Stiripentol

Name: Stiripentol

Introduction

Stiripentol is an anticonvulsant.

Stiripentol Dosage and Administration

General

Stiripentol is available in the following dosage form(s) and strength(s):

  • Capsules: 250 mg or 500 mg.1

  • Powder for oral suspension: 250 mg or 500 mg.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

  • Hematologic testing should be obtained prior to starting treatment with stiripentol.1

  • As is advisable for most antiepileptic drugs, if stiripentol treatment is discontinued, the drug should be withdrawn gradually to minimize the risk of increased seizure frequency and status epilepticus.1 In situations where rapid withdrawal of stiripentol is medically required, appropriate monitoring is recommended.1

  • 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.1

Pediatric Patients

Dosage and Administration in Children ≥2 Years of Age and Adolescents
  • The recommended oral dosage of stiripentol in pediatric patients 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).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 stiripentol strengths can be used to achieve this dosage.1

  • The maximum recommended total dosage is 3 g/day.1

  • Stiripentol capsules must be swallowed whole with a glass of water during a meal. Capsules should not be broken or opened.1

  • Stiripentol powder for oral suspension should be mixed in a glass of water and should be taken immediately after mixing during a meal. See full prescribing information for further instructions on preparation and administration of stiripentol powder for oral suspension.1

Adults

Dosage & Administration in Adults
  • The recommended oral dosage of stiripentol in adults 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).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 stiripentol strengths can be used to achieve this dosage.1

  • The maximum recommended total dosage is 3 g/day.1

  • Stiripentol capsules must be swallowed whole with a glass of water during a meal. Capsules should not be broken or opened.1

  • Stiripentol powder for oral suspension should be mixed in a glass of water and should be taken immediately after mixing during a meal. See full prescribing information for further instructions on preparation and administration of stiripentol powder for oral suspension.1

Cautions for Stiripentol

Contraindications

None.1

Warnings/Precautions

Somnolence

Stiripentol can cause somnolence. In controlled studies in patients with Dravet syndrome, the incidence of somnolence was 67% in stiripentol-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 stiripentol with clobazam results in increased levels of clobazam and its active metabolite. Other CNS depressants, including alcohol, could potentiate the somnolence effect of stiripentol.1

Prescribers should monitor patients for somnolence. If somnolence occurs during co-administration with clobazam, consider an initial dosage reduction of clobazam by 25%. If somnolence persists, further clobazam dosage 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 stiripentol on mental alertness is known.1

Decreased Appetite and Decreased Weight

Stiripentol can cause decreases in appetite and weight. In controlled studies in patients with Dravet syndrome, the incidence of decreased appetite was 46% in stiripentol-treated patients, compared to 10% in patients on placebo. The incidence of decreased weight was 27% in stiripentol-treated patients, compared to 6% in patients on placebo. Nausea and vomiting also occurred more frequently in stiripentol-treated patients. Given the frequency of these adverse reactions, the growth of pediatric patients treated with stiripentol 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.1

Neutropenia and Thrombocytopenia

Stiripentol can cause a significant decline in neutrophil count. In controlled studies in patients with Dravet syndrome, there were 31 patients treated with stiripentol 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/mm3 during the trial was observed in 13% of these stiripentol-treated patients, but not in any placebo-treated patients.1

Stiripentol can cause a significant decline in platelet count. In controlled studies in patients with Dravet syndrome, there were 31 patients treated with stiripentol 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 stiripentol-treated patients, but not in any placebo-treated patients.1

Hematologic testing should be obtained prior to starting treatment with stiripentol, and then every 6 months.1

Withdrawal Symptoms

As with most antiepileptic drugs, stiripentol should generally be withdrawn gradually to minimize the risk of increased seizure frequency and status epilepticus.1

In situations where rapid withdrawal of stiripentol is required (e.g., in the setting of a serious adverse reaction), appropriate monitoring is recommended.1

Risks in Patients with Phenylketonuria

Phenylalanine can be harmful to patients with phenylketonuria (PKU). Stiripentol powder for 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 stiripentol powder for suspension to a patient with PKU, consider the combined daily amount of phenylalanine from all sources, including stiripentol powder for suspension.1

Stiripentol capsules do not contain phenylalanine.1

Suicidal Behavior and Ideation

Anticonvulsants, including stiripentol, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any anticonvulsant 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.1

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different anticonvulsants showed that patients randomized to one of the anticonvulsants 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 anticonvulsant 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.1

The increased risk of suicidal thoughts or behavior with anticonvulsants was observed as early as one week after starting drug treatment with anticonvulsants 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.1

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with anticonvulsants of varying mechanisms of action and across a range of indications suggests that the risk applies to all anticonvulsants used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed.1

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.1

Anyone considering prescribing stiripentol or any other anticonvulsant must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which anticonvulsants 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.1

Patients, their caregivers, and families should be informed that anticonvulsants increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.1

Specific Populations

Pregnancy

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to anticonvulsants, such as stiripentol, during pregnancy. Physicians are advised to recommend that pregnant patients taking stiripentol 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/.1

Risk Summary: There are no adequate data on the developmental risks associated with the use of stiripentol 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.1

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.1

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/m2) basis.1

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/m2 basis.1

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/m2 basis.1

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.1

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for stiripentol and any potential adverse effects on the breastfed infant from stiripentol or from the underlying maternal condition.1

Pediatric Use

The safety and effectiveness of stiripentol 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 stiripentol in this pediatric population is supported by 2 multicenter placebo-controlled double-blind randomized studies.1

Safety and effectiveness in pediatric patients below the age of 2 years have not been established.1

Geriatric Use

Clinical studies of stiripentol 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 stiripentol in patients ≥65 years of age.1

Renal Impairment

There is no formal study of the pharmacokinetics and metabolism of stiripentol in patients with renal impairment. However, since stiripentol metabolites are eliminated mainly through the kidney, administration to patients with moderate or severe renal impairment is not recommended.1

Hepatic Impairment

There has been no formal study of the pharmacokinetics of stiripentol 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.1

Common Adverse Effects

Adverse reactions that occurred in at least 10% of stiripentol-treated patients and more frequently than on placebo were somnolence, decreased appetite, agitation, ataxia, weight decreased, hypotonia, nausea, tremor, dysarthria, and insomnia.1

Actions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

  • Stiripentol 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.1

  • Substrates of CYP2C8, CYP2C19, P-gp and BCRP may require a dose reduction.1

  • Substrates of CYP1A2, CYP2B6 and CYP3A4 may require a dose adjustment.1

  • Strong inducers of CYP1A2, CYP3A4 or CYP2C19: Consider dose increase of stiripentol.1

Advice to Patients

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).1

Inform patients or caregivers that stiripentol capsules must be swallowed whole with a glass of water during a meal. Capsules should not be broken or opened.1

Stiripentol powder for oral suspension should be mixed in a glass of water and should be taken immediately after mixing during a meal.1

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 stiripentol treatment.1

If applicable, caution patients about hazardous machinery, including automobiles, until they know how stiripentol affects them.1

Advise patients or caregivers that decreased appetite is frequent and nausea and vomiting can also occur during stiripentol treatment, which can cause loss of weight.1

Advise patients or caregivers that abrupt withdrawal of stiripentol may increase their risk of seizures or status epilepticus. Instruct patients or caregivers to not discontinue use of stiripentol without consulting with their healthcare provider.1

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 stiripentol and then every 6 months.1

Counsel patients, their caregivers, and their families that anticonvulsants, including stiripentol, 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.1

Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during stiripentol therapy. Encourage patients to enroll in the NAAED Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of anticonvulsants during pregnancy.1

Instruct patients to notify their physician if they are breast feeding or intend to breast feed during therapy.1

Additional Information

AHFSfirstRelease™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Why is this medication prescribed?

Stiripentol is used along with clobazam (Onfi®) to control seizures in adults and children 2 years of age and older who have Dravet syndrome (a disorder that begins in early childhood and causes seizures and later may lead to developmental delays and changes in eating, balance, and walking). Stiripentol is in a class of medications called anticonvulsants. It works by decreasing abnormal excitement activity in the brain.

What should I know about storage and disposal of this medication?

Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from {light,}excess heat and moisture (not in the bathroom).

It is important to keep all medication out of sight and reach of children as many containers (such as weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child-resistant and young children can open them easily. To protect young children from poisoning, always lock safety caps and immediately place the medication in a safe location – one that is up and away and out of their sight and reach. http://www.upandaway.org

Unneeded medications should be disposed of in special ways to ensure that pets, children, and other people cannot consume them. However, you should not flush this medication down the toilet. Instead, the best way to dispose of your medication is through a medicine take-back program. Talk to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in your community. See the FDA's Safe Disposal of Medicines website (http://goo.gl/c4Rm4p) for more information if you do not have access to a take-back program.

In case of emergency/overdose

In case of overdose, call the poison control helpline at 1-800-222-1222. Information is also available online at https://www.poisonhelp.org/help. If the victim has collapsed, had a seizure, has trouble breathing, or can't be awakened, immediately call emergency services at 911.

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