Mnemonic phrase: “Riled tech (with) Real uzi”
Pronunciation: RIL yoo zole / RIL yoo tek
Interactions: CYP1A2 substrate (tree)
Year approved: 1995
Cost: $36 (GoodRx) – $1,700
❖ Neuroprotectant
❖ Antiepileptic
❖ Anti-glutamatergic
❖ Voltage-gated Na+ channel blocker
FDA-approved for:
❖ Amyotrophic lateral sclerosis (ALS)
Used off-label for:
❖ Seizure disorders
❖ Multiple sclerosis
❖ Obsessive-compulsive disorder
❖ Depression (experimental)
Riluzole (Rilutek) was the first drug approved (1995) for the treatment of amyotrophic lateral sclerosis (ALS). It has neuroprotective, anticonvulsant, anxiolytic and anesthetic qualities. It is a promising candidate for treatment of psychiatric disorders. Its mechanisms overlap with traditional mood stabilizers, particularly lamotrigine (Lamictal). Mechanisms also overlap with ketamine and N-acetylcysteine (NAC).
Riluzole is an evidence-based third-line adjunctive treatment for OCD (Osser, 2021). It may have potential as an antidepressant. It may prove useful as an off-label treatment for bipolar depression. It is being studied for treatment-resistant anxiety disorders. It was found ineffective for PTSD.
ALS, also known as Lou Gehrig's disease, is a progressive neurodegenerative disease affecting motor neurons. Mean survival with ALS is 2–5 years after diagnosis. Dr Stephen Hawking lived more than 50 years with ALS, although with extraordinary support. Dr Hawking communicated through a voice synthesizer using a thumb switch and a blink-switch attached to his glasses.
The pathophysiology of ALS appears to involve sensitivity of motor neurons to damage by glutamate, the brain’s main excitatory neurotransmitter. Riluzole blocks glutamatergic neurotransmission by several mechanisms. Riluzole also inhibits protein kinase CK1δ, which plays a key role in TDP-43 proteinopathy, a pathological hallmark of ALS.
In ALS, riluzole improves overall survival (74% vs. 58% placebo at 12 months) and survival without tracheostomy (57% vs. 50% at 18 months).
In addition to modulating glutamate, riluzole has other antiepileptic mechanisms including blocking voltage-sensitive sodium channels and potentiating GABA(A) receptors (via an allosteric binding site). It also inhibits NMDA receptors, among other putative mechanisms.
Risks/Side Effects
Riluzole elevates liver enzymes. ~50% of riluzole-treated patients will experience at least one ALT/AST level above the upper limit of normal (ULN), ~8% will have elevations > 3x ULN, and about ~2% will have elevations > 5x ULN. Due to potential for liver injury, riluzole should be stopped if several LFTs (especially bilirubin) are elevated. Maximum increases in ALT usually occurred within 3 months of starting riluzole and were usually transient when < 5x ULN. There was one reported fatality due to riluzole-induced hepatitis. Patients should be discouraged from drinking excessive amounts of alcohol.
A single non-ALS patient with epilepsy treated with concomitant carbamazepine and phenobarbital experienced marked, rapid elevations of liver enzymes with jaundice (ALT 26x ULN, AST 17x ULN, and bilirubin 11x ULN) four months after starting riluzole. LFTs returned to normal 7 weeks after treatment discontinuation.
Among ~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. Patients should be warned to report any febrile illness to their physician to prompt checking WBC counts.
Patients should be warned about the potential for dizziness, vertigo, or somnolence and advised not to drive or operate machinery until tolerability is established.
Other side effects may include included asthenia (generalized weakness), headache, nausea, and abdominal pain.
Pharmacokinetics
A high fat meal decreases absorption of riluzole, reducing area-under-the-curve (AUC) by about 20% and peak blood levels by about 45%. Elimination half-life is ~12 hours. Riluzole is ~96% protein bound (to albumin and lipoproteins) at usual doses.
Metabolism of riluzole is mostly hepatic involving CYP1A2 and UGT-HP4. As with other 1A2 substrates (trees), blood levels tend to be higher in females (increase in AUC of ~45%)
AUC is increased ~1.7-fold in mild liver insufficiency and ~3-fold in moderate liver insufficiency. AUC is not affected by renal insufficiency or in individuals ≥ 70 years. As seen with other CYP1A2 substrates, riluzole levels tend to be higher in females and lower in smokers.
Dynamic interactions:
❖ Sedation / CNS depression
❖ Hepatotoxicity
❖ Neutropenia
Kinetic interactions:
❖ 1A2 substrate (tree)
❖ UGT-HP4 substrate
❖ Protein-bound
❖ Decreased absorption with food
Dosing
For ALS, the approved dose is 50 mg every 12 hours on an empty stomach (at least an hour before or two hours after a meal) to avoid a food-related decrease in bioavailability. Check liver enzymes prior to starting riluzole and every month x3, then every 3 months x3, then periodically. For psychiatric indications, a total daily dose of 100–200 mg was used.
Explanation of the interaction mnemonic framework can be found in Cafer's Psychopharmacology: Visualize to Memorize 270 Medication Mascots
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