

Flatulence (3%)

Increased cough (3%)

Peripheral edema (3%)

Urinary tract infection (3%)

Circumoral paresthesia (2%)

Somnolence (2%)

Vertigo (2%)

Eczema (2%)

Postmarketing Reports
Acute hepatitis

Icteric toxic hepatitis

Renal tubular impairment

Pancreatitis

Warnings
Contraindications
Hypersensitivity to drug or any component of the formulation

Cautions

Cases of severe neutropenia (absolute neutrophil count <500/mm3) within first 2 months of treatment reported; advise patients to report febrile illnesses

Interstitial lung disease, including hypersensitivity pneumonitis, reported in patients receiving therapy; discontinue immediately if interstitial lung disease develops

Hepatic injury

• Cases of drug-induced liver injury reported; asymptomatic elevations of hepatic transaminases reported and recurred in some patients upon rechallenging treatment (see Dosage Modifications)
• Monitor patients for signs and symptoms of hepatic injury, every month for first 3 months of treatment, and periodically thereafter; use is not recommended if patients develop hepatic transaminase levels greater than 5 times the ULN; discontinue therapy if there is evidence of liver dysfunction (eg, elevated bilirubin)
• Case reports of clinical hepatitis reported

Drug interactions overview

• Riluzole is a CYP1A substrate
• CYP1A2 inhibitors

1. In vitro findings suggest coadministration of riluzole with CYP1A2 inhibitors may increase in riluzole exposure
2. Coadministration with strong or moderate CYP1A2 inhibitors (eg, ciprofloxacin, enoxacin, fluvoxamine, methoxsalen, mexiletine, oral contraceptives, thiabendazole, vemurafenib, zileuton) may increase risk of riluzole-associated adverse reactions

• CYP1A2 inducers

In vitro findings suggest coadministration with CYP1A2 inducers may decrease in riluzole exposure, which may result in decreased efficacy

• Hepatotoxic drugs

Clinical trials in ALS patients excluded patients on concomitant medications which were potentially hepatotoxic (eg, allopurinol, methyldopa, sulfasalazine)

Pregnancy & Lactation
Pregnancy
There are no studies in pregnant women, and case reports have been inadequate to inform of drug-associated risk

Unknown if risk of major birth defects and miscarriage in patients with amyotrophic lateral sclerosis

Animal data

• In studies in which riluzole was orally administered to pregnant animals, developmental toxicity (decreased embryofetal/offspring viability, growth, and functional development) was observed at clinically relevant doses
• Based on these results, advise women of possible risks to fetus associated with use of riluzole during pregnancy
• In rats, oral administration of riluzole resulted in decreased fertility indices and increases in embryo lethality

Lactation
Unknown if distributed in human breast milk

Riluzole or its metabolites have been detected in milk of lactating rat

Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition

Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.

Pharmacology
Mechanism of Action
Benzothiazole

Mechanism of action in patients with ALS is unknown

Absorption
Bioavailability: ~60%

Peak plasma time: 0.8 hr

Food effects
Tablet: Decreases AUC by 20% and peak plasma concentration by 45%
Suspension: Decreases AUC by 9% and peak plasma concentration by 55%

Distribution
Protein binding: 96% (mainly to albumin and lipoproteins)

Metabolism
Metabolized by oxidation via CYP1A2

Direct and sequential glucuronidation: UGT-HP4

Metabolites: 6 major metabolites, some active

Elimination
Half-life: 12 hr

Accumulation: ~ 2-fold

Excretion: Feces (5%); urine (90%)

Pharmacogenomics
Patients of Japanese descent are more likely to have higher riluzole concentrations

In pharmacokinetic analyses, clearance was 50% lower in Japanese males compared with Caucasians, after normalizing for body weight

Mean AUC ~45% higher in females compared with males

Clearance in tobacco smokers is 20% greater than nonsmokers

Administration
Oral Administration
Administer at 1 hr before or 2 hr after a meal

Suspension: Gently shake bottle at least 30 sec prior to administration

Oral film

• Instruct patients and/or caregivers to read the “Instruction for Use” carefully for complete directions on how to properly dose and administer oral films
• Apply on top of the tongue where it adheres and dissolves
• Do not cut or split the film
• Do not administer with liquids
• As film dissolves, swallow saliva in a normal manner, but refrain from chewing, spitting or talking
• Take only 1 oral film at a time

Storage

Tablets and oral films: Store at 20-25ºC (68-77ºF), excursions permitted to 15-30ºC (59-86ºF)

Suspension

• Store at 20-25ºC (68-77ºF), excursions permitted to 15-30ºC (59-86ºF)
• Protect from bright light, do not freeze
• Discard after 15 days of initially opening of the bottle

Write a review