31/19. Stiripentol- (DIACOMIT) @ - ( Aug- 2018) to treat seizures associated with Dravet syndrome
Drug Name:31/19. Stiripentol- (DIACOMIT) @ - ( Aug- 2018) to treat seizures associated with Dravet syndrome
List Of Brands:
Indication Type Description:
Drug Interaction
Indication
Adverse Reaction
Contra-Indications
Dosages/ Overdosage Etc
Patient Information
Pharmacology/ Pharmacokinetics
Pregnancy and lactation
Drug Interaction:
DRUG INTERACTIONS-
• DIACOMIT increases the plasma concentration of clobazam and its metabolite through metabolic inhibition of CYP3A4 and CYP2C19. Consider dose reduction of clobazam in case of adverse reactions. • Substrates of CYP2C8, CYP2C19, P-gp and BCRP may require a dose reduction. • Substrates of CYP1A2, CYP2B6 and CYP3A4 may require a dose adjustment. • Strong inducers of CYP1A2, CYP3A4 or CYP2C19: Consider dose increase of DIACOMIT
Indication:
U.S. FDA APPROVED DRUGS DURING 2018
Sr.No- 31
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use DIACOMIT safely and effectively. See full prescribing information for D DIACOMIT (stiripentol) capsules, for oral use DIACOMIT (stiripentol) powder, for oral suspension
Initial U.S. Approval: 2018
INDICATIONS AND USAGE
DIACOMIT is indicated for the treatment of seizures associated with Dravet syndrome in patients 2 years of age and older taking clobazam. There are no clinical data to support the use of DIACOMIT as monotherapy in Dravet syndrome.
Adverse Reaction:
ADVERSE REACTIONS-
Adverse reactions that occurred in at least 10% of DIACOMIT-treated patients and more frequently than on placebo were somnolence, decreased appetite, agitation, ataxia, weight decreased, hypotonia, nausea, tremor, dysarthria, and insomnia.
DRUG INTERACTIONS-
• DIACOMIT increases the plasma concentration of clobazam and its metabolite through metabolic inhibition of CYP3A4 and CYP2C19. Consider dose reduction of clobazam in case of adverse reactions. • Substrates of CYP2C8, CYP2C19, P-gp and BCRP may require a dose reduction.
• Substrates of CYP1A2, CYP2B6 and CYP3A4 may require a dose adjustment. • Strong inducers of CYP1A2, CYP3A4 or CYP2C19: Consider dose increase of DIACOMIT
Contra-Indications:
CONTRAINDICATIONS- None
WARNINGS AND PRECAUTIONS-
•Somnolence: Monitor for somnolence, particularly when DIACOMIT is used concomitantly with other CNS depressants; If somnolence occurs during co-administration with clobazam, consider an initial reduction of clobazam by 25%.
• Decreased Appetite and Decreased Weight: the weight of patients and the growth rate of pediatric patients should be carefully monitored.
• Neutropenia and Thrombocytopenia: Blood counts should be obtained prior to starting treatment with DIACOMIT and then every 6 months.
• Withdrawal: DIACOMIT should be gradually withdrawn to minimize the risk of increased seizure frequency and status epilepticus.
• Risks in Patients with Phenylketonuria (PKU): DIACOMIT powder for suspension contains phenylalanine; consider total daily intake before prescribing to patients with PKU.
• Suicidal Behavior and Ideation: Monitor for suicidal thoughts or behaviors.
Dosages/ Overdosage Etc:
INDICATIONS AND USAGE
DIACOMIT is indicated for the treatment of seizures associated with Dravet syndrome in patients 2 years of age and older taking clobazam. There are no clinical data to support the use of DIACOMIT as monotherapy in Dravet syndrome.
DOSAGE AND ADMINISTRATION-
• The dosage of DIACOMIT is 50 mg/kg/day, administered by mouth in 2 or 3 divided doses. • Reduce dose or discontinue dose gradually. • Capsules must be swallowed whole with a glass of water during a meal. Capsules should not be broken or opened. • Powder for suspension should be mixed in a glass of water and should be taken immediately after mixing during a meal.
DOSAGE FORMS AND STRENGTHS- • Capsule: 250 mg or 500 mg • Powder for Oral Suspension: 250 mg or 500 mg
Patient Information:
PATIENT COUNSELING INFORMATION-
Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).
DIACOMIT Oral Capsule Administration- Inform patients or caregivers that DIACOMIT capsules must be swallowed whole with a glass of water during a meal. Capsules should not be broken or opened.
DIACOMIT Powder for Oral Suspension Administration DIACOMIT should be mixed in a glass of water and should be taken immediately after mixing during a meal [see Instructions for Use].
Somnolence - Advise patient or caregivers that somnolence may occur, and may require a decrease in the dose of clobazam .
Also, advise the patients and their caregivers to avoid alcohol consumption during DIACOMIT treatment.
If applicable, caution patients about hazardous machinery, including automobiles, until they know how DIACOMIT affects them.
Decreased Appetite and Decreased Weight - Advise patients or caregivers that decreased appetite is frequent and nausea and vomiting can also occur during DIACOMIT treatment, which can cause loss of weight
Withdrawal Symptoms- Advise patients or caregivers that abrupt withdrawal of DIACOMIT may increase their risk of seizures or status epilepticus
Instruct patients or caregivers to not discontinue use of DIACOMIT without consulting with their healthcare provider.
Neutropenia and Thrombocytopenia - Advise patients or caregivers of the risk of neutropenia and thrombocytopenia and the importance of hematologic testing, which should be obtained prior to starting treatment with DIACOMIT and then every 6 months.
Suicidal Thinking and Behavior- Counsel patients, their caregivers, and their families that AEDs, including DIACOMIT, may increase the risk of suicidal thoughts and behavior and advise them of the need to be alert for the emergence of worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thought of self-harm.
Patients or caregivers should report behaviors of concern immediately to healthcare providers.
Use in Pregnancy- Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during DIACOMIT therapy. Encourage patients to enroll in the NAAED Pregnancy registry if they become pregnant. This registry is collecting information about the safety of AEDs during pregnancy.
Use in Nursing - Instruct patients to notify their physician if they are breast feeding or intend to breast feed during therapy
Storage- Store in a dry place at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Store in original package to protect from light.
DIACOMIT Capsules and DIACOMIT Powder for Suspension manufactured by: BIOCODEX 1, avenue Blaise Pascal 60000 BEAUVAIS France
Pharmacology/ Pharmacokinetics:
CLINICAL PHARMACOLOGY-
1. Mechanism of Action- The mechanism by which DIACOMIT exerts its anticonvulsant effect in humans is unknown. Possible mechanisms of action include direct effects mediated through the gamma-aminobutyric acid (GABA)A receptor and indirect effects involving inhibition of cytochrome P450 activity with resulting increase in blood levels of clobazam and its active metabolite.
2. Pharmacodynamics - There are no relevant data on the pharmacodynamic effects of DIACOMIT.
3. Pharmacokinetics- The following pharmacokinetic properties of stiripentol have been found in studies in adult healthy volunteers and adult patients. Systemic exposure of stiripentol increases in a greater than dose proportional manner from 500 mg to 2000 mg.
Absorption: The median time to stiripentol peak plasma concentration is 2 to 3 hours.
Distribution: Protein binding of stiripentol is 99%.
Elimination: The elimination half-life of stiripentol ranges from 4.5 to 13 hours, increasing with doses of 500 mg, 1000 mg and 2000 mg.
Metabolism: On the basis of in vitro studies, the main liver cytochrome P450 (CYP) isoenzymes involved in metabolism are considered to be CYP1A2, CYP2C19, and CYP3A4.
Specific Populations- The effect of age (= 65 years), race, renal and hepatic impairment on stiripentol pharmacokinetics is unknown.
Sex does not have a clinically significant effect on the pharmacokinetics of DIACOMIT.
Pediatric Patients: In a study of children (median age 7.3 years) with Dravet syndrome treated with DIACOMIT, valproate, and clobazam, the apparent clearance and volume of distribution of stiripentol were related to body weight. Elimination half-life increased from 8.5 hr (for 10 kg) to 23.5 hr (for 60 kg).
Drug Interaction Studies- In Vitro Studies- The metabolic pathway for stiripentol has not been clearly elucidated. Stiripentol is a substrate of several CYP enzymes, including CYP1A2, CYP2C19, and CYP3A4. Stiripentol inhibits and induces CYP1A2, CYP2B6, and CYP3A4. Stiripentol also inhibits CYP2C8, CYP2C19, and drug transporters, including P-gp and BCRP, at clinically relevant concentrations.
Clinical Studies Antiepileptic drugs: Co-administration of clobazam with stiripentol increased concentrations of clobazam by approximately 2-fold and norclobazam (clobazam active metabolite) by 5-fold
Pregnancy and lactation:
USE IN SPECIFIC POPULATIONS-
1 Pregnancy - Pregnancy -Exposure Registry- There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, such as DIACOMIT, during pregnancy. Physicians are advised to recommend that pregnant patients taking DIACOMIT enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry.
Risk Summary- There are no adequate data on the developmental risks associated with the use of DIACOMIT in pregnant women.
The background risk of major birth defects and miscarriage in Dravet syndrome is unknown.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
2. Lactation- Risk Summary- There are no data on the presence of stiripentol in human milk, the effects on the breastfed infant, or the effects on milk production.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for DIACOMIT and any potential adverse effects on the breastfed infant from DIACOMIT or from the underlying maternal condition.
3. Pediatric Use- The safety and effectiveness of DIACOMIT for the treatment of seizures associated with Dravet syndrome in patients taking clobazam have been established in patients 2 to 18 years of age.
Use of DIACOMIT in this pediatric population is supported by 2 multicenter placebo-controlled double-blind randomized studies. Safety and effectiveness in pediatric patients below the age of 2 years have not been established.
4 Geriatric Use- Clinical studies of DIACOMIT in Dravet syndrome did not include patients =65 years of age to determine whether they respond differently from younger patients. The possibility of ageassociated hepatic and renal function abnormalities should be considered when using DIACOMIT in patients =65 years of age.
5. Renal Impairment - There is no formal study of the pharmacokinetics and metabolism of DIACOMIT in patients with renal impairment. However, since DIACOMIT metabolites are eliminated mainly through Kidney, administration to patients with moderate or severe renal impairment is not recommended.
6. Hepatic Impairment- There has been no formal study of the pharmacokinetics of DIACOMIT in patients with liver impairment. However, since the drug is mainly metabolized by the liver, administration to patients with moderate or severe liver impairment is not recommended.
OVERDOSAGE- There are no data concerning overdose in humans. In mice treated with high doses of stiripentol (600 to 1800 mg/kg i.p.), decreased motor activity and decreased respiration were observed. Treatment of an overdose should be supportive (symptomatic measures in intensive care units). For management of a suspected drug overdose, contact your regional Poison Control Center.