stiripentol 250 MG Powder for Oral Suspension [Diacomit]

INDICATIONS AND USAGE DIACOMIT is indicated for the treatment of seizures associated with Dravet syndrome (DS) in patients taking clobazam who are 6 months of age and older and weighing 7 kg or more. There are no clinical data to support the use of DIACOMIT as monotherapy in Dravet syndrome. DIACOMIT is indicated for the treatment of seizures associated with Dravet syndrome in patients taking clobazam who are 6 months of age and older and weighing 7 kg or more . There are no clinical data to support the use of DIACOMIT as monotherapy in Dravet syndrome. ( 1 )

DOSAGE AND ADMINISTRATION The dosage of DIACOMIT is 50 mg/kg/day, administered by mouth in 2 or 3 divided doses, depending on age and weight. ( 2.2 ) Capsules must be swallowed whole with a glass of water during a meal. Capsules should not be broken or opened. ( 2.3 ) Powder for suspension should be mixed in a glass of water and should be taken immediately after mixing during a meal. ( 2.3 ) Reduce dose or discontinue dose gradually. ( 2.5 ) 2.1 Laboratory Tests Prior to First Dose of DIACOMIT Hematologic testing should be obtained prior to starting treatment with DIACOMIT [see Warnings and Precautions (5.3) ]. 2.2 Dosing Information The recommended oral dosage of DIACOMIT is 50 mg/kg/day, administered in 2 or 3 divided doses (i.e., 16.67 mg/kg three times daily or 25 mg/kg twice daily), depending on the patient’s age and body weight as shown in Table 1. If the exact dosage is not achievable given the available strengths, round to the nearest possible dosage, which is usually within 50 mg to 150 mg of the recommended 50 mg/kg/day. A combination of the two DIACOMIT strengths can be used to achieve this dosage. The maximum recommended total dosage is 3,000 mg/day. Table 1. Recommended Dosage for Patients 6 Months of Age and Older Weighing 7 kg or More with Dravet Syndrome Age of Patient Body Weight Dosing Regimen (administered by mouth in equally divided doses) Total Daily Dose 6 months to less than 1 year 7 kg and above 25 mg/kg twice daily a,b 50 mg/kg/day 1 year and above 7 kg to less than 10 kg 25 mg/kg twice daily b 50 mg/kg/day 10 kg and above 25 mg/kg twice daily or 16.67 mg/kg three times daily 50 mg/kg/day Maximum daily dose is 3000 mg a Dosing frequency should not exceed twice daily to limit free water administration. b Dosing frequency should not exceed twice daily to avoid overexposures. 2.3 Administration Instructions DIACOMIT Capsules DIACOMIT capsules must be swallowed whole with a glass of water during a meal. Capsules should not be broken or opened. DIACOMIT for Oral Suspension DIACOMIT should be mixed in a glass of water (100 mL) and should be taken immediately after mixing during a meal. To be sure there is no medicine left in the glass, add a small amount of water (25 mL) to the drinking cup and drink all of the mixture [see Instructions for Use ] . 2.4 Missed Dose A missed dose should be taken as soon as possible. If it is almost time for the next dose, the missed dose should not be taken. Instead, the next scheduled dose should be taken. Doses should not be doubled. 2.5 Discontinuation of DIACOMIT As is advisable for most antiepileptic drugs, if DIACOMIT treatment is discontinued, the drug should be withdrawn gradually to minimize the risk of increased seizure frequency and status epilepticus [see Warnings and Precautions ( 5.4 )]. In situations where rapid withdrawal of DIACOMIT is medically required, appropriate monitoring is recommended.

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%. ( 5.1 ) Decreased Appetite and Decreased Weight: the weight of patients and the growth rate of pediatric patients should be carefully monitored. ( 5.2 ) Neutropenia and Thrombocytopenia: Blood counts should be obtained prior to starting treatment with DIACOMIT and then every 6 months. ( 5.3 ) Withdrawal : DIACOMIT should be gradually withdrawn to minimize the risk of increased seizure frequency and status epilepticus. ( 5.4 ) Risks in Patients with Phenylketonuria (PKU) : DIACOMIT for oral suspension contains phenylalanine; consider total daily intake before prescribing to patients with PKU. ( 5.5 ) Suicidal Behavior and Ideation : Monitor for suicidal thoughts or behaviors. ( 5.6 ) 5.1 Somnolence DIACOMIT can cause somnolence. In controlled studies in patients with Dravet syndrome, the incidence of somnolence was 67% in DIACOMIT-treated patients, compared to 23% in patients on placebo. All patients in both groups were on concomitant clobazam, which is also known to cause somnolence. Co-administration of DIACOMIT with clobazam results in increased levels of clobazam and its active metabolite [see Drug Interactions (7.1) ]. Other central nervous system CNS depressants, including alcohol, could potentiate the somnolence effect of DIACOMIT. Prescribers should monitor patients for somnolence. If somnolence occurs during co-administration with clobazam, consider an initial reduction of clobazam by 25%. If somnolence persists, further clobazam reduction by an additional 25% should be considered, as should adjustment of the dosage of other concomitant anticonvulsant drugs with sedating properties. Prescribers should caution patients against engaging in hazardous activities requiring mental alertness, such as operating dangerous machinery or motor vehicles, until the effect of DIACOMIT on mental alertness is known. 5.2 Decreased Appetite and Decreased Weight DIACOMIT can cause decreases in appetite and weight. In controlled studies in patients with Dravet syndrome, the incidence of decreased appetite was 46% in DIACOMIT-treated patients, compared to 10% in patients on placebo. The incidence of decreased weight was 27% in DIACOMIT-treated patients, compared to 6% in patients on placebo. Nausea and vomiting also occurred more frequently in DIACOMIT-treated patients [see Adverse Reactions (6.1) ] . Given the frequency of these adverse reactions, the growth of pediatric patients treated with DIACOMIT should be carefully monitored. In some cases, decreasing the dose of concomitant valproate by 30% per week can reduce the decrease in appetite and weight. 5.3 Neutropenia and Thrombocytopenia DIACOMIT can cause a significant decline in neutrophil count. In controlled studies in patients with Dravet syndrome, there were 31 patients treated with DIACOMIT who had both a baseline and end-of-study neutrophil count obtained. A decrease in neutrophil count from normal at baseline to less than 1500 cells/mm 3 during the trial was observed in 13% of these DIACOMIT- treated patients, but not in any placebo-treated patients. DIACOMIT can cause a significant decline in platelet count. In controlled studies in patients with Dravet syndrome, there were 31 patients treated with DIACOMIT who had both a baseline and end-of-study platelet count. A decrease in platelet count from normal at baseline to less than 150,000/µL during the trial was observed in 13% of these DIACOMIT-treated patients, but not in any placebo-treated patients. Hematologic testing should be obtained prior to starting treatment with DIACOMIT, and then every 6 months. 5.4 Withdrawal of Antiepileptic Drugs As with most antiepileptic drugs, DIACOMIT should generally be withdrawn gradually to minimize the risk of increased seizure frequency and status epilepticus . In situations where rapid withdrawal of DIACOMIT is required (e.g., in the setting of a serious adverse reaction), appropriate monitoring is recommended. 5.5 Risks in Patients with Phenylketonuria Phenylalanine can be harmful to patients with phenylketonuria (PKU). DIACOMIT for oral suspension contains phenylalanine, a component of aspartame. Each 250 mg packet contains 1.40 mg phenylalanine; each 500 mg packet contains 2.80 mg phenylalanine. Before prescribing DIACOMIT for oral Suspension to a patient with PKU, consider the combined daily amount of phenylalanine from all sources, including DIACOMIT for oral Suspension. DIACOMIT capsules do not contain phenylalanine. 5.6 Suicidal Behavior and Ideation AEDs, including DIACOMIT, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted relative risk 1.8, 95% confidence interval [CI]:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED treated patients was 0.43%, compared to 0.24% among 16,029 placebo treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug treated patients in the trials and none in placebo treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs. Table 2. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events per 1000 Patients Drug Patients with Events per 1000 Patients Relative Risk: Incidence of Drug Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events per 1000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing DIACOMIT or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that AEDs increase

CONTRAINDICATIONS None. None ( 4 )

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.