Consumer medicine information

Diacomit

Stiripentol

BRAND INFORMATION

Brand name

Diacomit

Active ingredient

Stiripentol

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Diacomit.

What is in this leaflet

This leaflet answers some common questions about DIACOMIT. As this leaflet does not contain all the available information, it is important that you talk to your doctor or pharmacist. All medicines have risks and benefits. Your doctor has weighed the risks of you receiving DIACOMIT against the benefits this medicine is expected to have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet. You may need to read it again.

What DIACOMIT is used for

Stiripentol, the active ingredient of DIACOMIT, belongs to a group of medicines called antiepileptics. It is used in conjunction with other antiepileptic medicines to treat a certain form of epilepsy called severe myoclonic epilepsy in infancy (Dravet syndrome), which affects infants and children. Your child’s doctor has prescribed this medicine to help treat your child’s epilepsy. It should always be taken in combination with other prescribed antiepileptic medicines under the direction of a doctor.

Before your child takes DIACOMIT

When your child must not take it:

Your child must NOT take DIACOMIT if he/she:

  • is allergic to stiripentol or to any of the other ingredients of DIACOMIT (listed at the end of this leaflet - (See "DIACOMIT description"). Signs of allergic reaction may include a skin rash, itching, shortness of breath or swelling of the face, lips or tongue.
  • has ever experienced attacks of delirium (a mental state with confusion, excitement, restlessness and hallucinations).

Before your child takes it:

Before your child starts taking DIACOMIT you should discuss with your child’s doctor any of the following points which apply to your child.

  • if your child has kidney or liver problems.
  • Your child’s liver function should be assessed prior to starting DIACOMIT and checked every 6 months.
  • Your child’s blood count should be assessed prior to starting DIACOMIT and checked every 6 months.
  • Because the frequency of gastrointestinal side effects with DIACOMIT, clobazam and valproate, such as anorexia, loss of appetite, vomiting, your child’s growth rate should be carefully monitored.
  • If your child is pregnant or could become pregnant. During pregnancy, effective antiepileptic treatment must NOT be stopped. Ask your child’s doctor or pharmacist for advice before taking any medicine.
  • Do not breastfeed if you are taking DIACOMIT. Breast-feeding is not recommended during treatment with this medicine. Ask your doctor or pharmacist for advice before taking any medicine.
  • Antiepileptic drugs may cause suicidal thoughts or actions. Ask your child’s doctor if your child have any signs of suicidal ideation or behaviour.
  • If your child is taking medicines containing:
    - cisapride (used to treat symptoms of night time heartburn);
    - pimozide (used to treat the symptoms of Tourette's syndrome e.g. vocal outbursts and uncontrolled, repeated movements of the body);
    - ergotamine (used to treat migraine);
    - dihydroergotamine (used to relieve the signs and symptoms of decreased mental capacity due to the aging process);
    - halofantrine (an antimalarial treatment);
    - quinidine (used to treat abnormal heart rhythms);
    - bepridil (used to control chest pain);
    - cyclosporine, tacrolimus, sirolimus (all three used to prevent rejections of liver, kidney and heart transplants);
    - statins (simvastatin and atorvastatin, both used to reduce the amount of cholesterol in blood) ;
    - antiepileptic medicines containing phenobarbital, primidone, phenytoin, carbamazepine, diazepam ;
  • Medicines containing:
    - midazolam or triazolam (medicines used to reduce anxiety and sleeplessness – in combination with DIACOMIT they may make your child very sleepy);
    - chlorpromazine (used for mental illness such as psychosis);
    - caffeine (this substance helps restore mental alertness) or theophylline (this substance is used in case of asthma). The combination with DIACOMIT should be avoided as it may increase their blood levels, leading to digestive disorders, racing heart and insomnia ;
  • Medicines metabolized by certain liver enzymes including:
    - citalopram (used in the treatment of depressive episodes) ;
    - omeprazole (used in case of gastric ulcer);
    - HIV protease inhibitors (used in the treatment of HIV);
    - astemizole, chlorpheniramine (antihistamines);
    - calcium channel blockers (used in the treatment of angina or troubles of heart rhythm) ;
    - oral contraceptives ;
    - propranolol, carvedilol, timolol (used in the treatment of high blood pressure );
    - fluoxetine, paroxetine, sertraline, imipramine, clomipramine (antidepressants) ;
    - haloperidol (antipsychotics) ;
    - codeine, dextromethorphan, tramadol (used in the treatment of pain).

Please tell your child’s doctor or pharmacist if your child is using or has recently used any other medicines, including medicines obtained without a prescription, dietary supplements and herbal medicines.

How to take DIACOMIT

It is important that your child takes this medicine as directed by the doctor. Your child’s doctor will tell you how much you should take, when and how often. Follow your child’s doctor's instructions. If you are unsure ask your doctor or pharmacist.

How much should your child take:

The dose is adjusted by the doctor according to your child’s age, weight and condition, generally 50 mg per kg bodyweight and per day. This should be split into 2 or 3 doses as advised by your child’s doctor.

When and how should your child take DIACOMIT:

Your child should take this medicine at regular intervals as directed by your child’s doctor: it is recommended to split the medicine dose in 2 or 3 daily intakes (totalling 50 mg per kg per day), for example morning - noon - bed-time, to cover the night-and-day period.

Dose increases should be gradual, taking place over a few weeks while the dose(s) of the other antiepileptic medicine(s) is (are) reduced at the same time. Your child’s doctor will tell you the new dose(s) of the other antiepileptic medicine(s).

If you have the impression that the effect of this medicine is too strong or too weak, talk to your child’s doctor or pharmacist. The dose will be adjusted by the doctor according to your child’s condition.

Please consult your child’s doctor in the event of any side effects as the doctor may have to adjust the dose(s) of this medicine and the other antiepileptic medicine(s).

There are slight differences between the DIACOMIT capsules and powder for oral suspension. If your child experiences any problems when switching from taking the capsules to the powder for oral suspension or vice versa please inform your child’s doctor. In case of switch between capsule and powder formulations it should be done under the close supervision of the doctor.

In case of vomiting within the first few minutes of intake it is assumed that no medicine has been absorbed and a new dose should be given.

However, the situation is different if the vomiting occurs more than one hour after medicine intake because stiripentol is quickly absorbed. In such a case, it is assumed that a significant fraction of the administered dose has been absorbed systemically from the digestive tract. Thus, there would be no need for a new intake or for an adjustment of the next dose.

Capsules: DIACOMIT capsules should be swallowed whole with water. The capsules should not be chewed.

Powder for suspension: DIACOMIT powder for suspension should be mixed in a glass of water and should be taken immediately after mixing during a meal.

Your child should take DIACOMIT with food, it should NOT be taken on an empty stomach. For food and drinks to be avoided, see the section “While your child is taking DIACOMIT” below.

Contact your child’s doctor if you know or think your child has taken more medicine than he or she should have.

If you or your child forgets to take DIACOMIT:

It is important that your child takes this medicine regularly at the same time each day. If your child forgets to take a dose, he or she should take it as soon as you remember unless it is time for the next dose. In that case carry on with the next dose as normal. Your child should not take a double dose to make up for a forgotten individual dose.

If your child stops taking DIACOMIT:

Your child must not stop taking this medicine unless the doctor tells you to. Stopping treatment suddenly can lead to an outbreak of seizures.

If you have any further questions on the use of this medicine, ask your child’s doctor or pharmacist.

While your child is taking DIACOMIT

Things you must not do:

Do NOT take DIACOMIT with milk or dairy products (for example yoghurt, soft cream cheeses), fruit juice, fizzy drinks or food and drinks that contain caffeine or theophylline (for example cola, chocolate, coffee, tea and energy drinks).

During pregnancy, effective antiepileptic treatment must NOT be stopped. If your child may be or is pregnant, please ask your child’s doctor for advice.

Breast-feeding is NOT recommended during treatment with this medicine. Ask your doctor or pharmacist for advice before taking any medicine.

This medicine may make your child feel sleepy. Your child should NOT use any tools, machines, ride or drive if affected in this way. Check with your child’s doctor.

Do not give DIACOMIT to anyone else, even if they have the same symptoms as your child.

Things you must do:

If your child is about to be started on any new medicine, tell your child’s doctor or pharmacist that your child is taking DIACOMIT.

Things to be careful of:

Capsules:

This medicine contains 0.16 mg sodium per 250 mg capsule and 0.32 mg sodium per 500 mg capsule. This should be taken into consideration by patients on a controlled sodium diet.

Powder for suspension:

This medicine contains 0.11 mg sodium per 250 mg sachet and 0.22 mg sodium per 500 mg sachet. To be taken into consideration by patients on a controlled sodium diet.

This medicine contains a source of phenylalanine. May be harmful for people with phenylketonuria.

If you have been told by your doctor that you have an intolerance to aspartame or some sugars, contact your doctor before taking this medicinal product.

Side Effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Tell your child’s doctor if you notice any of the following side effects:

Very common side effects (may affect more than one in 10 people):

  • loss of appetite, weight loss (especially when combined with the antiepileptic medicine sodium valproate);
  • insomnia (sleeplessness), drowsiness;
  • ataxia (inability to coordinate muscle movements), hypotonia (low muscle strength), dystonia (involuntary muscle contractions).

Common side effects (may affect up to 1 in 10 people):

  • raised levels of liver enzymes, especially when given with either of the antiepileptic medicines carbamazepine and sodium valproate;
  • aggressiveness, irritability, agitation, hyperexcitability (state of being unusually excitable);
  • sleep disorders (abnormal sleeping);
  • hyperkinesis (exaggerated movements);
  • nausea, vomiting;
  • a low number of a type of white blood cells.

Uncommon side effects (may affect up to 1 in 100 people):

  • double vision when used in combination with the antiepileptic medicine carbamazepine;
  • sensitivity to light;
  • rash, skin allergy, urticaria (pinkish, itchy swellings on the skin);
  • fatigue (tiredness).

Rare side effects (may affect up to 1 in 1,000 people)

  • decrease of platelet level in the blood
  • Abnormal liver function test

To eliminate these side effects, your child’s doctor may have to change the dose(s) of DIACOMIT and/or one of the other medicines prescribed for your child.

If your child gets any side effects talk to your child’s doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

Overdosage

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26), or go to the emergency department of your nearest hospital, if you think your child or anyone else may have taken too much DIACOMIT. Do this, even if there are no signs of discomfort or poisoning.

DIACOMIT description

The active substance is stiripentol.

Capsule

Each capsule contains 250 mg or 500 mg of stiripentol.

Each capsule also contains the following inactive ingredients:

  • povidone
  • sodium starch glycolate type A
  • magnesium stearate
  • The printing ink contains shellac and iron oxide black

The DIACOMIT 250 mg capsule is pink with a capsule shell that is made of gelatin, titanium dioxide, erythrosine, indigo carmine, and imprinted with “Diacomit 250 mg”.

The DIACOMIT 500mg capsule is white with a capsule shell that is made of gelatin, titanium dioxide, and imprinted with “Diacomit 500 mg”.

The 250 mg and 500 mg capsules are supplied in plastic bottles containing 60 capsules in cardboard cartons.

Oral suspension

Each sachet contains 250 mg or 500 mg of stiripentol.

Each sachet also contains the following inactive ingredients:

  • aspartame
  • glucose liquid spray
  • povidone
  • sodium starch glycolate type A
  • erythrosine
  • titanium dioxide
  • tutti frutti flavour
  • carmellose
  • hydroxyethylcellulose

The DIACOMIT 250 mg and 500 mg sachet of powder for oral suspension contains pale pink powder.The sachets are supplied in boxes of 60 sachets.

Storage

Keep DIACOMIT in the original package in order to protect from light.

Store DIACOMIT below 25°C. Keep the bottle and the sachet pack in a cool, dry place and away from direct heat and sunlight. Do not store in the bathroom or near a sink.

Keep DIACOMIT where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Your child should not take DIACOMIT after the expiry date, which is stated on the label. The expiry date refers to the last day of that month.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

DIACOMIT is sponsored in Australia by:

Chiesi Australia Pty Ltd
Suite 3, 22 Gillman Street
Hawthorn East Victoria 3123
Australia
Email: [email protected]
Website: www.chiesi.com.au

This leaflet was revised in May 2021

AUST R 280985 - 250 mg capsule

AUST R 281294 - 500 mg capsule

AUST R 281460 - 250 mg powder for oral suspension

AUST R 281461 - 500 mg powder for oral suspension

Published by MIMS September 2021

BRAND INFORMATION

Brand name

Diacomit

Active ingredient

Stiripentol

Schedule

S4

 

1 Name of Medicine

Diacomit (stiripentol).

2 Qualitative and Quantitative Composition

Stiripentol 250 mg and 500 mg capsule.
Stiripentol 250 mg and 500 mg powder for oral suspension.
Each capsule contains either 250 mg or 500 mg stiripentol as the active ingredient.
Each sachet contains either 250 mg or 500 mg stiripentol as the active ingredient.
Excipients with a known effect in powders for oral suspensions: aspartame and sugars.
Capsules contain no excipients with a known effect.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

250 mg capsule appears as an opaque pink capsule of size 2 with self-locking closure, imprinted with "Diacomit 250 mg".
Diacomit 500 mg capsule appears as a white capsule of size 0 with self-locking closure, imprinted with "Diacomit 500 mg".
Diacomit 250 mg and 500 mg powder for oral suspension is a pale pink powder filled in a single dose sachet.

4 Clinical Particulars

4.1 Therapeutic Indications

Diacomit is indicated for adjunctive treatment of generalised tonic-clonic and clonic seizures associated with severe myoclonic epilepsy in infancy (SMEI, also known as Dravet syndrome) in patients whose seizures are not adequately controlled with a benzodiazepine (usually clobazam) and valproate.

4.2 Dose and Method of Administration

Dosage.

Prescriptions and treatment should be initiated by neurologists experienced in the diagnosis and management of epilepsy, with continuation of patient management by general paediatricians and practitioners when the initiating neurologist is unavailable.

General.

The dose of stiripentol is calculated on a mg/kg body weight basis.
It is recommended to split the daily dose in two or three daily intakes (totalling the daily recommended dose per kg and per day). The initiation of adjunctive therapy with stiripentol should be undertaken gradually using upwards dose escalation to reach the recommended dose of 50 mg/kg/day.
Stiripentol dosage escalation should be gradual, starting with 20 mg/kg/day for 1 week, then 30 mg/kg/day for 1 week. Further dosage escalation is age dependent:
children less than 6 years should receive an additional 20 mg/kg/day in the third week, thus achieving the recommended dose of 50 mg/kg/day in three weeks;
children from 6 to less than 12 years should receive an additional 10 mg/kg/day each week, thus achieving the recommended dose of 50 mg/kg/day in four weeks;
children and adolescents 12 years and older should receive an additional 5 mg/kg/day each week until the optimum dose is reached based on clinical judgment.
The recommended dose of 50 mg/kg/day is based on the available clinical study findings and was the only dose of Diacomit evaluated in the pivotal studies (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
There are no clinical study data to support the clinical safety of stiripentol administered at daily doses greater than 50 mg/kg/day.
There are no clinical study data to support the use of stiripentol as monotherapy in Dravet syndrome.

Dose adjustments of other antiepileptics used in combination with stiripentol.

Despite the absence of comprehensive pharmacology data on potential drug interactions, the following advice regarding modification of the dose and dosage schedules of other anti-epileptic medicinal products administered in conjunction with stiripentol is provided based on clinical experience.

Clobazam.

In the pivotal studies, when the use of stiripentol was initiated, the daily dose of clobazam was 0.5 mg/kg/day usually administered in divided doses, twice daily. In the event of clinical signs of adverse reactions or overdose of clobazam (i.e. drowsiness, hypotonia, and irritability in young children), this daily dose was reduced by 25% every week.
Approximately two to three fold increases in clobazam and five fold increases in norclobazam plasma levels respectively have been reported with co-administration of stiripentol in children with Dravet syndrome.

Valproate.

The potential for metabolic interaction between stiripentol and valproate is considered modest and thus, no modification of valproate dosage should be needed when stiripentol is added, except for clinical safety reasons. In the pivotal studies in the event of gastrointestinal adverse reactions such as loss of appetite, loss of weight, the daily dose of valproate was reduced by around 30% every week.

Effect of formulation.

The sachet formulation (Cmax = 7.32 microgram/mL) has a slightly higher Cmax than the capsules (Cmax = 5.99 microgram/mL) and thus the formulations are not bioequivalent. It is recommended that if a switch of formulations is required this is done under clinical supervision, in case of problems with tolerability (see Section 5 Pharmacological Properties).

Renal and hepatic impairment.

Stiripentol is not recommended for use in patients with impaired hepatic and/or renal function (see Section 4.4 Special Warnings and Precautions for Use).

Method of administration.

The capsule should be swallowed whole with a glass of water during a meal.
The powder should be mixed in a glass of water and should be taken immediately after mixing during a meal.
Stiripentol must always be taken with food as it degrades rapidly in an acidic environment (e.g. exposure to gastric acid in an empty stomach).
Diacomit should not be taken with milk or dairy products (yoghurt, soft cream cheese, etc.), carbonated drinks, fruit juice or food and drinks that contain caffeine or theophylline.

Drug discontinuation.

Antiepileptic drugs, including Diacomit, should be withdrawn gradually to minimise the potential for seizures or increased seizure frequency. In clinical trials in children with Dravet syndrome, dosages were gradually reduced over a period lasting at least one month.
In situation where rapid withdrawal of Diacomit is medically required, appropriate monitoring is recommended.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.
A past history of psychoses in the form of episodes of delirium.

4.4 Special Warnings and Precautions for Use

Identified precautions.

The pivotal clinical evaluation of Diacomit was in children of 3 years of age and over with SMEI. Children under 3 years of age and adults were not studied in the pivotal trials therefore efficacy and safety for those populations were not established in the pivotal trials.

Drug interactions.

Carbamazepine, phenytoin and phenobarbital.

Carbamazepine, phenytoin, and phenobarbital should generally not be used in conjunction with stiripentol in the management of Dravet syndrome.
Phenytoin and phenobarbital can significantly decrease the serum concentration of stiripentol. Stiripentol can significantly increase the serum concentration of carbamazepine, phenytoin, and phenobarbital. Furthermore, there is evidence that these drugs have the potential to worsen seizure activity in patients with Dravet syndrome, even though these drugs may have a role in a subset of patients with Dravet syndrome.
It is recommended that carbamazepine, phenytoin, and phenobarbital be used in conjunction with stiripentol only under expert supervision with appropriate monitoring.

Clobazam and valproate.

The daily dosage of clobazam and/or valproate should be reduced according to the onset of side effects whilst on stiripentol therapy (see Section 4.2 Dose and Method of Administration).

Substances interfering with CYP enzymes.

Stiripentol is an inhibitor of the enzymes CYP1A2, CYP2C8, CYP2C19, CYP3A4, CYP2C9 and CYP2D6 and may markedly increase the plasma concentrations of substances metabolised by these enzymes and increase the risk of adverse reactions (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). In vitro data also suggest that STP induces the activity of CYP1A2 and CYP2B/3A, but the clinical relevance of this is uncertain. In vitro studies suggested that stiripentol phase 1 metabolism is catalysed by CYP1A2, CYP2C9, CYP2C19 and CYP3A4/5 and possibly other enzymes. Caution is advised when combining stiripentol with other substances that inhibit or induce one or more of these enzymes.

Blood count.

Neutropenia may be associated with the administration of stiripentol, clobazam and valproate. Blood counts should be assessed prior to starting treatment with stiripentol. Unless otherwise clinically indicated, blood counts should be checked every 6 months.

Neurologic/psychiatric.

Patients should be monitored for somnolence and drowsiness, particularly when stiripentol is used concomitantly with other central nervous depressant. An adjustment of the dosage of concomitant clobazam or other anti-epileptic dugs could be considered. Patients (or their parents or carers) should be advised to not operate machinery or drive.
Movement disorders including ataxia, hypotonia, tremor, hyperkinesia, dysarthria and equilibrium disorders have been reported in patients treated with Diacomit for Dravet syndrome.

Suicidal ideation and behaviour.

Suicidal ideation and behaviour have been reported in patients treated with antiepileptic agents in several indications.
All patients treated with antiepileptic drugs, irrespective of indication, should be monitored for signs of suicidal ideation and behaviour and appropriate treatment should be considered. Patients (or their parents or carers) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

Use in hepatic impairment.

Liver function.

In patients newly prescribed stiripentol, raised γGT (notably when combined with valproate) are observed with a common frequency, whilst abnormal liver function tests (increases in AST and/or ALT) are also reported with a rare frequency. Liver function (γGT, AST and ALT levels) should therefore be assessed prior to starting treatment with stiripentol and, unless otherwise clinically indicated, should be checked every 6 months.
Stiripentol is primarily metabolised by the liver and primarily excreted by the kidney.
In the absence of specific clinical data in patients with impaired hepatic or renal function, stiripentol is not recommended for use in patients with impaired hepatic and/or renal function.

Use in renal impairment.

Stiripentol is primarily metabolised by the liver and primarily excreted by the kidney.
In the absence of specific clinical data in patients with impaired hepatic or renal function, stiripentol is not recommended for use in patients with impaired hepatic and/or renal function.

Use in the elderly.

No data are available.

Paediatric use.

Growth rate of children.

Due to the frequency of gastrointestinal adverse reactions to treatment with stiripentol and valproate (anorexia, loss of appetite, nausea, vomiting), the growth rate of children under this combination of treatment should be carefully monitored.

Effects on laboratory tests.

In the event of an abnormal blood count or liver function test finding, the clinical decision for continuing use or adjusting the dose of stiripentol in conjunction with adjusting the doses of clobazam and valproate needs to be made on an individual patient basis taking into consideration the potential clinical benefits and risks.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Stiripentol is subject to non-linear pharmacokinetics (see Section 5 Pharmacological Properties).

Potential medicinal product interactions affecting stiripentol.

The influence of other antiepileptic medicinal products on stiripentol pharmacokinetics is not well established.
The impact of macrolides and azole antifungal agents, that are known to be inhibitors of CYP3A4 and substrates of the same enzyme, on stiripentol metabolism is not known. Likewise, the effect of stiripentol on their metabolism is not known.
In vitro studies suggested that stiripentol phase 1 metabolism is catalysed by CYP1A2, CYP2C19 and CYP3A4 and possibly other enzymes. Caution is advised when combining stiripentol with other substances that inhibit or induce one or more of these enzymes.

Effect of stiripentol on cytochrome P450 enzymes.

Many of these interactions have been partially confirmed by in vitro studies and in clinical trials. The increase in steady state levels with the combined use of stiripentol, valproate, and clobazam is similar in adults and children, though inter-individual variability is marked.
At therapeutic concentrations, stiripentol significantly inhibits several CYP450 isoenzymes: for example, CYP2C19, CYP1A2, CYP2C8, CYP2D6, CYP2C9 and CYP3A4. As a result, pharmacokinetic interactions of metabolic origin with other medicines may be expected. These interactions may result in increased systemic levels of these active substances that may lead to enhanced pharmacological effects and to an increase in adverse reactions. In vitro data also suggest that stiripentol induces the activity of CYP1A2 and CYP2B/3A, but the clinical relevance of this is uncertain.
Caution must be exercised if clinical circumstances require combining stiripentol with substances metabolised by CYP2C19 (e.g. citalopram, omeprazole) or CYP3A4 (e.g. HIV protease inhibitors, antihistamines such as astemizole and chlorpheniramine, calcium channel blockers, statins, oral contraceptives, codeine) due to the increased risk of adverse reactions (see further in this section for antiepileptic medicines). Monitoring of plasma concentrations or adverse reactions is recommended. A dose adjustment may be necessary.
Co-administration with CYP3A4 substrates with a narrow therapeutic index should be avoided due to the markedly increased risk of severe adverse reactions.
Data on the potential for inhibition of CYP1A2 are limited, and therefore, interactions with theophylline and caffeine cannot be excluded because of the increased plasma levels of theophylline and caffeine which may occur via inhibition of their hepatic metabolism, potentially leading to toxicity. Use in combination with stiripentol is not recommended. This warning is not only restricted to medicinal products but also to a considerable number of foods and nutritional products aimed at children, such as cola drinks, which contain significant quantities of caffeine or chocolate, which contains trace amounts of theophylline.
As stiripentol inhibited CYP2D6 in vitro at concentrations that are achieved clinically in plasma, substances that are metabolised by this isoenzyme like: beta-blockers (propranolol, carvedilol, timolol), antidepressants (fluoxetine, paroxetine, sertraline, imipramine, clomipramine), antipsychotics (haloperidol), analgesics (codeine, dextromethorphan, tramadol) may be subject to metabolic interactions with stiripentol. A dose-adjustment may be necessary for substances metabolised by CYP2D6 and that are individually dose titrated.

Effect of stiripentol on GABA receptor site.

Stiripentol is a positive allosteric modulator of the GABAA receptor. There is a potential for it to act synergistically with other allosteric modulators at the same site (e.g. benzodiazepines, non-benzodiazepines, barbiturates, bromides or neuroactive steroids) to enhance GABAergic neurotransmission.

Potential for stiripentol to interact with other medicinal products.

In the absence of available clinical data, caution should be taken with the following clinically relevant interactions with stiripentol, see Table 1 and Table 2.
CYP3A4 inhibitors, such a stiripentol, may increase the exposure of oestrogen or progestin containing contraceptives when used concomitantly. Oestrogen or progestin containing contraceptives may increase the exposure of CYP1A2 or CYP3A substrates, such a stiripentol. The clinical significance of these potential interactions is not known.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There were no effects on fertility in male and female rats following oral administration of STP at doses up to 800 mg/kg/day (equivalent to about 3-fold the MRHD, based on body surface area). As no human clinical data are available, the potential risk for humans is unknown.
(Category B3)

Risk related to epilepsy and antiepileptic medicinal products in general.

It has been shown that in the offspring of women with epilepsy, the prevalence of malformations is two to three times greater than reported in the general population. Although other factors, e.g. the epilepsy, can contribute, available evidence suggests that this increase, to a large extent, is caused by the treatment. In the treated population, an increase in malformations has been noted with polytherapy.
However, effective anti-epileptic therapy should not be interrupted during pregnancy, since the aggravation of the illness may be detrimental to both the mother and the foetus.

Risk related to stiripentol.

No data on exposed pregnancies are available. Stiripentol and/or its metabolites cross the placenta in rats. There was no evidence of teratogenicity in mice or rabbits treated with STP during the period of organogenesis at oral doses up to 800 mg/kg/day, which is about 2-fold (mice) and 6-fold (rabbits) the MRHD, based on body surface area. Increased numbers of resorptions were reported in mouse embryofetal development studies at doses of ≥ 200 mg/kg/day (0.4 times the MRHD based on BSA), and also in the rabbit embryofetal development study at a dose of 800 mg/kg/day (6 times the MRHD based on BSA). Rats treated with oral STP from early or late gestation to weaning showed maternotoxicity and reduced pup survival and reflex development at 800 mg/kg/day (equivalent to about 3-fold the mg/m2 MRHD); the no-effect dose was 200 mg/kg/day.
In view of the indication, administration of stiripentol during pregnancy and in women of childbearing potential would not be expected. The clinical decision for use of stiripentol in pregnancy needs to be made on an individual patient basis taking into consideration the potential clinical benefits and risks. Caution should be exercised when prescribing to pregnant women and use of efficient methods of contraception is advisable.
 It is not expected that Dravet syndrome affected women will conceive and have children. However, as there are no human studies on the excretion of stiripentol in breast milk, and given that stiripentol passes freely from plasma into milk in the goat, breast feeding is not recommended while on treatment with stiripentol. In the unlikely event that stiripentol therapy is maintained while breast feeding, the breast fed infant should be carefully monitored for potential adverse effects.

4.7 Effects on Ability to Drive and Use Machines

Patients with Dravet syndrome would not be expected to drive or operate machinery due to the nature of the underlying disease and the effects of long term administration of anticonvulsant medicines.
Stiripentol may cause dizziness and ataxia that may affect ability to drive and use machines and patients should not drive or use machinery whilst on stiripentol therapy.

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

Clinical trial experience. Two prospective, randomised, 8-week treatment, double-blind, placebo-controlled trials were conducted in Dravet syndrome patients (STICLO France and STICLO Italy). In both trials, stiripentol was added on to treatment with valproate and clobazam. The dose of stiripentol was 50 mg/kg/day.
Table 3 lists the adverse events that were reported during the studies. No patient died during these double-blind, placebo-controlled studies.

Tabulated list of adverse reactions.

Post marketing experience. The most common side effects with Diacomit (seen in more than 1 in 10 patients) are anorexia, weight loss, insomnia, drowsiness, ataxia, hypotonia and dystonia.
Adverse effects encountered most often are as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse effects are presented in order of decreasing severity. These data are presented in Table 4.
Gastrointestinal adverse events.

Weight loss and anorexia.

Anorexia and weight loss are very common adverse effects.
In two double-blind, placebo-controlled trials in Dravet syndrome patients, gastrointestinal adverse events most often reported in patients receiving stiripentol were loss of appetite in 39% of the treated patients and loss of weight in 24% of the treated patients.

Nausea and vomiting.

Nausea and vomiting are common adverse effects.
In 2 double-blind, placebo-controlled trials in Dravet syndrome patients, nausea and vomiting were observed in 15% of the treated patients.
Due to the frequency of gastrointestinal adverse reactions to treatment with stiripentol and valproate (anorexia, loss of appetite, nausea, vomiting), the growth rate of children under this combination of treatment should be carefully monitored.

Abnormal liver function tests.

Raised γGT (notably when combined with carbamazepine and valproate) is a common adverse effect.
Liver function should be assessed prior to starting treatment with stiripentol. Unless otherwise clinically indicated, liver function should be checked every 6 months. As the drug is metabolised mainly by the liver, stiripentol is not recommended for use in patients with impaired hepatic function.
Central nervous system adverse events. Drowsiness, ataxia, hypotonia, dystonia and insomnia are very common adverse effects.
In 2 double-blind, placebo-controlled trials in Dravet syndrome patients, drowsiness/sleepiness were observed in 67% of the treated patients, hyperexcitability/agitation in 21% of treated patients, aggressiveness/irritability in 15% of treated patients, hypotonia in 15% of the treated patients, and ataxia in 12% of the treated patients.
Patients should be monitored for somnolence and drowsiness, particularly when stiripentol is used concomitantly with other central nervous depressant. An adjustment of the dosage of concomitant clobazam or other anti-epileptic drugs could be considered. Patients should be advised to not operate machinery or drive.
Thrombocytopenia and neutropenia. Neutropenia is a common adverse effect. Thrombocytopenia is a rare adverse effect.
In 2 double-blind, placebo-controlled trials in Dravet syndrome patients, neutropenia was observed in 9% of the treated patients and thrombocytopenia in 6% of the treated patients.
Blood counts should be assessed prior to starting treatment with stiripentol. Unless otherwise clinically indicated, blood counts should be checked every 6 months.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Data on clinical overdose are not available. Treatment is supportive (symptomatic measures in intensive care units).
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia) or the New Zealand Poisons Centre on 0800 POISON or 0800 764 766.

5 Pharmacological Properties

Pharmacology data are mainly based on four clinical pharmacokinetics studies in healthy adult volunteers, one population pharmacokinetics study in children with Dravet syndrome, three efficacy studies in the target population that generated supportive pharmacokinetics data and studies from the clinical literature.

5.1 Pharmacodynamic Properties

Mechanism of action.

The mechanism of antiepileptic activity of stiripentol is based on the potentiation of the GABAergic transmissions in the CNS. In vitro, stiripentol has been shown to directly enhance GABAA receptor-mediated transmission by acting both post-synaptically at a neuronal site coupled to the GABAA receptor and pre-synaptically to increase GABA release from nerve terminals. In rodent models, stiripentol appears to increase brain levels of GABA. This could occur by inhibition of synaptosomal uptake of GABA and/or inhibition of GABA transaminase. Stiripentol has been shown to enhance GABAA receptor-mediated transmission in the immature rat hippocampus and increase the mean open-duration (but not the open-frequency) of GABAA receptor chloride channels.
Stiripentol also potentiates the efficacy of clobazam and other anticonvulsants, as a result of the pharmacokinetic interactions (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). This effect of stiripentol is mainly based on metabolic inhibition of several isoenzymes, in particular CYP450 3A4 and 2C19, involved in the hepatic metabolism of other anti-epileptic medicines.

Clinical trials.

The efficacy of stiripentol, as an add-on therapy to optimised treatment with valproate and clobazam in patients presenting with Dravet syndrome has been demonstrated in two randomised, double-blind, placebo-controlled clinical trials. These trials, designated STICLO France and STICLO Italy, involved 41 (age range: 3.0-20.7) and 23 patients (age range: 3.5-18.9) respectively. Both studies were conducted according to similar design to evaluate the responder rate to treatment, where the responder was defined as a patient who achieved ≥ 50% decrease in the frequency of generalised clonic or tonic-clonic seizures during the double-blind treatment period compared to baseline (i.e. placebo run-in).
Eligible patients were included initially in a 1-month baseline period during which they continued to receive their optimised antiepileptic treatment. Following this 1-month baseline, patients were randomly allocated to receive either stiripentol (50 mg/kg/day) or placebo added on to their antiepileptic treatment. The frequency of generalised clonic or tonic-clonic seizures during the trial was recorded by the patients and or their caregivers, using a diary. Patients were treated double-blind for 2 months.
Results of each clinical trial are presented separately as well as pooled. Several criteria allow to pool the results of STICLO France and STICLO Italy. The data poolability from the two STICLO trials was assessed statistically and results indicated that the data were poolable using the demographic and primary endpoints data.
In study STICLO France, total of 41 patients were enrolled; 21 were randomised to receive stiripentol and 20 were randomised to receive placebo. One patient in the stiripentol group was excluded. For study STICLO Italy, 23 patients were enrolled; 12 were randomised to STP, and 11 to placebo. All were judged to be evaluable. A summary of the baseline demographic data is provided in Table 5.
Table 6 summarises the antiepileptic efficacy of stiripentol in each STICLO trial, as well as the results of the pooled analysis (STICLO Total).
In both STICLO trials, stiripentol was significantly more efficacious than placebo, as determined by response rate (refer to Table 6). In STICLO France, 15 of 21 (71.4%) patients on STP versus 1 of 20 (5.0%) patients on placebo met the criterion for response (≥ 50% reduction in generalised tonic-clonic seizure frequency); the difference between treatment groups was statistically significant (p < 0.0001). In STICLO Italy, 8 of 12 (66.7%) patients randomised to STP versus 1 of 11 (9.1%) patients randomised to placebo met the criterion for response; the difference between treatment groups was statistically significant (p = 0.0098). In both STICLO trials, STP was also superior to placebo as judged by mean percent reduction in frequency of generalised clonic or tonic-clonic seizures (STICLO France: p = 0.0003; STICLO Italy: p = 0.0056).
When efficacy results of both STICLO trials were pooled, 23 of 33 (69.7%) patients on stiripentol versus 2 of 31 (6.5%) patients on placebo met the criterion for response (p < 0.0001). Mean percent reduction in seizure frequency was 66% in the pooled STP group versus an increase of 4% in the pooled placebo groups (p < 0.0001).

5.2 Pharmacokinetic Properties

Studies in children of various ages showed that the pharmacokinetic behaviour of stiripentol is influenced by age and body weight. Stiripentol should be adjusted accordingly by reducing the daily dose as body weight and age increase.

Absorption.

Stiripentol is quickly absorbed. The Tmax times were 2.42 hours for single doses of stiripentol 500 mg and 1,000 mg and 2.96 hours for 2,000 mg. According to Michaelis‐Menten kinetics there is some evidence for non‐linearity regarding stiripentol absorption. Following the oral administration of 500 mg, 1,000 mg and 2,000 mg of stiripentol in healthy volunteers the following data were determined, see Table 7.
The absolute bioavailability of stiripentol is not known since an intravenous formulation is not available for testing. It is well absorbed by the oral route since the majority of an oral dose is excreted in urine. Relative bioavailability between the capsules and powder for oral suspension in sachet formulations has been studied in healthy male volunteers after a 1,000 mg single oral administration. Cmax of the sachet was slightly higher (23%) compared with the capsule and did not meet the criteria for bioequivalence. Tmax was similar with both formulations. Clinical supervision is recommended if switching between the stiripentol capsule and powder for oral suspension in sachet formulations.

Distribution.

Stiripentol binds extensively to circulating plasma proteins (about 99% at clinical plasma concentrations).
In a population pharmacokinetic study conducted in Dravet syndrome patients at steady state receiving the combination valproate + clobazam + stiripentol, the apparent volume of stiripentol distribution according to weight was as follows (see Table 8).

Metabolism.

Stiripentol is primarily metabolised by the liver.
Stiripentol undergoes extensive first-pass metabolism in the liver with CYP1A2, CYP2C19 and CYP3A4 being the main isozymes involved in stiripentol metabolism. Stiripentol is mainly metabolised by glucuronidation and oxidative cleavage.
Stiripentol is supplied as a racemic mixture, and after administration R-enantiomer is the predominant enantiomer, but glucuronidation appears to favour the S-enantiomer.
Elimination of a single dose was mainly (73%) via the kidney after extensive metabolisation (13 different metabolites) by the liver (Cytochrome P 450).

Excretion.

Stiripentol is primarily excreted by the kidney.
Systemic exposure to stiripentol increases markedly compared to dose proportionality. In healthy adults, 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. Clearance is decreased after repeated administration of stiripentol, probably due to inhibition of the cytochrome P450 isoenzymes responsible for its metabolism. The half-life of elimination was in the range of 4.5 hours to 13 hours, increasing with dose.
Similarly, in a population pharmacokinetic study conducted in Dravet syndrome patients at steady state receiving the combination valproate + clobazam + stiripentol, the apparent volume of stiripentol distribution according to weight was as follows (see Table 9).

5.3 Preclinical Safety Data

Genotoxicity.

There was no evidence for genotoxic potential in in vitro assays for gene mutation or unscheduled DNA synthesis. A positive in vitro chromosomal aberration assay in Chinese Hamster Ovary cells (observed at the highest concentration) was not confirmed in a similar assay with human lymphocytes or in a mouse micronucleus test in vivo. The genotoxic potential of STP is considered to be low.

Carcinogenicity.

There was no evidence of carcinogenicity in rats following oral administration of STP for 2 years at doses up to 800 mg/kg/day. This dose is approximately 3-4 times the MRHD based on body surface area, and systemic exposure (plasma AUC) was about 4-fold the estimated exposure in adults at the MRHD. In mice treated orally for 78 weeks, there was an increase in the incidence of hepatic adenomas and carcinomas at doses of 200 or 600 mg/kg/day. These doses are about 0.5 to 2-fold the MRHD based on body surface area, and plasma exposure was about 2-fold the paediatric Cmax; the no-effect dose was 60 mg/kg/day. In view of the lack of genotoxicity of STP and the known susceptibility of the mouse liver to tumour formation in response to hepatic enzyme induction, this finding is not considered to indicate a risk of tumorigenicity in patients.

6 Pharmaceutical Particulars

6.1 List of Excipients

Capsules.

Povidone, sodium starch glycolate type A, magnesium stearate, gelatin, titanium dioxide, erythrosine (Diacomit 250 mg only), indigo carmine (Diacomit 250 mg only).
Printing Ink: Shellac, iron oxide black.

Powder for oral suspension.

Aspartame, spray-dried liquid glucose, povidone, sodium starch glycolate type A, erythrosine, titanium dioxide, carmellose hyetellose, Arome Polv tutti frutti 25 H 245.

6.2 Incompatibilities

See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C. Store in original container to protect from light.

6.5 Nature and Contents of Container

Diacomit 250 mg and 500 mg capsules are supplied in high density polyethylene bottles with tamper-evident seal and child-resistant polypropylene screw cap. Each bottle contains 60 capsules.
Diacomit 250 mg and 500 mg powder for oral suspension are packaged in paper/aluminium/high density polyethylene film sachet. The sachets are supplied in boxes of 60 sachets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Stiripentol is a white to pale yellow crystalline powder, practically insoluble in water at 25°C, sparingly soluble in chloroform and soluble in acetone, ethanol, ether, acetonitrile and dichloromethane.

Chemical structure.


CAS number.

49763-96-4.

Molecular formula.

C14H18O3.
Relative molecular mass: 234.3 g/mol.
Stiripentol is obtained as a racemate.

7 Medicine Schedule (Poisons Standard)

Schedule 4.

Summary Table of Changes