Diacomit

Uses

Diacomit is an anticonvulsant agent used with clobazam and valproate as an adjunct to treat refractory generalized tonic-clonic seizures in Dravet syndrome.

Indicated for use in conjunction with clobazam and valproate as adjunctive therapy of refractory generalized tonic-clonic seizures in patients with severe myoclonic epilepsy in infancy (SMEI, Dravet’s syndrome) whose seizures are not adequately controlled with clobazam and valproate.

Diacomit is also used to associated treatment for these conditions: Dravet Syndrome

How Diacomit works

Diacomit enhances GABAergic inhibition and prolongs the open duration of GABA-A receptor chloride channels by a barbiturate-like mechanism . It binds to GABA-A receptors containing any of the α, β, γ, or δ-subunits but displays strongest potency when bound to receptors containing α3 or δ subunits . Diacomit is an inhibitor of lactate dehydrogenase (LDH), which plays a physiological role in energy metabolism of neurons and regulation of neuronal excitation. It binds to the site separate from lactate and pyruvate binding sites of the enzyme and inhibits both pyruvate-to-lactate conversion and lactate-to-pyruvate conversion . LDH inhibitors including stiripentol as antiepileptic treatments mimic ketogenic diet, where the energy source in the brain is switched from glucose to mainly ketone bodies. The ketone bodies directly regulate neuronal excitation and seizures via ATP-sensitive potassium channels and vesicular glutamate transporters . As a potent inhibitor of hepatic cytochrome P450 enzymes, mainly CYP3A4 and CYP2C19, stiripentol co-administration with other antiepileptic drugs elevates the free unchanged active drugs (such as carbamazepine, sodium valproate, phenytoin, phenobarbital and many benzodiazepines) in the circulation to mediate their therapeutic actions.

Toxicity

Most common adverse effects include anorexia, loss of appetite, nausea, vomiting, weight loss, reversible neutropenia, insomnia, drowsiness, ataxia, dystonia, hyperkinesia, hypotonia. Aggression, irritability, behaviour disorders, opposing behaviour, hyper excitability and sleep disorders may also be observed. Diacomit does not demonstrate teratogenic, mutagenic, clastogenic, or carcinogenic potential . Oral LD50 in rats is >3 g/kg .

Food Interaction

• Avoid alcohol. Ingesting alcohol may increase the dizziness and drowsiness that can be caused by stiripentol.
• Avoid St. John's Wort. This herb induces the CYP3A metabolism of stiripentol and may reduce its serum concentration.
• Take with a full glass of water.
• Take with food.

[Moderate] GENERALLY AVOID: Taking stiripentol on an empty stomach may reduce its oral bioavailability.

Diacomit degrades rapidly when exposed to gastric acid in an empty stomach.

GENERALLY AVOID: Alcohol may potentiate the depressant effects of stiripentol on the central nervous system.

Concomitant use may result in increased sedation and dizziness as well as impairment of psychomotor skills.

GENERALLY AVOID: It is not known whether stiripentol may reduce theophylline and caffeine metabolism, as data on the potential for inhibition of CYP450 1A2 are limited.

Consumption of foods and nutritional products such as cola drinks (which contain significant quantities of caffeine) and chocolate (which contains caffeine and trace amounts of theophylline) may be unsafe during treatment with stiripentol, particularly in children.

MANAGEMENT: Diacomit should be taken during a meal for optimal absorption; however, it should not be taken with milk, dairy products (e.g., yogurt, soft cream cheese), fruit juice, or carbonated beverages.

Patients should be advised to avoid or limit consumption of alcohol and to avoid activities requiring mental alertness such as driving or operating hazardous machinery until they know how the medication affects them.

Food and beverages that may contain caffeine or theophylline such as colas, chocolate, coffee, tea, or energy drinks should also be avoided during treatment with stiripentol.

Diacomit Drug Interaction

Moderate: divalproex sodium, ethanol, lithium, tramadolUnknown: charcoal, levocarnitine, sulfamethoxazole / trimethoprim, ubiquinone, copper gluconate, glycerin, heparin, sodium iodide, arginine, levocarnitine, cysteine, acetaminophen, bioflavonoids, vitamin a topical, bioflavonoids, sotalol

Diacomit Disease Interaction

Moderate: suicidal tendency, neutropenia/thrombocytopenia, phenylketonuria, decreased appetite/weight, hepatic impairment, renal impairment, somnolence

Volume of Distribution

The average volume of distribution is 1.03 L/kg but does not display a dose-dependent relationship. It is expected to be distributed into the extravascular space and with a high degree of tissue binding .

Elimination Route

Absorption of stiripentol is quick with the peak plasma concentration reached within 1.5 hours following oral administration. The systemic exposure increases in a dose-proportional relationship . It is rapidly taken up into the brain and enters the cerebellum and medulla. It displays low bioavailability due to water insolubility and metabolism .

Half Life

Elimination half life is approximately ranges from 4.5 to 13 hours, in a dose-dependent manner .

Clearance

Plasma clearance decreases markedly at high doses; it falls from approximately 40 L/kg/day at the dose of 600 mg/day to about 8 L/kg/day at the dose of 2,400 mg . Decreased clearance is probably explained by inhibition of the cytochrome P450 isoenzymes that catalyzes stiripentol metabolism .

Elimination Route

Renal elimination is mainly responsible for excretion of stiripentol. About 73% of total administered dose is found in urine as metabolites, while further 13-24% of the total dose is recovered in faeces as unchanged substance .

Innovators Monograph

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