Stiripentol

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 )

Capsules 250 mg: size 2, pink, and imprinted with “Diacomit” and “250mg” 500 mg: size 0, white, and imprinted with “Diacomit” and “500mg” For Oral Suspension Pale pink fruit flavored powder packaged in packets. Each packet contains either 250 mg or 500 mg of stiripentol Capsule: 250 mg or 500 mg ( 3 ) For Oral Suspension: 250 mg or 500 mg ( 3 )

None. None ( 4 )

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 ( 5.3 ) Withdrawal : DIACOMIT should be gradually withdrawn to minimize the risk of increased seizure frequency and status epilepticus.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. […]

The following serious or otherwise clinically significant adverse reactions are described elsewhere in the labeling: Somnolence [see Warnings and Precautions (5.1) ] Decreased Appetite and Decreased Weight [see Warnings and Precautions (5.2) ] Neutropenia and Thrombocytopenia [see Warnings and Precautions (5.3) ] Withdrawal Symptoms [see Warnings and Precautions (5.4) ] Risks in Patients with Phenylketonuria [see Warnings and Precautions (5.5) ] Suicidal Behavior and Ideation [see Warnings and Precautions (5.6) ] 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact BIOCODEX at 1-866-330-3050 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug, and may not reflect the rates observed in practice. During its development for the treatment of seizures associated with Dravet syndrome, DIACOMIT was administered to 55 healthy male volunteers and 438 patients with Dravet syndrome, including 310 patients treated for 12 months or more. The conditions and duration of exposure varied greatly, and included single- and multiple-dose clinical pharmacology studies in healthy male volunteers, 2 randomized, double-blind, placebo-controlled, 12-week studies in patients with Dravet syndrome (Sticlo France and Sticlo Italy), and open-label long-term studies. In Sticlo France and Sticlo Italy, 33 patients received DIACOMIT and 31 patients received placebo for a treatment duration of 8 weeks [see Clinical Studies ( 14 )] . Adverse reactions from these trials are presented below. Approximately 53% of patients were female and the mean age was 9.2 years. All patients were taking clobazam and valproate. There were 2 patients in whom adverse reactions led to discontinuation of DIACOMIT treatment: one patient had an adverse reaction of status epilepticus; the second patient had drowsiness, balance impaired and sialorrhea. The most common adverse reactions, occurring in at least 10% of DIACOMIT-treated patients and more frequently than on placebo, included somnolence (67%), decreased appetite (45%), agitation (27%), ataxia (27%), weight decreased (27%), hypotonia (24%), nausea (15%), tremor (15%), dysarthria (12%), and insomnia (12%). Table 3 lists the adverse reactions that occurred in 5% or more of DIACOMIT-treated patients and at a rate greater than in patients on placebo in the 2 randomized, double-blind, placebo-controlled, clinical trials in patients with Dravet syndrome (Sticlo France and Sticlo Italy). Table 3. Adverse Reactions in 5% or More of DIACOMIT-Treated Patients and More Frequently than on Placebo in Patients with Dravet Syndrome (Sticlo France and Sticlo Italy) Sticlo France and Sticlo Italy– Pooled Total DIACOMIT (50mg/kg/day) Placebo Adverse Reactions N=33 % N=31 % Gastrointestinal disorders Nausea 15 3 Vomiting 9 0 Salivary hypersecretion 6 0 General disorders and administration site conditions Fatigue 9 3 Pyrexia 6 3 Infections and infestations Bronchitis 6 0 Nasopharyngitis 6 0 Investigations Weight decreased 27 6 Weight increased 6 3 Metabolism and nutrition disorders Decreased appetite 46 10 Nervous system disorders Somnolence 67 23 Ataxia 27 23 Hypotonia 18 13 Tremor 15 10 Dysarthria 12 0 Psychiatric disorders Agitation 27 16 Insomnia 12 7 Aggression 9 0 Adverse Reactions in Pediatric Patients 6 months to Less Than 2 Years of Age In five open-label studies including pediatric patients 6 months to less than 2 years of age with Dravet syndrome, a total of 106 patients received DIACOMIT, with 81 patients exposed for at least 6 months, and 69 patients exposed for at least 1 year. Adverse reactions in pediatric patients with Dravet syndrome who were 6 months to less than 2 years of age were similar to those seen in patients in Sticlo France and Sticlo Italy.

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of DIACOMIT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Infections and infestations: Pneumonia

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. ( 7.1 ) Substrates of CYP2C8, CYP2C19, P-gp and BCRP may require a dose reduction. (7.1) Substrates of CYP1A2, CYP2B6 and CYP3A4 may require a dose adjustment. ( 7.1 ) Strong inducers of CYP1A2, CYP3A4 or CYP2C19: Consider dose increase of DIACOMIT. ( 7.2 )

7.1 Effect of DIACOMIT on Other Drugs CYP1A2, CYP2B6, CYP3A4, CYP2C8, CYP2C19, P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) Substrates In vitro data show that stiripentol is both an inhibitor and inducer of CYP1A2, CYP2B6, and CYP3A4. Because of potential drug-drug interactions, consider dose adjustment of CYP1A2 substrates (e.g., theophylline, caffeine), CYP2B6 substrates (e.g., sertraline, thiotepa), and CYP3A4 substrates (e.g., midazolam, triazolam, quinidine), as clinically appropriate, when administered concomitantly with DIACOMIT. Because of potential inhibition of enzyme/transporter activity, consider a reduction in dosage of substrates of CYP2C8, CYP2C19 (e.g., diazepam, clopidogrel), P-gp (e.g., carbamazepine), and BCRP (e.g., methotrexate, prazosin, glyburide), if adverse reactions are experienced when administered concomitantly with DIACOMIT. Clobazam Co-administration of DIACOMIT (which inhibits CYP 3A4 and 2C19) with clobazam results in increased plasma concentrations of clobazam (a substrate of CYP3A4) and norclobazam, the active metabolite of clobazam (a substrate of CYP2C19) [see Clinical Pharmacology (12.3) ] . This may increase the risk of clobazam-related adverse reactions. Consider a reduction in dosage of clobazam if adverse reactions are experienced when co-administered with DIACOMIT [see Warnings and Precautions (5.1) ].

7.2 Effect of Other Drugs on DIACOMIT Induction-based interactions leading to decreases in DIACOMIT concentrations are possible when co-administered with a potent CYP1A2, CYP3A4, or CYP2C19 inducer, such as rifampin, phenytoin, phenobarbital and carbamazepine, as these enzymes all metabolize stiripentol. Concomitant use of strong inducers with DIACOMIT should be avoided, or dosage adjustments should be made. 7.3 CNS Depressants and Alcohol Concomitant use of DIACOMIT with other CNS depressants, including alcohol, may increase the risk of sedation and somnolence [see Warnings and Precautions (5.1) ].

Pregnancy: Based on animal data, may cause fetal harm. ( 8.1 )

8.1 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. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves or their caregiver. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/. Risk Summary There are no adequate data on the developmental risks associated with the use of DIACOMIT in pregnant women. Administration of stiripentol to pregnant animals produced evidence of developmental toxicity, including increased incidences of fetal malformations, increased embryofetal and pup mortality, and decreased embryofetal and pup growth, at maternal doses lower than the recommended clinical dose [see Animal Data ] . 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. Data Animal Data Oral administration of stiripentol (0, 50, 200, or 800 mg/kg/day) to pregnant mice throughout the period of organogenesis resulted in increased embryofetal mortality and decreased fetal body weights at all doses and an increased incidence of malformations at the high dose, with no evidence of maternal toxicity. The lowest effect dose for developmental toxicity in mice (50 mg/kg/day) was less than the recommended human dose (RHD) of 50 mg/kg/day on a body surface area (mg/m 2 ) basis. Oral administration of stiripentol (0, 50, 200, or 800 mg/kg/day) to pregnant rabbits throughout organogenesis resulted in increased embryofetal mortality at the mid and high dose and decreased fetal body weights at all doses. The mid and high doses were associated with maternal toxicity. The lowest effect dose for developmental toxicity in rabbits (50 mg/kg/day) was less than the RHD on a mg/m 2 basis. Oral administration of stiripentol (0, 50, 200, or 800 mg/kg/day) to rats throughout pregnancy and lactation resulted in decreased pup survival, decreased pup body weights at birth and throughout lactation, and deficits in pup reflex development at the high dose, which was also associated with maternal toxicity. The no-effect dose for pre- and postnatal developmental toxicity in rats (200 mg/kg) was less than the RHD on a mg/m 2 basis.

8.2 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.

8.4 Pediatric Use The safety and effectiveness of DIACOMIT have been established for the treatment of seizures associated with Dravet syndrome in patients taking clobazam who are 6 months and older and weighing 7 kg or more. Use of DIACOMIT in this pediatric population is supported by 2 multicenter placebo-controlled, double-blind randomized studies in patients 3 to 18 years of age with additional pharmacokinetic and safety data in patients 6 months to less than 3 years of age [see Clinical Studies ( 14 )]. The safety and effectiveness of DIACOMIT have not been established in pediatric patients below the age of 6 months or who weigh less than 7 kg.

8.5 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 age-associated hepatic and renal function abnormalities should be considered when using DIACOMIT in patients ≥65 years of age [see Clinical Pharmacology (12.3) ] .

8.6 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 the kidney, administration to patients with moderate or severe renal impairment is not recommended.

8.7 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.

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.