ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Diacomit 250 mg hard capsules
2.
Each capsule contains 250 mg of stiripentol.
Excipients: 0.16 mg sodium per capsule.
For a full list of excipients, see section 6.1.
3.
Hard capsules
Size 2 pink capsule
4.
Diacomit is indicated for use in conjunction with clobazam and valproate as adjunctive therapy of
refractory generalized tonic-clonic seizures in patients with severe myoclonic epilepsy in infancy
(SMEI, Dravet’s syndrome) whose seizures are not adequately controlled with clobazam and
valproate.
Diacomit should only be administered under the supervision of a paediatrician / paediatric neurologist
experienced in the diagnosis and management of epilepsy in infants and children.
The capsule should be swallowed whole with a glass of water during a meal.
The dose of Diacomit is calculated on a mg/kg body weight basis.
The daily dosage may be administered in 2 or 3 divided doses.
The initiation of adjunctive therapy with Diacomit should be undertaken over 3 days using upwards
dose escalation to reach the recommended dose of 50 mg/kg/day administered in conjunction with
clobazam and valproate. This recommended dose is based on the available clinical study findings and
was the only dose of Diacomit evaluated in the pivotal studies (see section 5.1).
There are no clinical study data to support the clinical safety of Diacomit administered at daily doses
greater than 50 mg/kg/day.
There are no clinical study data to support the use of Diacomit as monotherapy in Dravet’s syndrome.
Dose adjustments of other antiepileptics used in combination with Diacomit
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 Diacomit is provided based on clinical experience.
1
- Clobazam
In the pivotal studies, when the use of Diacomit 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 side
effects or overdosage 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 Diacomit in children with Dravet’s syndrome.
- Valproate
The potential for metabolic interaction between Diacomit and valproate is considered modest and thus,
no modification of valproate dosage should be needed when Diacomit 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.
Abnormal Laboratory Findings
In the event of an abnormal blood count or liver function test finding, the clinical decision for
continuing use or adjusting the dose of Diacomit 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 (see section 4.4).
Effects of food
Diacomit 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.
Effect of formulation
The sachet formulation has a slightly higher C
max
than the capsules 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 5.2).
Children aged less than 3 years
The pivotal clinical evaluation of Diacomit was in children of 3 years of age and over with SMEI. The
clinical decision for use of Diacomit in children with SMEI less than 3 years of age needs to be made
on an individual patient basis taking into consideration the potential clinical benefits and risks. In this
younger group of patients, adjunctive therapy with Diacomit should only be started when the diagnosis
of SMEI has been clinically confirmed (see section 5.1). Data are limited about the use of Diacomit
under 12 months of age.
Patients with renal and hepatic impairment
Diacomit is not recommended for use in patients with impaired hepatic and/or renal function (see
section 4.4).
Hypersensitivity to the active substance or to any of the excipients.
A past history of psychoses in the form of episodes of delirium.
Carbamazepine, phenytoin and phenobarbital should not be used in conjunction with Diacomit in the
management of Dravet’s syndrome. The daily dosage of clobazam and/or valproate should be reduced
according to the onset of side effects whilst on Diacomit therapy (see section 4.2).
Given the frequency of gastrointestinal adverse reactions to treatment with Diacomit and valproate
(anorexia, loss of appetite, nausea, vomiting), the growth rate of children under this combination of
treatment should be carefully monitored.
2
Neutropenia may be associated with the administration of Diacomit, clobazam and valproate. Blood
counts should be assessed prior to starting treatment with Diacomit. Unless otherwise clinically
indicated, blood counts should be checked every 6 months.
Liver function should be assessed prior to starting treatment with Diacomit. Unless otherwise
clinically indicated, liver function should be checked every 6 months.
In the absence of specific clinical data in patients with impaired hepatic or renal function, Diacomit is
not recommended for use in patients with impaired hepatic and/or renal function.
Stiripentol is an inhibitor of the enzymes CYP2C19, CYP3A4 and CYP2D6 and may markedly
increase the plasma concentrations of drugs metabolised by these enzymes and increase the risk of
adverse effects (see section 4.5).
In vitro
studies suggested that stiripentol phase 1 metabolism is
catalyzed by CYP1A2, CYP2C19 and CYP3A4 and possibly other enzymes. Caution is advised when
combining stiripentol with other drugs that inhibit or induce one or more of these enzymes.
The pivotal clinical studies did not include children below 3 years old. As a consequence, it is
recommended that children between 6 months and 3 years of age are carefully monitored whilst on
Diacomit therapy.
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 on stiripentol metabolism, that are known to be
inhibitors of CYP3A4 and substrates of the same enzyme, is not known. Likewise, the effect of
stiripentol on their metabolism is not known.
In vitro
studies suggested that stiripentol phase 1 metabolism is catalyzed by CYP1A2, CYP2C19 and
CYP3A4 and possibly other enzymes. Caution is advised when combining stiripentol with other drugs
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 Diacomit, 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, CYP2D6 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 side effects and adverse reactions.
Caution must be exercised if clinical circumstances require combining stiripentol with drugs
metabolised by CYP2C19 (e.g. citalopram, omeprazole) or CYP3A4 (e.g. HIV protease inhibitors,
antihistamines such as astemizole, chlorpheniramine, calcium channel blockers, statins, oral
contraceptives, codeine) due to the increased risk of adverse events (see further in this section for
antiepileptic drugs). Monitoring of plasma concentrations or adverse effects 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 effects.
Data on the potential for inhibition of CYP1A2 are limited, and therefore, interactions with
theophylline and caffeine cannot be excluded. Use in combination with stiripentol is not
recommended. This warning is not only restricted to medicinal products but also to a considerable
3
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, drugs
that are metabolized 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 drugs metabolised by CYP2D6
and that are individually dose titrated.
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:
Undesirable combinations (to be avoided unless strictly necessary)
- Rye ergot alkaloids (ergotamine, dihydroergotamine)
Ergotism with possibility of necrosis of the extremities (inhibition of hepatic elimination of rye ergot).
- Cisapride, halofantrine, pimozide, quinidine, bepridil
Increased risk of cardiac arrhythmias and torsades de pointes/wave burst arrhythmia in particular.
- Immunosuppressants (tacrolimus, cyclosporine, sirolimus)
Raised blood levels of immunosuppressants (decreased hepatic metabolism).
- Statins (atorvastatin, simvastatin, etc.)
Increased risk of dose-dependent adverse reactions such as rhabdomyolysis (decreased hepatic
metabolism of cholesterol-lowering agent).
Combinations requiring precautions
- Midazolam, triazolam, alprazolam
Increased plasma benzodiazepine levels may occur via decreased hepatic metabolism leading to
excessive sedation.
- Theophylline, caffeine
Increased plasma levels of theophylline and caffeine may occur via inhibition of their hepatic
metabolism, potentially leading to toxicity. These combinations should be avoided.
- Chlorpromazine
Stiripentol enhances the central depressant effect of chlorpromazine.
- Effects on other AEDs
Inhibition of CYP450 isoenzyme CYP2C19 and CYP3A4 may provoke pharmacokinetic interactions
(inhibition of their hepatic metabolism) with phenobarbital, primidone, phenytoin, carbamazepine,
clobazam (see section 4.2), valproate (see section 4.2), diazepam (enhanced myorelaxation),
ethosuximide, and tiagabine. The consequences are increased plasma levels of these anticonvulsants
with potential risk of overdose. Clinical monitoring of plasma levels of other anticonvulsants when
combined with stiripentol with possible dose adjustments is recommended.
- Topiramate
In a French compassionate use program for Diacomit, topiramate was added to Diacomit, clobazam
and valproate in 41% of 230 cases. Based on the clinical observations in this group of patients, there is
no evidence to suggest that a change in topiramate dose and dosage schedules is needed if co-
administered with stiripentol.
With regard to topiramate, it is considered that potential competition of inhibition on CYP2C19 should
not occur because it probably requires plasma concentrations 5-15 times higher than plasma
concentrations obtained with the standard recommended topiramate dose and dosage schedules.
4
- Levetiracetam
Levetiracetam does not undergo hepatic metabolism to a major extent. As a result, no pharmacokinetic
metabolic drug interaction between stiripentol and levetiracetam is anticipated.
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 the rate of approximately 3% 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 Diacomit:
No data on exposed pregnancies are available. Animal studies do not indicate direct or indirect
harmful effects with respect to pregnancy, foetal development, parturition or postnatal development at
non-maternotoxic doses (see section 5.3). In view of the indication, administration of Diacomit during
pregnancy and in women of childbearing potential would not be expected. The clinical decision for
use of Diacomit 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.
During pregnancy:
Effective anticonvulsant treatment with Diacomit must not be stopped during pregnancy as worsening
of the disease is potentially harmful to both mother and foetus.
In the absence of human studies on excretion in breast milk, and given that stiripentol passes freely
from plasma into milk in the goat, breast-feeding is not recommended during treatment. In case
Diacomit therapy is continued during breast-feeding, the breast-fed infant should be carefully
observed for potential adverse effects.
Patients with SMEI 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 drugs.
Diacomit may cause dizziness and ataxia that may affect ability to drive and use machines and patients
should not drive or use machinery whilst on Diacomit therapy.
Adverse reactions encountered most often are as follows: very common (≥ 1/10), common (≥ 1/100,
< 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000,
including isolated cases), frequency not known (cannot be estimated from the available data). Within
each frequency grouping, undesirable effects are presented in order of decreasing severity.
5
System/organ classes
System Organ
Class
Very common
Common
Uncommon
Rare
(MedDRA
terminology)
Blood and
lymphatic
system
disorders
Neutropenia
Persistent severe
neutropenia usually
resolves spontaneously
when Diacomit is
stopped.
Metabolism
and nutrition
disorders
Anorexia, loss of
appetite, weight
loss (especially
when combined
with sodium
valproate)
Psychiatric
disorders
Insomnia
Aggressiveness,
irritability, behaviour
disorders, opposing
behaviour,
hyperexcitability, sleep
disorders
Nervous system
disorders
Drowsiness, ataxia,
hypotonia, dystonia
Hyperkinesias
Eye disorders
Diplopia (when
used in
combination
with
carbamazepine)
Gastrointestinal
disorders
Nausea, vomiting
Skin and
subcutaneous
tissue disorders
Photosensitivity,
rash, cutaneous
allergy, urticaria
General
disorders
Fatigue
Investigations
Raised γGT (notably
when combined with
carbamazepine and
valproate).
Liver
function test
abnormal
Many of the above adverse reactions are often due to an increase in plasma levels of other
anticonvulsant medicinal products (see sections 4.4 and 4.5) and may regress when the dose of these
medicinal products is reduced.
Data on clinical overdose are not available. Treatment is supportive (symptomatic measures in
intensive care units).
6
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other Antiepileptics, ATC code: N03AX17
In animal models, stiripentol antagonizes seizures induced by electric shock, pentetrazole and
bicuculline. In rodent models, stiripentol appears to increase brain levels of gamma-aminobutyric acid
(GABA) - the major inhibitory neurotransmitter in mammalian brain. This could occur by inhibition of
synaptosomal uptake of GABA and/or inhibition of GABA transaminase. Stiripentol has also been
shown to enhance GABAA receptor-mediated transmission in the immature rat hippocampus and
increase the mean open-duration (but not the frequency) of GABAA receptor chloride channels by a
barbiturate-like mechanism. Stiripentol potentiates the efficacy of other anticonvulsants, such as
carbamazepine, sodium valproate, phenytoin, phenobarbital and many benzodiazepines, as the result
of pharmacokinetic interactions. The second 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 drugs.
The pivotal clinical evaluation of Diacomit was in children of 3 years of age and over with SMEI.
A French compassionate use program included children from 6 months of age because the diagnosis of
Dravet’s syndrome may be made with confidence at that age in some patients. The clinical decision for
use of Diacomit in children with SMEI less than 3 years of age needs to be made on an individual
patient basis taking into consideration the potential clinical benefits and risks (see section 4.2).
41 children with SMEI were included in a randomised, placebo-controlled, add-on trial. After a
baseline period of 1 month, placebo (n=20) or stiripentol (n=21) was added to valproate and clobazam
during a double-blind period of 2 months. Patients then received stiripentol in an open fashion.
Responders were defined as having more than 50% reduction in the frequency of clonic (or tonic-
clonic) seizures during the second month of the double-blind period compared with baseline. 15 (71%)
patients were responders on stiripentol (including nine free of clonic or tonic-clonic seizures), whereas
there was only one (5%) on placebo (none was seizure free; stiripentol 95% CI 52.1-90.7 vs. placebo
0-14.6). The 95% CI of the difference was 42.2-85.7. Percentage of change from baseline was higher
on stiripentol (-69%) than on placebo (+7%), p< 0.0001. 21 patients on stiripentol had moderate side-
effects (drowsiness, loss of appetite) compared with eight on placebo, but side-effects disappeared
when the dose of comedication was decreased in 12 of the 21 cases (Chiron et al, Lancet, 2000).
This medicinal product has been authorised under a “conditional approval” scheme. This means that
further evidence on this medicinal product is awaited, in particular about the efficacy of stiripentol in
combination with the maximum safe dose of the add-on therapy. A study is being conducted to
investigate this. The European Medicines Agency (EMA) will review new information on the product
every year and this SmPC will be updated as necessary.
5.2 Pharmacokinetic properties
The following pharmacokinetic properties of stiripentol have been reported from studies in adult
healthy volunteers and adult patients.
Absorption / Bioavailability:
Stiripentol is quickly absorbed, with a time to peak plasma concentration of about 1.5 hours. 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.
Distribution:
Stiripentol binds extensively to circulating plasma proteins (about 99%).
7
Elimination:
Systemic exposure to stiripentol increases markedly compared to dose proportionality. 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.
Metabolism:
Stiripentol is extensively metabolized, 13 different metabolites having been found in urine. The main
metabolic processes are demethylenation and glucuronidation, although precise identification of the
enzymes involved has not yet been achieved.
On the basis of
in vitro
studies, the principal liver cytochrome P450 isoenzymes involved in phase 1
metabolism are considered to be CYP1A2, CYP2C19 and CYP3A4.
Excretion:
Most stiripentol is excreted via the kidney.
Urinary metabolites of stiripentol accounted collectively for the majority (73%) of an oral acute dose
whereas a further 13-24% was recovered in faeces as unchanged drug.
max max
of the sachet was
slightly higher (23%) compared with the capsule and did not meet the criteria for bioequivalence. T
max
was similar with both formulations. Clinical supervision is recommended if switching between the
stiripentol capsule and powder for oral suspension in sachet formulations.
Paediatric Population Pharmacokinetic Study
A population pharmacokinetic study was conducted in 35 children with Dravet Syndrome treated with
stiripentol and two drugs not known to affect stiripentol pharmacokinetics, valproate and clobazam.
The median age was 7.3 years (range: 1 to 17.6 years) and the median daily dose of stiripentol was
45.4 mg/kg/day (range: 27.1 to 89.3 mg/kg/day) received in two or three divided doses.
The data were best fitted with a one compartment model with first order absorption and elimination
processes. The population estimate for the absorption rate constant Ka was 2.08 hr -1 (standard
deviation of random effect = 122%). Clearance and volume of distribution were related to body weight
by an allometric model with exponents of 0.433 and 1, respectively: as body weight increased from 10
to 60 kg, apparent oral clearance increased from 2.60 to 5.65 L/hr and apparent volume of distribution
increased from 32.0 to 191.8
K
As a result, elimination half-life increased from 8.5hr (for 10 kg) to
23.5 hr (for 60 kg).
5.3 Preclinical safety data
Toxicity studies in animals (rat, monkey, mouse) have not revealed any consistent pattern of toxicity
apart from liver enlargement associated with hepatocellular hypertrophy, which occurred when high
doses of stiripentol were administered to both rodents and nonrodents. This finding is considered to be
an adaptive response to a high metabolic burden on the liver.
Stiripentol was not teratogenic when tested in the rat and rabbit; in one study in the mouse, but not in
several other similar studies, a low incidence of cleft palate formation was observed at a maternotoxic
dose (800 mg/kg/day). These studies in mice and rabbits were undertaken prior to the introduction of
Good Laboratory Practice requirements. Studies in the rat on fertility and general reproductive
performance and on pre- and postnatal development were uneventful except for a minor reduction in
the survival of pups nursed by mothers exhibiting toxic responses to stiripentol at a dose of
800 mg/kg/day (see section 4.6).
Genotoxicity studies have not detected any mutagenic or clastogenic activity.
Carcinogenicity studies gave negative results in the rat. In the mouse there was only a small increase
in the incidence of hepatic adenomas and carcinomas in animals treated with 200 or 600 mg/kg/day for
8
Bioavailability / Bioequivalence:
Relative bioavailabilty 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. The two
formulations were bioequivalent in terms of AUC but not in terms of C . C
78 weeks but not in those given 60 mg/kg/day. In view of the lack of genotoxicity of stiripentol and
the well known, special susceptibility of the mouse liver to tumour formation in the presence of
hepatic enzyme induction, this finding is not considered to indicate a risk of tumorigenicity in patients.
6.
6.1 List of excipients
povidone K29/32
sodium starch glycolate (type A)
magnesium stearate
Capsule shell
Gelatin
Titanium dioxide (E171)
Erythrosine (E127)
Indigotine (E132)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
Store in the original package in order to protect from light.
6.5 Nature and contents of container
Polypropylene bottle with tamper-evident seal and polyethylene screw cap.
Bottles of 30, 60 and 90 capsules in cardboard cartons. Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements.
7.
Biocodex, 7 Avenue Gallieni, 94250 Gentilly, France.
8.
EU/1/06/367/001-3
9.
Date of first authorization: 04 January 2007
Date of latest renewal:
0/
Detailed information on this product is available on the website of the European Medicines Agency
00
1.
Diacomit 500 mg hard capsules
2.
Each capsule contains 500 mg of stiripentol.
Excipients: 0.32 mg sodium per capsule.
For a full list of excipients, see section 6.1.
3.
Hard capsules
Size 0, white capsule
4.
Diacomit is indicated for use in conjunction with clobazam and valproate as adjunctive therapy of
refractory generalized tonic-clonic seizures in patients with severe myoclonic epilepsy in infancy
(SMEI, Dravet’s syndrome) whose seizures are not adequately controlled with clobazam and
valproate.
Diacomit should only be administered under the supervision of a paediatrician / paediatric neurologist
experienced in the diagnosis and management of epilepsy in infants and children.
The capsule should be swallowed whole with a glass of water during a meal.
The dose of Diacomit is calculated on a mg/kg body weight basis.
The daily dosage may be administered in 2 or 3 divided doses.
The initiation of adjunctive therapy with Diacomit should be undertaken over 3 days using upwards
dose escalation to reach the recommended dose of 50 mg/kg/day administered in conjunction with
clobazam and valproate. This recommended dose is based on the available clinical study findings and
was the only dose of Diacomit evaluated in the pivotal studies (see section 5.1).
There are no clinical study data to support the clinical safety of Diacomit administered at daily doses
greater than 50 mg/kg/day.
There are no clinical study data to support the use of Diacomit as monotherapy in Dravet’s syndrome.
Dose adjustments of other antiepileptics used in combination with Diacomit
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 Diacomit is provided based on clinical experience.
01
- Clobazam
In the pivotal studies, when the use of Diacomit 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 side
effects or overdosage 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 Diacomit in children with Dravet’s syndrome.
- Valproate
The potential for metabolic interaction between Diacomit and valproate is considered modest and thus,
no modification of valproate dosage should be needed when Diacomit 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.
Abnormal Laboratory Findings
In the event of an abnormal blood count or liver function test finding, the clinical decision for
continuing use or adjusting the dose of Diacomit 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 (see section 4.4).
Effects of food
Diacomit 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.
Effect of formulation
The sachet formulation has a slightly higher C
max
than the capsules 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 5.2).
Children aged less than 3 years
The pivotal clinical evaluation of Diacomit was in children of 3 years of age and over with SMEI. The
clinical decision for use of Diacomit in children with SMEI less than 3 years of age needs to be made
on an individual patient basis taking into consideration the potential clinical benefits and risks. In this
younger group of patients, adjunctive therapy with Diacomit should only be started when the diagnosis
of SMEI has been clinically confirmed (see section 5.1). Data are limited about the use of Diacomit
under 12 months of age.
Patients with renal and hepatic impairment
Diacomit is not recommended for use in patients with impaired hepatic and/or renal function (see
section 4.4).
Hypersensitivity to the active substance or to any of the excipients.
A past history of psychoses in the form of episodes of delirium.
Carbamazepine, phenytoin and phenobarbital should not be used in conjunction with Diacomit in the
management of Dravet’s syndrome. The daily dosage of clobazam and/or valproate should be reduced
according to the onset of side effects whilst on Diacomit therapy (see section 4.2).
Given the frequency of gastrointestinal adverse reactions to treatment with Diacomit and valproate
(anorexia, loss of appetite, nausea, vomiting), the growth rate of children under this combination of
treatment should be carefully monitored.
02
Neutropenia may be associated with the administration of Diacomit, clobazam and valproate. Blood
counts should be assessed prior to starting treatment with Diacomit. Unless otherwise clinically
indicated, blood counts should be checked every 6 months.
Liver function should be assessed prior to starting treatment with Diacomit. Unless otherwise
clinically indicated, liver function should be checked every 6 months.
In the absence of specific clinical data in patients with impaired hepatic or renal function, Diacomit is
not recommended for use in patients with impaired hepatic and/or renal function.
Stiripentol is an inhibitor of the enzymes CYP2C19, CYP3A4 and CYP2D6 and may markedly
increase the plasma concentrations of drugs metabolised by these enzymes and increase the risk of
adverse effects (see section 4.5).
In vitro
studies suggested that stiripentol phase 1 metabolism is
catalyzed by CYP1A2, CYP2C19 and CYP3A4 and possibly other enzymes. Caution is advised when
combining stiripentol with other drugs that inhibit or induce one or more of these enzymes.
The pivotal clinical studies did not include children below 3 years old. As a consequence, it is
recommended that children between 6 months and 3 years of age are carefully monitored whilst on
Diacomit therapy.
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 on stiripentol metabolism, that are known to be
inhibitors of CYP3A4 and substrates of the same enzyme, is not known. Likewise, the effect of
stiripentol on their metabolism is not known.
In vitro
studies suggested that stiripentol phase 1 metabolism is catalyzed by CYP1A2, CYP2C19 and
CYP3A4 and possibly other enzymes. Caution is advised when combining stiripentol with other drugs
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 Diacomit, 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, CYP2D6 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 side effects and adverse reactions.
Caution must be exercised if clinical circumstances require combining stiripentol with drugs
metabolised by CYP2C19 (e.g. citalopram, omeprazole) or CYP3A4 (e.g. HIV protease inhibitors,
antihistamines such as astemizole, chlorpheniramine, calcium channel blockers, statins, oral
contraceptives, codeine) due to the increased risk of adverse events (see further in this section for
antiepileptic drugs). Monitoring of plasma concentrations or adverse effects 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 effects.
Data on the potential for inhibition of CYP1A2 are limited, and therefore, interactions with
theophylline and caffeine cannot be excluded. Use in combination with stiripentol is not
recommended. This warning is not only restricted to medicinal products but also to a considerable
03
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, drugs
that are metabolized 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 drugs metabolised by CYP2D6
and that are individually dose titrated.
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:
Undesirable combinations (to be avoided unless strictly necessary)
- Rye ergot alkaloids (ergotamine, dihydroergotamine)
Ergotism with possibility of necrosis of the extremities (inhibition of hepatic elimination of rye ergot).
- Cisapride, halofantrine, pimozide, quinidine, bepridil
Increased risk of cardiac arrhythmias and torsades de pointes/wave burst arrhythmia in particular.
- Immunosuppressants (tacrolimus, cyclosporine, sirolimus)
Raised blood levels of immunosuppressants (decreased hepatic metabolism).
- Statins (atorvastatin, simvastatin, etc.)
Increased risk of dose-dependent adverse reactions such as rhabdomyolysis (decreased hepatic
metabolism of cholesterol-lowering agent).
Combinations requiring precautions
- Midazolam, triazolam, alprazolam
Increased plasma benzodiazepine levels may occur via decreased hepatic metabolism leading to
excessive sedation.
- Theophylline, caffeine
Increased plasma levels of theophylline and caffeine may occur via inhibition of their hepatic
metabolism, potentially leading to toxicity. These combinations should be avoided.
- Chlorpromazine
Stiripentol enhances the central depressant effect of chlorpromazine.
- Effects on other AEDs
Inhibition of CYP450 isoenzyme CYP2C19 and CYP3A4 may provoke pharmacokinetic interactions
(inhibition of their hepatic metabolism) with phenobarbital, primidone, phenytoin, carbamazepine,
clobazam (see section 4.2), valproate (see section 4.2), diazepam (enhanced myorelaxation),
ethosuximide, and tiagabine. The consequences are increased plasma levels of these anticonvulsants
with potential risk of overdose. Clinical monitoring of plasma levels of other anticonvulsants when
combined with stiripentol with possible dose adjustments is recommended.
- Topiramate
In a French compassionate use program for Diacomit, topiramate was added to Diacomit, clobazam
and valproate in 41% of 230 cases. Based on the clinical observations in this group of patients, there is
no evidence to suggest that a change in topiramate dose and dosage schedules is needed if co-
administered with stiripentol.
With regard to topiramate, it is considered that potential competition of inhibition on CYP2C19 should
not occur because it probably requires plasma concentrations 5-15 times higher than plasma
concentrations obtained with the standard recommended topiramate dose and dosage schedules.
04
- Levetiracetam
Levetiracetam does not undergo hepatic metabolism to a major extent. As a result, no pharmacokinetic
metabolic drug interaction between stiripentol and levetiracetam is anticipated.
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 the rate of approximately 3% 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 Diacomit:
No data on exposed pregnancies are available. Animal studies do not indicate direct or indirect
harmful effects with respect to pregnancy, foetal development, parturition or postnatal development at
non-maternotoxic doses (see section 5.3). In view of the indication, administration of Diacomit during
pregnancy and in women of childbearing potential would not be expected. The clinical decision for
use of Diacomit 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.
During pregnancy:
Effective anticonvulsant treatment with Diacomit must not be stopped during pregnancy as worsening
of the disease is potentially harmful to both mother and foetus.
In the absence of human studies on excretion in breast milk, and given that stiripentol passes freely
from plasma into milk in the goat, breast-feeding is not recommended during treatment. In case
Diacomit therapy is continued during breast-feeding, the breast-fed infant should be carefully
observed for potential adverse effects.
Patients with SMEI 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 drugs.
Diacomit may cause dizziness and ataxia that may affect ability to drive and use machines and patients
should not drive or use machinery whilst on Diacomit therapy.
Adverse reactions encountered most often are as follows: very common (≥ 1/10), common (≥ 1/100,
< 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000,
including isolated cases), frequency not known (cannot be estimated from the available data). Within
each frequency grouping, undesirable effects are presented in order of decreasing severity.
05
System/organ classes
System Organ
Class
Very common
Common
Uncommon
Rare
(MedDRA
terminology)
Blood and
lymphatic
system
disorders
Neutropenia
Persistent severe
neutropenia usually
resolves spontaneously
when Diacomit is
stopped.
Metabolism
and nutrition
disorders
Anorexia, loss of
appetite, weight
loss (especially
when combined
with sodium
valproate)
Psychiatric
disorders
Insomnia
Aggressiveness,
irritability, behaviour
disorders, opposing
behaviour,
hyperexcitability, sleep
disorders
Nervous system
disorders
Drowsiness,
ataxia, hypotonia,
dystonia
Hyperkinesias
Eye disorders
Diplopia (when
used in
combination
with
carbamazepine)
Gastrointestinal
disorders
Nausea, vomiting
Skin and
subcutaneous
tissue disorders
Photosensitivity,
rash, cutaneous
allergy, urticaria
General
disorders
Fatigue
Investigations
Raised γGT (notably
when combined with
carbamazepine and
valproate).
Liver
function test
abnormal
Many of the above adverse reactions are often due to an increase in plasma levels of other
anticonvulsant medicinal products (see sections 4.4 and 4.5) and may regress when the dose of these
medicinal products is reduced.
Data on clinical overdose are not available. Treatment is supportive (symptomatic measures in
intensive care units).
06
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other Antiepileptics, ATC code: N03AX17
In animal models, stiripentol antagonizes seizures induced by electric shock, pentetrazole and
bicuculline. In rodent models, stiripentol appears to increase brain levels of gamma-aminobutyric acid
(GABA) - the major inhibitory neurotransmitter in mammalian brain. This could occur by inhibition of
synaptosomal uptake of GABA and/or inhibition of GABA transaminase. Stiripentol has also been
shown to enhance GABAA receptor-mediated transmission in the immature rat hippocampus and
increase the mean open-duration (but not the frequency) of GABAA receptor chloride channels by a
barbiturate-like mechanism. Stiripentol potentiates the efficacy of other anticonvulsants, such as
carbamazepine, sodium valproate, phenytoin, phenobarbital and many benzodiazepines, as the result
of pharmacokinetic interactions. The second 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 drugs.
The pivotal clinical evaluation of Diacomit was in children of 3 years of age and over with SMEI.
A French compassionate use program included children from 6 months of age because the diagnosis of
Dravet’s syndrome may be made with confidence at that age in some patients. The clinical decision for
use of Diacomit in children with SMEI less than 3 years of age needs to be made on an individual
patient basis taking into consideration the potential clinical benefits and risks (see section 4.2).
41 children with SMEI were included in a randomised, placebo-controlled, add-on trial. After a
baseline period of 1 month, placebo (n=20) or stiripentol (n=21) was added to valproate and clobazam
during a double-blind period of 2 months. Patients then received stiripentol in an open fashion.
Responders were defined as having more than 50% reduction in the frequency of clonic (or tonic-
clonic) seizures during the second month of the double-blind period compared with baseline. 15 (71%)
patients were responders on stiripentol (including nine free of clonic or tonic-clonic seizures), whereas
there was only one (5%) on placebo (none was seizure free; stiripentol 95% CI 52.1-90.7 vs. placebo
0-14.6). The 95% CI of the difference was 42.2-85.7. Percentage of change from baseline was higher
on stiripentol (-69%) than on placebo (+7%), p<0.0001. 21 patients on stiripentol had moderate side-
effects (drowsiness, loss of appetite) compared with eight on placebo, but side-effects disappeared
when the dose of comedication was decreased in 12 of the 21 cases (Chiron et al, Lancet, 2000).
This medicinal product has been authorised under a “conditional approval” scheme. This means that
further evidence on this medicinal product is awaited, in particular about the efficacy of stiripentol in
combination with the maximum safe dose of the add-on therapy. A study is being conducted to
investigate this. The European Medicines Agency (EMA) will review new information on the product
every year and this SmPC will be updated as necessary.
5.2 Pharmacokinetic properties
The following pharmacokinetic properties of stiripentol have been reported from studies in adult
healthy volunteers and adult patients.
Absorption / Bioavailability:
Stiripentol is quickly absorbed, with a time to peak plasma concentration of about 1.5 hours. 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.
Distribution:
Stiripentol binds extensively to circulating plasma proteins (about 99%).
07
Elimination:
Systemic exposure to stiripentol increases markedly compared to dose proportionality. 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.
Metabolism:
Stiripentol is extensively metabolized, 13 different metabolites having been found in urine. The main
metabolic processes are demethylenation and glucuronidation, although precise identification of the
enzymes involved has not yet been achieved.
On the basis of
in vitro
studies, the principal liver cytochrome P450 isoenzymes involved in phase 1
metabolism are considered to be CYP1A2, CYP2C19 and CYP3A4.
Excretion:
Most stiripentol is excreted via the kidney.
Urinary metabolites of stiripentol accounted collectively for the majority (73%) of an oral acute dose
whereas a further 13-24% was recovered in faeces as unchanged drug.
max max
of the sachet was
slightly higher (23%) compared with the capsule and did not meet the criteria for bioequivalence. T
max
was similar with both formulations. Clinical supervision is recommended if switching between the
stiripentol capsule and powder for oral suspension in sachet formulations.
Paediatric Population Pharmacokinetic Study
A population pharmacokinetic study was conducted in 35 children with Dravet Syndrome treated with
stiripentol and two drugs not known to affect stiripentol pharmacokinetics, valproate and clobazam.
The median age was 7.3 years (range: 1 to 17.6 years) and the median daily dose of stiripentol was
45.4 mg/kg/day (range: 27.1 to 89.3 mg/kg/day) received in two or three divided doses.
The data were best fitted with a one compartment model with first order absorption and elimination
processes. The population estimate for the absorption rate constant Ka was 2.08 hr -1 (standard
deviation of random effect = 122%). Clearance and volume of distribution were related to body weight
by an allometric model with exponents of 0.433 and 1, respectively: as body weight increased from 10
to 60 kg, apparent oral clearance increased from 2.60 to 5.65 L/hr and apparent volume of distribution
increased from 32.0 to 191.8
K
As a result, elimination half-life increased from 8.5hr (for 10 kg) to
23.5 hr (for 60 kg).
5.3 Preclinical safety data
Toxicity studies in animals (rat, monkey, mouse) have not revealed any consistent pattern of toxicity
apart from liver enlargement associated with hepatocellular hypertrophy, which occurred when high
doses of stiripentol were administered to both rodents and nonrodents. This finding is considered to be
an adaptive response to a high metabolic burden on the liver.
Stiripentol was not teratogenic when tested in the rat and rabbit; in one study in the mouse, but not in
several other similar studies, a low incidence of cleft palate formation was observed at a maternotoxic
dose (800 mg/kg/day). These studies in mice and rabbits were undertaken prior to the introduction of
Good Laboratory Practice requirements. Studies in the rat on fertility and general reproductive
performance and on pre- and postnatal development were uneventful except for a minor reduction in
the survival of pups nursed by mothers exhibiting toxic responses to stiripentol at a dose of
800 mg/kg/day (see section 4.6).
Genotoxicity studies have not detected any mutagenic or clastogenic activity.
Carcinogenicity studies gave negative results in the rat. In the mouse there was only a small increase
in the incidence of hepatic adenomas and carcinomas in animals treated with 200 or 600 mg/kg/day for
08
Bioavailability / Bioequivalence:
Relative bioavailabilty 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. The two
formulations were bioequivalent in terms of AUC but not in terms of C . C
78 weeks but not in those given 60 mg/kg/day. In view of the lack of genotoxicity of stiripentol and
the well known, special susceptibility of the mouse liver to tumour formation in the presence of
hepatic enzyme induction, this finding is not considered to indicate a risk of tumorigenicity in patients.
6.
6.1 List of excipients
povidone K29/32
sodium starch glycolate (type A)
magnesium stearate
Capsule shell
Gelatin
Titanium dioxide (E171)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
Store in the original package in order to protect from light.
6.5 Nature and contents of container
Polypropylene bottle with tamper-evident seal and polyethylene screw cap.
Bottles of 30, 60 and 90 capsules in cardboard cartons. Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements.
7.
Biocodex, 7 Avenue Gallieni, 94250 Gentilly, France.
8.
EU/1/06/367/004-6
9.
Date of first authorization: 04 January 2007
Date of latest renewal:
1/
Detailed information on this product is available on the website of the European Medicines Agency
10
1.
Diacomit 250 mg powder for oral suspension in sachets.
2.
Each sachet contains 250 mg of stiripentol.
Excipients: 0.11 mg sodium per sachet.
Each sachet contains 2.5 mg of aspartame, 500 mg of glucose liquid spray and 2.4 mg of sorbitol.
For a full list of excipients, see section 6.1.
3.
Powder for oral suspension
Pale pink crystalline powder
4.
Diacomit is indicated for use in conjunction with clobazam and valproate as adjunctive therapy of
refractory generalized tonic-clonic seizures in patients with severe myoclonic epilepsy in infancy
(SMEI, Dravet’s syndrome) whose seizures are not adequately controlled with clobazam and
valproate.
Diacomit should only be administered under the supervision of a paediatrician / paediatric neurologist
experienced in the diagnosis and management of epilepsy in infants and children.
The powder should be mixed in a glass of water and should be taken immediately after mixing during
a meal.
The dose of Diacomit is calculated on a mg/kg body weight basis.
The daily dosage may be administered in 2 or 3 divided doses.
The initiation of adjunctive therapy with Diacomit should be undertaken over 3 days using upwards
dose escalation to reach the recommended dose of 50 mg/kg/day administered in conjunction with
clobazam and valproate. This recommended dose is based on the available clinical study findings and
was the only dose of Diacomit evaluated in the pivotal studies (see section 5.1).
There are no clinical study data to support the clinical safety of Diacomit administered at daily doses
greater than 50 mg/kg/day.
There are no clinical study data to support the use of Diacomit as monotherapy in Dravet’s syndrome.
Dose adjustments of other antiepileptics used in combination with Diacomit
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 Diacomit is provided based on clinical experience.
11
- Clobazam
In the pivotal studies, when the use of Diacomit 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 side
effects or overdosage 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 Diacomit in children with Dravet’s syndrome.
- Valproate
The potential for metabolic interaction between Diacomit and valproate is considered modest and thus,
no modification of valproate dosage should be needed when Diacomit 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.
Abnormal Laboratory Findings
In the event of an abnormal blood count or liver function test finding, the clinical decision for
continuing use or adjusting the dose of Diacomit 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 (see section 4.4).
Effects of food
Diacomit 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.
Effect of formulation
The sachet formulation has a slightly higher C
max
than the capsules 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 5.2).
Children aged less than 3 years
The pivotal clinical evaluation of Diacomit was in children of 3 years of age and over with SMEI. The
clinical decision for use of Diacomit in children with SMEI less than 3 years of age needs to be made
on an individual patient basis taking into consideration the potential clinical benefits and risks. In this
younger group of patients, adjunctive therapy with Diacomit should only be started when the diagnosis
of SMEI has been clinically confirmed (see section 5.1). Data are limited about the use of Diacomit
under 12 months of age.
Patients with renal and hepatic impairment
Diacomit is not recommended for use in patients with impaired hepatic and/or renal function (see
section 4.4).
Hypersensitivity to the active substance or to any of the excipients.
A past history of psychoses in the form of episodes of delirium.
Carbamazepine, phenytoin and phenobarbital should not be used in conjunction with Diacomit in the
management of Dravet’s syndrome. The daily dosage of clobazam and/or valproate should be reduced
according to the onset of side effects whilst on Diacomit therapy (see section 4.2).
Given the frequency of gastrointestinal adverse reactions to treatment with Diacomit and valproate
(anorexia, loss of appetite, nausea, vomiting), the growth rate of children under this combination of
treatment should be carefully monitored.
12
Neutropenia may be associated with the administration of Diacomit, clobazam and valproate. Blood
counts should be assessed prior to starting treatment with Diacomit. Unless otherwise clinically
indicated, blood counts should be checked every 6 months.
Liver function should be assessed prior to starting treatment with Diacomit. Unless otherwise
clinically indicated, liver function should be checked every 6 months.
In the absence of specific clinical data in patients with impaired hepatic or renal function, Diacomit is
not recommended for use in patients with impaired hepatic and/or renal function.
Stiripentol is an inhibitor of the enzymes CYP2C19, CYP3A4 and CYP2D6 and may markedly
increase the plasma concentrations of drugs metabolised by these enzymes and increase the risk of
adverse effects (see section 4.5).
In vitro
studies suggested that stiripentol phase 1 metabolism is
catalyzed by CYP1A2, CYP2C19 and CYP3A4 and possibly other enzymes. Caution is advised when
combining stiripentol with other drugs that inhibit or induce one or more of these enzymes.
The pivotal clinical studies did not include children below 3 years old. As a consequence, it is
recommended that children between 6 months and 3 years of age are carefully monitored whilst on
Diacomit therapy.
Diacomit powder for oral suspension in sachet contains aspartame, a source of phenylalanine.
Therefore it may be harmful for people with phenylketonuria. Patients with rare glucose-galactose
malabsorption should not take this medicine, as the formulation contains glucose. As the flavouring
component contains small amount of sorbitol, patients with hereditary problems of fructose intolerance
should not take this medicine.
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 on stiripentol metabolism, that are known to be
inhibitors of CYP3A4 and substrates of the same enzyme, is not known. Likewise, the effect of
stiripentol on their metabolism is not known.
In vitro
studies suggested that stiripentol phase 1 metabolism is catalyzed by CYP1A2, CYP2C19 and
CYP3A4 and possibly other enzymes. Caution is advised when combining stiripentol with other drugs
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 Diacomit, 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, CYP2D6 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 side effects and adverse reactions.
Caution must be exercised if clinical circumstances require combining stiripentol with drugs
metabolised by CYP2C19 (e.g. citalopram, omeprazole) or CYP3A4 (e.g. several HIV protease
inhibitors, antihistamines, astemizole, chlorpheniramine, calcium channel blockers, statins, oral
contraceptives, codeine) due to the increased risk of adverse events (see further in this section for
antiepileptic drugs). Monitoring of plasma concentrations or adverse effects is recommended. A dose
adjustment may be necessary.
13
Co-administration with CYP3A4 substrates with a narrow therapeutic index should be avoided due to
the markedly increased risk of severe adverse effects.
Data on the potential for inhibition of CYP1A2 are limited, and therefore, interactions with
theophylline and caffeine cannot be excluded. 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, drugs
that are metabolized 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 drugs metabolised by CYP2D6
and that are individually dose titrated.
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:
Undesirable combinations (to be avoided unless strictly necessary)
- Rye ergot alkaloids (ergotamine, dihydroergotamine)
Ergotism with possibility of necrosis of the extremities (inhibition of hepatic elimination of rye ergot).
- Cisapride, halofantrine, pimozide, quinidine, bepridil
Increased risk of cardiac arrhythmias and torsades de pointes/wave burst arrhythmia in particular.
- Immunosuppressants (tacrolimus, cyclosporine, sirolimus)
Raised blood levels of immunosuppressants (decreased hepatic metabolism).
- Statins (atorvastatin, simvastatin, etc.)
Increased risk of dose-dependent adverse reactions such as rhabdomyolysis (decreased hepatic
metabolism of cholesterol-lowering agent).
Combinations requiring precautions
- Midazolam, triazolam, alprazolam
Increased plasma benzodiazepine levels may occur via decreased hepatic metabolism leading to
excessive sedation.
- Theophylline, caffeine
Increased plasma levels of theophylline and caffeine may occur via inhibition of their hepatic
metabolism, potentially leading to toxicity. These combinations should be avoided.
- Chlorpromazine
Stiripentol enhances the central depressant effect of chlorpromazine.
- Effects on other AEDs
Inhibition of CYP450 isoenzyme CYP2C19 and CYP3A4 may provoke pharmacokinetic interactions
(inhibition of their hepatic metabolism) with phenobarbital, primidone, phenytoin, carbamazepine,
clobazam (see section 4.2), valproate (see section 4.2), diazepam (enhanced myorelaxation),
ethosuximide, and tiagabine. The consequences are increased plasma levels of these anticonvulsants
with potential risk of overdose. Clinical monitoring of plasma levels of other anticonvulsants when
combined with stiripentol with possible dose adjustments is recommended.
- Topiramate
In a French compassionate use program for Diacomit, topiramate was added to Diacomit, clobazam
and valproate in 41% of 230 cases. Based on the clinical observations in this group of patients, there is
14
no evidence to suggest that a change in topiramate dose and dosage schedules is needed if co-
administered with stiripentol.
With regard to topiramate, it is considered that potential competition of inhibition on CYP2C19 should
not occur because it probably requires plasma concentrations 5-15 times higher than plasma
concentrations obtained with the standard recommended topiramate dose and dosage schedules.
- Levetiracetam
Levetiracetam does not undergo hepatic metabolism to a major extent. As a result, no pharmacokinetic
metabolic drug interaction between stiripentol and levetiracetam is anticipated.
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 the rate of approximately 3% 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 Diacomit:
No data on exposed pregnancies are available. Animal studies do not indicate direct or indirect
harmful effects with respect to pregnancy, foetal development, parturition or postnatal development at
non-maternotoxic doses (see section 5.3). In view of the indication, administration of Diacomit during
pregnancy and in women of childbearing potential would not be expected. The clinical decision for
use of Diacomit 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.
During pregnancy:
Effective anticonvulsant treatment with Diacomit must not be stopped during pregnancy as worsening
of the disease is potentially harmful to both mother and foetus.
In the absence of human studies on excretion in breast milk, and given that stiripentol passes freely
from plasma into milk in the goat, breast-feeding is not recommended during treatment. In case
Diacomit therapy is continued during breast-feeding, the breast-fed infant should be carefully
observed for potential adverse effects.
Patients with SMEI 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 drugs.
Diacomit may cause dizziness and ataxia that may affect ability to drive and use machines and patients
should not drive or use machinery whilst on Diacomit therapy.
Adverse reactions encountered most often are as follows: very common (≥ 1/10), common (≥ 1/100,
< 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000,
including isolated cases), frequency not known (cannot be estimated from the available data). Within
each frequency grouping, undesirable effects are presented in order of decreasing severity.
15
System/organ classes
System Organ
Class
Very common
Common
Uncommon
Rare
(MedDRA
terminology)
Blood and
lymphatic
system
disorders
Neutropenia
Persistent severe
neutropenia usually
resolves spontaneously
when Diacomit is
stopped.
Metabolism
and nutrition
disorders
Anorexia, loss of
appetite, weight
loss (especially
when combined
with sodium
valproate)
Psychiatric
disorders
Insomnia
Aggressiveness,
irritability, behaviour
disorders, opposing
behaviour,
hyperexcitability, sleep
disorders
Nervous system
disorders
Drowsiness,
ataxia, hypotonia,
dystonia
Hyperkinesias
Eye disorders
Diplopia (when
used in
combination
with
carbamazepine)
Gastrointestinal
disorders
Nausea, vomiting
Skin and
subcutaneous
tissue disorders
Photosensitivity,
rash, cutaneous
allergy, urticaria
General
disorders
Fatigue
Investigations
Raised γGT (notably
when combined with
carbamazepine and
valproate).
Liver function
test abnormal
Many of the above adverse reactions are often due to an increase in plasma levels of other
anticonvulsant medicinal products (see sections 4.4 and 4.5) and may regress when the dose of these
medicinal products is reduced.
Data on clinical overdose are not available. Treatment is supportive (symptomatic measures in
intensive care units).
16
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other Antiepileptics, ATC code: N03AX17
In animal models, stiripentol antagonizes seizures induced by electric shock, pentetrazole and
bicuculline. In rodent models, stiripentol appears to increase brain levels of gamma-aminobutyric acid
(GABA) - the major inhibitory neurotransmitter in mammalian brain. This could occur by inhibition of
synaptosomal uptake of GABA and/or inhibition of GABA transaminase. Stiripentol has also been
shown to enhance GABAA receptor-mediated transmission in the immature rat hippocampus and
increase the mean open-duration (but not the frequency) of GABAA receptor chloride channels by a
barbiturate-like mechanism. Stiripentol potentiates the efficacy of other anticonvulsants, such as
carbamazepine, sodium valproate, phenytoin, phenobarbital and many benzodiazepines, as the result
of pharmacokinetic interactions. The second 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 drugs.
The pivotal clinical evaluation of Diacomit was in children of 3 years of age and over with SMEI.
A French compassionate use program included children from 6 months of age because the diagnosis of
Dravet’s syndrome may be made with confidence at that age in some patients. The clinical decision for
use of Diacomit in children with SMEI less than 3 years of age needs to be made on an individual
patient basis taking into consideration the potential clinical benefits and risks (see section 4.2).
41 children with SMEI were included in a randomised, placebo-controlled, add-on trial. After a
baseline period of 1 month, placebo (n=20) or stiripentol (n=21) was added to valproate and clobazam
during a double-blind period of 2 months. Patients then received stiripentol in an open fashion.
Responders were defined as having more than 50% reduction in the frequency of clonic (or tonic-
clonic) seizures during the second month of the double-blind period compared with baseline. 15 (71%)
patients were responders on stiripentol (including nine free of clonic or tonic-clonic seizures), whereas
there was only one (5%) on placebo (none was seizure free; stiripentol 95% CI 52.1-90.7 vs. placebo
0-14.6). The 95% CI of the difference was 42.2-85.7. Percentage of change from baseline was higher
on stiripentol (-69%) than on placebo (+7%), p<0.0001. 21 patients on stiripentol had moderate side-
effects (drowsiness, loss of appetite) compared with eight on placebo, but side-effects disappeared
when the dose of comedication was decreased in 12 of the 21 cases (Chiron et al, Lancet, 2000).
This medicinal product has been authorised under a “conditional approval” scheme. This means that
further evidence on this medicinal product is awaited, in particular about the efficacy of stiripentol in
combination with the maximum safe dose of the add-on therapy. A study is being conducted to
investigate this. The European Medicines Agency (EMA) will review new information on the product
every year and this SmPC will be updated as necessary.
5.2 Pharmacokinetic properties
The following pharmacokinetic properties of stiripentol have been reported from studies in adult
healthy volunteers and adult patients.
Absorption / Bioavailability:
Stiripentol is quickly absorbed, with a time to peak plasma concentration of about 1.5 hours. 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.
Distribution:
Stiripentol binds extensively to circulating plasma proteins (about 99%).
17
Elimination:
Systemic exposure to stiripentol increases markedly compared to dose proportionality. 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.
Metabolism:
Stiripentol is extensively metabolized, 13 different metabolites having been found in urine. The main
metabolic processes are demethylenation and glucuronidation, although precise identification of the
enzymes involved has not yet been achieved.
On the basis of
in vitro
studies, the principal liver cytochrome P450 isoenzymes involved in phase 1
metabolism are considered to be CYP1A2, CYP2C19 and CYP3A4.
Excretion:
Most stiripentol is excreted via the kidney.
Urinary metabolites of stiripentol accounted collectively for the majority (73%) of an oral acute dose
whereas a further 13-24% was recovered in faeces as unchanged drug.
max max
of the sachet was
slightly higher (23%) compared with the capsule and did not meet the criteria for bioequivalence. T
max
was similar with both formulations. Clinical supervision is recommended if switching between the
stiripentol capsule and powder for oral suspension in sachet formulations.
Paediatric Population Pharmacokinetic Study
A population pharmacokinetic study was conducted in 35 children with Dravet Syndrome treated with
stiripentol and two drugs not known to affect stiripentol pharmacokinetics, valproate and clobazam.
The median age was 7.3 years (range: 1 to 17.6 years) and the median daily dose of stiripentol was
45.4 mg/kg/day (range: 27.1 to 89.3 mg/kg/day) received in two or three divided doses.
The data were best fitted with a one compartment model with first order absorption and elimination
processes. The population estimate for the absorption rate constant Ka was 2.08 hr -1 (standard
deviation of random effect = 122%). Clearance and volume of distribution were related to body weight
by an allometric model with exponents of 0.433 and 1, respectively: as body weight increased from 10
to 60 kg, apparent oral clearance increased from 2.60 to 5.65 L/hr and apparent volume of distribution
increased from 32.0 to 191.8
K
As a result, elimination half-life increased from 8.5hr (for 10 kg) to
23.5 hr (for 60 kg).
5.3 Preclinical safety data
Toxicity studies in animals (rat, monkey, mouse) have not revealed any consistent pattern of toxicity
apart from liver enlargement associated with hepatocellular hypertrophy, which occurred when high
doses of stiripentol were administered to both rodents and nonrodents. This finding is considered to be
an adaptive response to a high metabolic burden on the liver.
Stiripentol was not teratogenic when tested in the rat and rabbit; in one study in the mouse, but not in
several other similar studies, a low incidence of cleft palate formation was observed at a maternotoxic
dose (800 mg/kg/day). These studies in mice and rabbits were undertaken prior to the introduction of
Good Laboratory Practice requirements. Studies in the rat on fertility and general reproductive
performance and on pre- and postnatal development were uneventful except for a minor reduction in
the survival of pups nursed by mothers exhibiting toxic responses to stiripentol at a dose of
800 mg/kg/day (see section 4.6).
Genotoxicity studies have not detected any mutagenic or clastogenic activity.
Carcinogenicity studies gave negative results in the rat. In the mouse there was only a small increase
in the incidence of hepatic adenomas and carcinomas in animals treated with 200 or 600 mg/kg/day for
18
Bioavailability / Bioequivalence:
Relative bioavailabilty 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. The two
formulations were bioequivalent in terms of AUC but not in terms of C . C
78 weeks but not in those given 60 mg/kg/day. In view of the lack of genotoxicity of stiripentol and
the well known, special susceptibility of the mouse liver to tumour formation in the presence of
hepatic enzyme induction, this finding is not considered to indicate a risk of tumorigenicity in patients.
6.
6.1 List of excipients
povidone K29/32
sodium starch glycolate type A
glucose liquid, spray dried
erythrosine (E127)
titanium dioxide (E171)
aspartame (E951)
tutti frutti flavour (contains sorbitol)
carmellose sodium
hydroxyethylcellulose.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
Store in the original package in order to protect from light.
6.5 Nature and contents of container
Sachets are made with a composite paper/aluminium/polyethylene film.
Boxes of 30, 60 and 90 sachets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements.
7.
Biocodex, 7 Avenue Gallieni, 94250 Gentilly, France.
8.
EU/1/06/367/007-9
9.
Date of first authorization: 04 January 2007
Date of latest renewal:
2/
Detailed information on this product is available on the website of the European Medicines Agency
20
1.
Diacomit 500 mg powder for oral suspension in sachets.
2.
Each sachet contains 500 mg of stiripentol.
Excipients: 0.22 mg sodium per sachet.
Each sachet contains 5 mg of aspartame, 1,000 mg of glucose liquid spray and 4.8 mg of sorbitol.
For a full list of excipients, see section 6.1.
3.
Powder for oral suspension
Pale pink crystalline powder
4.
Diacomit is indicated for use in conjunction with clobazam and valproate as adjunctive therapy of
refractory generalized tonic-clonic seizures in patients with severe myoclonic epilepsy in infancy
(SMEI, Dravet’s syndrome) whose seizures are not adequately controlled with clobazam and
valproate.
Diacomit should only be administered under the supervision of a paediatrician / paediatric neurologist
experienced in the diagnosis and management of epilepsy in infants and children.
The powder should be mixed in a glass of water and should be taken immediately after mixing during
a meal.
The dose of Diacomit is calculated on a mg/kg body weight basis.
The daily dosage may be administered in 2 or 3 divided doses.
The initiation of adjunctive therapy with Diacomit should be undertaken over 3 days using upwards
dose escalation to reach the recommended dose of 50 mg/kg/day administered in conjunction with
clobazam and valproate. This recommended dose is based on the available clinical study findings and
was the only dose of Diacomit evaluated in the pivotal studies (see section 5.1).
There are no clinical study data to support the clinical safety of Diacomit administered at daily doses
greater than 50 mg/kg/day.
There are no clinical study data to support the use of Diacomit as monotherapy in Dravet’s syndrome.
Dose adjustments of other antiepileptics used in combination with Diacomit
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 Diacomit is provided based on clinical experience.
21
- Clobazam
In the pivotal studies, when the use of Diacomit 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 side
effects or overdosage 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 Diacomit in children with Dravet’s syndrome.
- Valproate
The potential for metabolic interaction between Diacomit and valproate is considered modest and thus,
no modification of valproate dosage should be needed when Diacomit 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.
Abnormal Laboratory Findings
In the event of an abnormal blood count or liver function test finding, the clinical decision for
continuing use or adjusting the dose of Diacomit 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 (see section 4.4).
Effects of food
Diacomit 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.
Effect of formulation
The sachet formulation has a slightly higher C
max
than the capsules 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 5.2).
Children aged less than 3 years
The pivotal clinical evaluation of Diacomit was in children of 3 years of age and over with SMEI. The
clinical decision for use of Diacomit in children with SMEI less than 3 years of age needs to be made
on an individual patient basis taking into consideration the potential clinical benefits and risks. In this
younger group of patients, adjunctive therapy with Diacomit should only be started when the diagnosis
of SMEI has been clinically confirmed (see section 5.1). Data are limited about the use of Diacomit
under 12 months of age.
Patients with renal and hepatic impairment
Diacomit is not recommended for use in patients with impaired hepatic and/or renal function (see
section 4.4).
Hypersensitivity to the active substance or to any of the excipients.
A past history of psychoses in the form of episodes of delirium.
Carbamazepine, phenytoin and phenobarbital should not be used in conjunction with Diacomit in the
management of Dravet’s syndrome. The daily dosage of clobazam and/or valproate should be reduced
according to the onset of side effects whilst on Diacomit therapy (see section 4.2).
Given the frequency of gastrointestinal adverse reactions to treatment with Diacomit and valproate
(anorexia, loss of appetite, nausea, vomiting), the growth rate of children under this combination of
treatment should be carefully monitored.
22
Neutropenia may be associated with the administration of Diacomit, clobazam and valproate. Blood
counts should be assessed prior to starting treatment with Diacomit. Unless otherwise clinically
indicated, blood counts should be checked every 6 months.
Liver function should be assessed prior to starting treatment with Diacomit. Unless otherwise
clinically indicated, liver function should be checked every 6 months.
In the absence of specific clinical data in patients with impaired hepatic or renal function, Diacomit is
not recommended for use in patients with impaired hepatic and/or renal function.
Stiripentol is an inhibitor of the enzymes CYP2C19, CYP3A4 and CYP2D6 and may markedly
increase the plasma concentrations of drugs metabolised by these enzymes and increase the risk of
adverse effects (see section 4.5).
In vitro
studies suggested that stiripentol phase 1 metabolism is
catalyzed by CYP1A2, CYP2C19 and CYP3A4 and possibly other enzymes. Caution is advised when
combining stiripentol with other drugs that inhibit or induce one or more of these enzymes.
The pivotal clinical studies did not include children below 3 years old. As a consequence, it is
recommended that children between 6 months and 3 years of age are carefully monitored whilst on
Diacomit therapy.
Diacomit powder for oral suspension in sachet contains aspartame, a source of phenylalanine.
Therefore it may be harmful for people with phenylketonuria. Patients with rare glucose-galactose
malabsorption should not take this medicine, as the formulation contains glucose. As the flavouring
component contains small amount of sorbitol, patients with hereditary problems of fructose intolerance
should not take this medicine.
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 on stiripentol metabolism, that are known to be
inhibitors of CYP3A4 and substrates of the same enzyme, is not known. Likewise, the effect of
stiripentol on their metabolism is not known.
In vitro
studies suggested that stiripentol phase 1 metabolism is catalyzed by CYP1A2, CYP2C19 and
CYP3A4 and possibly other enzymes. Caution is advised when combining stiripentol with other drugs
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 Diacomit, 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, CYP2D6 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 side effects and adverse reactions.
Caution must be exercised if clinical circumstances require combining stiripentol with drugs
metabolised by CYP2C19 (e.g. citalopram, omeprazole) or CYP3A4 (e.g. several HIV protease
inhibitors, antihistamines, astemizole, chlorpheniramine, calcium channel blockers, statins, oral
contraceptives, codeine) due to the increased risk of adverse events (see further in this section for
antiepileptic drugs). Monitoring of plasma concentrations or adverse effects is recommended. A dose
adjustment may be necessary.
23
Co-administration with CYP3A4 substrates with a narrow therapeutic index should be avoided due to
the markedly increased risk of severe adverse effects.
Data on the potential for inhibition of CYP1A2 are limited, and therefore, interactions with
theophylline and caffeine cannot be excluded. 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, drugs
that are metabolized 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 drugs metabolised by CYP2D6
and that are individually dose titrated.
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:
Undesirable combinations (to be avoided unless strictly necessary)
- Rye ergot alkaloids (ergotamine, dihydroergotamine)
Ergotism with possibility of necrosis of the extremities (inhibition of hepatic elimination of rye ergot).
- Cisapride, halofantrine, pimozide, quinidine, bepridil
Increased risk of cardiac arrhythmias and torsades de pointes/wave burst arrhythmia in particular.
- Immunosuppressants (tacrolimus, cyclosporine, sirolimus)
Raised blood levels of immunosuppressants (decreased hepatic metabolism).
- Statins (atorvastatin, simvastatin, etc.)
Increased risk of dose-dependent adverse reactions such as rhabdomyolysis (decreased hepatic
metabolism of cholesterol-lowering agent).
Combinations requiring precautions
- Midazolam, triazolam, alprazolam
Increased plasma benzodiazepine levels may occur via decreased hepatic metabolism leading to
excessive sedation.
- Theophylline, caffeine
Increased plasma levels of theophylline and caffeine may occur via inhibition of their hepatic
metabolism, potentially leading to toxicity. These combinations should be avoided.
- Chlorpromazine
Stiripentol enhances the central depressant effect of chlorpromazine.
- Effects on other AEDs
Inhibition of CYP450 isoenzyme CYP2C19 and CYP3A4 may provoke pharmacokinetic interactions
(inhibition of their hepatic metabolism) with phenobarbital, primidone, phenytoin, carbamazepine,
clobazam (see section 4.2), valproate (see section 4.2), diazepam (enhanced myorelaxation),
ethosuximide, and tiagabine. The consequences are increased plasma levels of these anticonvulsants
with potential risk of overdose. Clinical monitoring of plasma levels of other anticonvulsants when
combined with stiripentol with possible dose adjustments is recommended.
- Topiramate
In a French compassionate use program for Diacomit, topiramate was added to Diacomit, clobazam
and valproate in 41% of 230 cases. Based on the clinical observations in this group of patients, there is
24
no evidence to suggest that a change in topiramate dose and dosage schedules is needed if co-
administered with stiripentol.
With regard to topiramate, it is considered that potential competition of inhibition on CYP2C19 should
not occur because it probably requires plasma concentrations 5-15 times higher than plasma
concentrations obtained with the standard recommended topiramate dose and dosage schedules.
- Levetiracetam
Levetiracetam does not undergo hepatic metabolism to a major extent. As a result, no pharmacokinetic
metabolic drug interaction between stiripentol and levetiracetam is anticipated.
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 the rate of approximately 3% 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 Diacomit:
No data on exposed pregnancies are available. Animal studies do not indicate direct or indirect
harmful effects with respect to pregnancy, foetal development, parturition or postnatal development at
non-maternotoxic doses (see section 5.3). In view of the indication, administration of Diacomit during
pregnancy and in women of childbearing potential would not be expected. The clinical decision for
use of Diacomit 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.
During pregnancy:
Effective anticonvulsant treatment with Diacomit must not be stopped during pregnancy as worsening
of the disease is potentially harmful to both mother and foetus.
In the absence of human studies on excretion in breast milk, and given that stiripentol passes freely
from plasma into milk in the goat, breast-feeding is not recommended during treatment. In case
Diacomit therapy is continued during breast-feeding, the breast-fed infant should be carefully
observed for potential adverse effects.
Patients with SMEI 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 drugs.
Diacomit may cause dizziness and ataxia that may affect ability to drive and use machines and patients
should not drive or use machinery whilst on Diacomit therapy.
Adverse reactions encountered most often are as follows: very common (≥ 1/10), common (≥ 1/100,
< 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000,
including isolated cases), frequency not known (cannot be estimated from the available data). Within
each frequency grouping, undesirable effects are presented in order of decreasing severity.
25
System/organ classes
System Organ
Class
Very common
Common
Uncommon
Rare
(MedDRA
terminology)
Blood and
lymphatic
system
disorders
Neutropenia
Persistent severe
neutropenia usually
resolves spontaneously
when Diacomit is
stopped.
Metabolism
and nutrition
disorders
Anorexia, loss of
appetite, weight
loss (especially
when combined
with sodium
valproate)
Psychiatric
disorders
Insomnia
Aggressiveness,
irritability, behaviour
disorders, opposing
behaviour,
hyperexcitability, sleep
disorders
Nervous system
disorders
Drowsiness,
ataxia, hypotonia,
dystonia
Hyperkinesias
Eye disorders
Diplopia (when
used in
combination
with
carbamazepine)
Gastrointestinal
disorders
Nausea, vomiting
Skin and
subcutaneous
tissue disorders
Photosensitivity,
rash, cutaneous
allergy, urticaria
General
disorders
Fatigue
Investigations
Raised γGT (notably
when combined with
carbamazepine and
valproate).
Liver function
test abnormal
Many of the above adverse reactions are often due to an increase in plasma levels of other
anticonvulsant medicinal products (see sections 4.4 and 4.5) and may regress when the dose of these
medicinal products is reduced.
Data on clinical overdose are not available. Treatment is supportive (symptomatic measures in
intensive care units).
26
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other Antiepileptics, ATC code: N03AX17
In animal models, stiripentol antagonizes seizures induced by electric shock, pentetrazole and
bicuculline. In rodent models, stiripentol appears to increase brain levels of gamma-aminobutyric acid
(GABA) - the major inhibitory neurotransmitter in mammalian brain. This could occur by inhibition of
synaptosomal uptake of GABA and/or inhibition of GABA transaminase. Stiripentol has also been
shown to enhance GABAA receptor-mediated transmission in the immature rat hippocampus and
increase the mean open-duration (but not the frequency) of GABAA receptor chloride channels by a
barbiturate-like mechanism. Stiripentol potentiates the efficacy of other anticonvulsants, such as
carbamazepine, sodium valproate, phenytoin, phenobarbital and many benzodiazepines, as the result
of pharmacokinetic interactions. The second 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 drugs.
The pivotal clinical evaluation of Diacomit was in children of 3 years of age and over with SMEI.
A French compassionate use program included children from 6 months of age because the diagnosis of
Dravet’s syndrome may be made with confidence at that age in some patients. The clinical decision for
use of Diacomit in children with SMEI less than 3 years of age needs to be made on an individual
patient basis taking into consideration the potential clinical benefits and risks (see section 4.2).
41 children with SMEI were included in a randomised, placebo-controlled, add-on trial. After a
baseline period of 1 month, placebo (n=20) or stiripentol (n=21) was added to valproate and clobazam
during a double-blind period of 2 months. Patients then received stiripentol in an open fashion.
Responders were defined as having more than 50% reduction in the frequency of clonic (or tonic-
clonic) seizures during the second month of the double-blind period compared with baseline. 15 (71%)
patients were responders on stiripentol (including nine free of clonic or tonic-clonic seizures), whereas
there was only one (5%) on placebo (none was seizure free; stiripentol 95% CI 52.1-90.7 vs. placebo
0-14.6). The 95% CI of the difference was 42.2-85.7. Percentage of change from baseline was higher
on stiripentol (-69%) than on placebo (+7%), p<0.0001. 21 patients on stiripentol had moderate side-
effects (drowsiness, loss of appetite) compared with eight on placebo, but side-effects disappeared
when the dose of comedication was decreased in 12 of the 21 cases (Chiron et al, Lancet, 2000).
This medicinal product has been authorised under a “conditional approval” scheme. This means that
further evidence on this medicinal product is awaited, in particular about the efficacy of stiripentol in
combination with the maximum safe dose of the add-on therapy. A study is being conducted to
investigate this. The European Medicines Agency (EMA) will review new information on the product
every year and this SmPC will be updated as necessary.
5.2 Pharmacokinetic properties
The following pharmacokinetic properties of stiripentol have been reported from studies in adult
healthy volunteers and adult patients.
Absorption / Bioavailability:
Stiripentol is quickly absorbed, with a time to peak plasma concentration of about 1.5 hours. 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.
Distribution:
Stiripentol binds extensively to circulating plasma proteins (about 99%).
27
Elimination:
Systemic exposure to stiripentol increases markedly compared to dose proportionality. 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.
Metabolism:
Stiripentol is extensively metabolized, 13 different metabolites having been found in urine. The main
metabolic processes are demethylenation and glucuronidation, although precise identification of the
enzymes involved has not yet been achieved.
On the basis of
in vitro
studies, the principal liver cytochrome P450 isoenzymes involved in phase 1
metabolism are considered to be CYP1A2, CYP2C19 and CYP3A4.
Excretion:
Most stiripentol is excreted via the kidney.
Urinary metabolites of stiripentol accounted collectively for the majority (73%) of an oral acute dose
whereas a further 13-24% was recovered in faeces as unchanged drug.
max max
of the sachet was
slightly higher (23%) compared with the capsule and did not meet the criteria for bioequivalence. T
max
was similar with both formulations. Clinical supervision is recommended if switching between the
stiripentol capsule and powder for oral suspension in sachet formulations.
Paediatric Population Pharmacokinetic Study
A population pharmacokinetic study was conducted in 35 children with Dravet Syndrome treated with
stiripentol and two drugs not known to affect stiripentol pharmacokinetics, valproate and clobazam.
The median age was 7.3 years (range: 1 to 17.6 years) and the median daily dose of stiripentol was
45.4 mg/kg/day (range: 27.1 to 89.3 mg/kg/day) received in two or three divided doses.
The data were best fitted with a one compartment model with first order absorption and elimination
processes. The population estimate for the absorption rate constant Ka was 2.08 hr -1 (standard
deviation of random effect = 122%). Clearance and volume of distribution were related to body weight
by an allometric model with exponents of 0.433 and 1, respectively: as body weight increased from 10
to 60 kg, apparent oral clearance increased from 2.60 to 5.65 L/hr and apparent volume of distribution
increased from 32.0 to 191.8
K
As a result, elimination half-life increased from 8.5hr (for 10 kg) to
23.5 hr (for 60 kg).
5.3 Preclinical safety data
Toxicity studies in animals (rat, monkey, mouse) have not revealed any consistent pattern of toxicity
apart from liver enlargement associated with hepatocellular hypertrophy, which occurred when high
doses of stiripentol were administered to both rodents and nonrodents. This finding is considered to be
an adaptive response to a high metabolic burden on the liver.
Stiripentol was not teratogenic when tested in the rat and rabbit; in one study in the mouse, but not in
several other similar studies, a low incidence of cleft palate formation was observed at a maternotoxic
dose (800 mg/kg/day). These studies in mice and rabbits were undertaken prior to the introduction of
Good Laboratory Practice requirements. Studies in the rat on fertility and general reproductive
performance and on pre- and postnatal development were uneventful except for a minor reduction in
the survival of pups nursed by mothers exhibiting toxic responses to stiripentol at a dose of
800 mg/kg/day (see section 4.6).
Genotoxicity studies have not detected any mutagenic or clastogenic activity.
Carcinogenicity studies gave negative results in the rat. In the mouse there was only a small increase
in the incidence of hepatic adenomas and carcinomas in animals treated with 200 or 600 mg/kg/day for
28
Bioavailability / Bioequivalence:
Relative bioavailabilty 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. The two
formulations were bioequivalent in terms of AUC but not in terms of C . C
78 weeks but not in those given 60 mg/kg/day. In view of the lack of genotoxicity of stiripentol and
the well known, special susceptibility of the mouse liver to tumour formation in the presence of
hepatic enzyme induction, this finding is not considered to indicate a risk of tumorigenicity in patients.
6.
6.1 List of excipients
povidone K29/32
sodium starch glycolate type A
glucose liquid, spray dried
erythrosine (E127)
titanium dioxide (E171)
aspartame (E951)
tutti frutti flavour (contains sorbitol)
carmellose sodium
hydroxyethylcellulose.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
Store in the original package in order to protect from light.
6.5 Nature and contents of container
Sachets are made with a composite paper/aluminium/polyethylene film.
Boxes of 30, 60 and 90 sachets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements.
7.
Biocodex, 7 Avenue Gallieni, 94250 Gentilly, France.
8.
EU/1/06/367/010-12
9.
Date of first authorization: 04 January 2007
Date of latest renewal:
3/
Detailed information on this product is available on the website of the European Medicines Agency
30
ANNEX II
A. MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
31
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
B. CONDITIONS OF THE MARKETING AUTHORISATION
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product
Characteristics, section 4.2).
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 1.0
(01-Mar-2006) presented in Module 1.8.1. of the Marketing Authorisation Application, is in place and
functioning before and whilst the product is on the market.
Risk Management plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 2.0 (08-Jul-2009) of the Risk Management Plan
(RMP) presented in Module 1.8.2. of the Marketing Authorisation and any subsequent updates of the
RMP agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, any
updated RMP should be submitted at the same time as the following Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
•
At the request of the EMA
C. SPECIFIC OBLIGATIONS TO BE FULFILLED BY THE MARKETING
AUTHORISATION HOLDER
Area
1
Description
Due date
2
Clinical
The Marketing Authorisation Holder shall complete the study
30 July 2011
32
within the specified time frame. The results of which shall be
taken into account in the risk benefit balance during the
assessment of the application for a renewal:
1.
A multicentre randomised controlled trial comparing
topiramate, stiripentol and clobazam as adjunctive therapy
to valproate and clobazam in paediatric patients with
Dravet’s syndrome (SMEI) not adequately controlled with
clobazam and valproate, and auxiliary pharmacogenetic
study by 30 July 2011 (STP 167).
33
ANNEX III
LABELLING AND PACKAGE LEAFLET
34
A. LABELLING
35
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
1.
Diacomit 250 mg capsules
Stiripentol
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
1 capsule contains 250 mg stiripentol.
3.
LIST OF EXCIPIENTS
0.16 mg sodium per capsule
See leaflet for further information.
4.
30 hard capsules
60 hard capsules
90 hard capsules
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For oral use.
These capsules should be swallowed whole with water. The capsules should not be chewed.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP.:
9.
SPECIAL STORAGE CONDITIONS
Store in the original package in order to protect from light.
36
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
EU/1/06/367/001 30 capsules
EU/1/06/367/002 60 capsules
EU/1/06/367/003 90 capsules
13. BATCH NUMBER
Lot:
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Diacomit 250 mg capsules
37
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
BOTTLE LABEL TEXT
1.
Diacomit 250 mg capsules
Stiripentol
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
1 capsule contains 250 mg stiripentol.
3.
LIST OF EXCIPIENTS
0.16 mg sodium per capsule
See leaflet for further information.
4.
30 hard capsules
60 hard capsules
90 hard capsules
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For oral use.
These capsules should be swallowed whole with water. The capsules should not be chewed.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP.:
9.
SPECIAL STORAGE CONDITIONS
Store in the original package in order to protect from light.
38
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
EU/1/06/367/001 30 capsules
EU/1/06/367/002 60 capsules
EU/1/06/367/003 90 capsules
13. BATCH NUMBER
Lot:
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
4/
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
1.
Diacomit 500 mg capsules
Stiripentol
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
1 capsule contains 500 mg stiripentol.
3.
LIST OF EXCIPIENTS
0.32 mg sodium per capsule.
See leaflet for further information.
4.
30 hard capsules
60 hard capsules
90 hard capsules
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For oral use.
These capsules should be swallowed whole with water. The capsules should not be chewed.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP.:
9.
SPECIAL STORAGE CONDITIONS
Store in the original package in order to protect from light.
40
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
EU/1/06/367/004 30 capsules
EU/1/06/367/005 60 capsules
EU/1/06/367/006 90 capsules
13. BATCH NUMBER
Lot:
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Diacomit 500 mg capsules
41
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
BOTTLE LABEL TEXT
1.
Diacomit 500 mg capsules
Stiripentol
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
1 capsule contains 500 mg stiripentol.
3.
LIST OF EXCIPIENTS
0.32 mg sodium per capsule.
See leaflet for further information.
4.
30 hard capsules
60 hard capsules
90 hard capsules
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For oral use.
These capsules should be swallowed whole with water. The capsules should not be chewed.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP.:
9.
SPECIAL STORAGE CONDITIONS
Store in the original package in order to protect from light.
42
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
EU/1/06/367/004 30 capsules
EU/1/06/367/005 60 capsules
EU/1/06/367/006 90 capsules
13. BATCH NUMBER
Lot:
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
43
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
1.
Diacomit 250 mg powder for oral suspension
Stiripentol
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
1 sachet contains 250 mg stiripentol.
3.
LIST OF EXCIPIENTS
Aspartame (E951)
Sorbitol
Glucose liquid spray dried
0.11 mg sodium per sachet
See leaflet for further information.
4.
30 sachets, powder for oral suspension
60 sachets, powder for oral suspension
90 sachets, powder for oral suspension
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For oral use.
The powder should be mixed in a glass of water and should be taken immediately after mixing during
a meal.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP.:
44
9.
SPECIAL STORAGE CONDITIONS
Store in the original package in order to protect from light.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
EU/1/06/367/007 30 sachets
EU/1/06/367/008 60 sachets
EU/1/06/367/009 90 sachets
13. BATCH NUMBER
Lot:
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Diacomit 250 mg powder for oral suspension
45
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
SACHET LABEL TEXT
1.
Diacomit 250 mg powder for oral suspension
Stiripentol
For oral use.
2.
METHOD OF ADMINISTRATION
Read the package leaflet before use.
3.
EXPIRY DATE
EXP.:
4.
BATCH NUMBER
Lot:
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
250 mg stiripentol
6.
OTHER
Store in the original package in order to protect from light.
46
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
1.
Diacomit 500 mg powder for oral suspension
Stiripentol
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
1 sachet contains 500 mg stiripentol.
3.
LIST OF EXCIPIENTS
Aspartame (E951)
Sorbitol
Glucose liquid spray dried
0.22 mg sodium per sachet
See leaflet for further information.
4.
30 sachets, powder for oral suspension
60 sachets, powder for oral suspension
90 sachets, powder for oral suspension
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For oral use.
The powder should be mixed in a glass of water and should be taken immediately after mixing during
a meal.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP.:
47
9.
SPECIAL STORAGE CONDITIONS
Store in the original package in order to protect from light.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
EU/1/06/367/010 30 sachets
EU/1/06/367/011 60 sachets
EU/1/06/367/012 90 sachets
13. BATCH NUMBER
Lot:
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Diacomit 500 mg powder for oral suspension
48
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
SACHET LABEL TEXT
1.
Diacomit 500 mg powder for oral suspension
Stiripentol
For oral use.
2.
METHOD OF ADMINISTRATION
Read the package leaflet before use.
3.
EXPIRY DATE
EXP.:
4.
BATCH NUMBER
Lot:
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
500 mg stiripentol
6.
OTHER
Store in the original package in order to protect from light.
5/
B. PACKAGE LEAFLET
50
PACKAGE LEAFLET: INFORMATION FOR THE USER
Diacomit 250 mg hard capsules
Stiripentol
Diacomit 500 mg hard capsules
Stiripentol
Read all of this leaflet carefully before your child starts taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your child’s doctor or pharmacist.
-
This medicine has been prescribed for your child. Do not pass it on to others. It may harm them,
even if their symptoms are the same as your child’s.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your child’s doctor or pharmacist.
In this leaflet:
1.
What Diacomit is and what it is used for
2.
Before your child takes Diacomit
3.
How to take Diacomit
5
How to store Diacomit
6.
Further information
1.
WHAT DIACOMIT IS AND WHAT IT IS USED FOR
Diacomit belongs to a group of medicines called antiepileptics.
It is used in conjunction with clobazam and valproate to treat a certain form of epilepsy called severe
myoclonic epilepsy in infancy (Dravet’s syndrome), which affects 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.
2.
BEFORE YOUR CHILD TAKES DIACOMIT
Your child must NOT take Diacomit
•
if your child is
allergic
(hypersensitive) to stiripentol or to any of the other ingredients of
Diacomit.
•
if your child has ever experienced
attacks of delirium.
Take special care with Diacomit
•
if your child has
kidney or liver problems.
•
if your child is using
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 drug);
-
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).
51
4.
Possible side effects
•
if your child uses one of the following products:
-
antiepileptic medicines containing:
phenobarbital, primidone, phenytoin, carbamazepine, diazepam.
-
medicines containing:
midazolam or triazolam (drugs 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).
-
medicines, beverages and foods containing:
caffeine or theophylline (these substances help restore mental alertness). The combination with
Diacomit should be avoided as it may increase their blood levels, leading to digestive disorders,
racing heart and insomnia.
Using other medicines
If your child needs to use other medicines, please see above
“Take special care with Diacomit”
.
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.
Taking Diacomit with food and drink
Your child should take Diacomit with food, it should NOT be taken on an empty stomach. Do NOT
take Diacomit with milk or dairy products (yoghurt, soft cream cheeses, etc), fruit juice, fizzy drinks
or food and drinks that contain caffeine or theophylline (for example cola, chocolate, coffee, tea and
energy drinks).
Pregnancy
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.
Ask your child’s doctor or pharmacist for advice before taking any medicine.
Breast-feeding
Breast-feeding is not recommended during treatment with this medicine.
Ask your child’s doctor or pharmacist for advice before taking any medicine.
Driving and using machines
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.
3.
HOW TO TAKE DIACOMIT
Your child should always take these capsules exactly as your child’s doctor has told you. You should
check with your child’s doctor or pharmacist if you are not sure.
Dosage
The dose is adjusted by the doctor according to your child’s condition, generally 50 mg per kg
bodyweight and per day.
How to take the Diacomit capsules
These capsules should be swallowed whole with water. The capsules should not be chewed. For food
and drinks to be avoided, see the section
“Taking Diacomit with food and drink”
above.
When to take Diacomit
Your child should take this medicine two or three times a day at regular intervals as directed by your
child’s doctor.
52
Dose adjustment
Any increase in dose should be gradual over 3 days while the dose of the other antiepileptic
medicine(s) is reduced at the same time. Your child’s doctor will tell you the new dose 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 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 doctor.
If your child takes more Diacomit than he or she should
Contact your child’s doctor if you know or think your child has taken more medicine than he or she
should have.
If 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 product, ask your child’s doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Diacomit can cause side effects, although not everybody gets them.
Very common side effects
(more than one in 10 patients):
•
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
(muscle disorders).
Common side effects
(between one in 100 patients and one in 10 patients):
•
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
(between one in 1,000 patients and one in 100 patients):
•
double vision when used in combination with the antiepileptic medicine carbamazepine;
•
sensitivity to light;
•
rash, skin allergy, urticaria (pinkish, itchy swellings on the skin);
53
•
fatigue (tiredness).
To eliminate these side effects, your child’s doctor may have to change the dose of concomitant
medicines, or the dosage of Diacomit.
If any of these side effects persists or gets serious, or if you notice any side effects not listed in this
leaflet, please tell your child’s doctor or pharmacist.
5.
HOW TO STORE DIACOMIT
•
Keep out of the reach and sight of children.
•
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.
•
Store in the original package in order to protect from light.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Diacomit 250 mg contains
•
The active substance is stiripentol. Each capsule contains 250 mg of stiripentol.
•
The other ingredients in this medicine are povidone K29/32, sodium starch glycolate type A and
magnesium stearate.
•
The capsule shell is made of gelatin, titanium dioxide (E171), erythrosine (E127), indigotin
(E132).
What Diacomit 500 mg contains
•
The active substance is stiripentol. Each capsule contains 500 mg of stiripentol.
•
The other ingredients in this medicine are povidone K29/32, sodium starch glycolate type A and
magnesium stearate.
•
The capsule shell is made of gelatin, titanium dioxide (E171).
What Diacomit 250 mg looks like and contents of the pack
Diacomit 250 mg capsules are pink.
The capsules are supplied in plastic bottles containing 30, 60 and 90 capsules in cardboard cartons.
Not all pack sizes may be marketed.
Diacomit is also available as 500 mg capsules for oral use and 250 mg and 500 mg powder for oral
suspension in sachets.
What Diacomit 500 mg looks like and contents of the pack
Diacomit 500 mg capsules are white.
The capsules are supplied in plastic bottles containing 30, 60 and 90 capsules in cardboard cartons.
Not all pack sizes may be marketed.
Diacomit is also available as 250 mg capsules for oral use and 250 mg and 500 mg powder for oral
suspension in sachets.
Marketing Authorisation Holder
7 avenue Gallieni - 94250 Gentilly - France
Tel: + 33 1 41 24 30 00 - e-mail:
webar@biocodex.fr
54
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
AT/BE/BG/CZ/CY/EE/EL/ES/FR/HU/IE/IS/IT/LT/LU/LV/MT/NL/PL/PT/RO/SI/SK/UK
7 avenue Gallieni - F-94250 Gentilly
Tél/Tel.: + 33 (0)1 41 24 30 00
e-mail: webar@biocodex.fr
DE
Desitin Arzneimittel GmbH
Weg beim Jäger 214
D-22335 Hamburg
Tel: +49 (0)40 59101 525
e-mail:
epi.info@desitin.de
DK
Desitin Pharma AS
Havnegade 55, st. tv.
1058 Kopenhagen K
Denmark
Tel: 0045-33-73 00 73
e-mail: desitin@desitin.dk
NO
Desitin Pharma AS
Niels Leuchs vei 99
1359 Eiksmarka
Norway
Tel: 0047 67 15 92 30
e-mail: firmapost@desitin.no
FI/SE
Desitin Pharma AB
Krokslätts Torg 5
43137 Mölndal
Sweden
Tel: 0046-31-20 23 10
e-mail: info@desitin.se
This leaflet was last approved in
This medicine has been given “conditional approval”. This means that there is more definitive
evidence to come about this medicine for the treatment of this form of epilepsy when stiripentol is
used in conjunction with clobazam and valproate. The European Medicines Agency (EMA) will
review new information on the medicine every year and this leaflet will be updated as necessary.
Detailed information on this medicine is available on the European Medicine Agency (EMA) website:
http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments.
55
PACKAGE LEAFLET: INFORMATION FOR THE USER
Diacomit 250 mg powder for oral suspension in sachets
Stiripentol
Diacomit 500 mg powder for oral suspension in sachets
Stiripentol
Read all of this leaflet carefully before your child starts taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your child’s doctor or pharmacist.
-
This medicine has been prescribed for your child. Do not pass it on to others. It may harm them,
even if their symptoms are the same as your child’s.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your child’s doctor or pharmacist.
In this leaflet:
1.
What Diacomit is and what it is used for
2.
Before your child takes Diacomit
3.
How to take Diacomit
5
How to store Diacomit
6.
Further information
1.
WHAT DIACOMIT IS AND WHAT IT IS USED FOR
Diacomit belongs to a group of medicines called antiepileptics.
It is used in conjunction with clobazam and valproate to treat a certain form of epilepsy called severe
myoclonic epilepsy in infancy (Dravet’s syndrome), which affects 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.
2.
BEFORE YOUR CHILD TAKES DIACOMIT
Your child must NOT take Diacomit
•
if your child is
allergic
(hypersensitive) to stiripentol or to any of the other ingredients of
Diacomit.
•
if your child has ever experienced
attacks of delirium.
Take special care with Diacomit
•
if your child has
kidney or liver problems.
•
if your child is using
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 drug);
-
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).
56
4.
Possible side effects
•
if your child uses one of the following products:
-
antiepileptic medicines containing:
phenobarbital, primidone, phenytoin, carbamazepine, diazepam.
-
medicines containing:
midazolam or triazolam (drugs 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).
-
medicines, beverages and foods containing:
caffeine or theophylline (these substances help restore mental alertness). The combination with
Diacomit should be avoided as it may increase their blood levels, leading to digestive disorders,
racing heart and insomnia.
If your child has problems with certain ingredients of Diacomit (e.g. aspartame, glucose, sorbitol). In
this case, please see below:
“Important information about some of the ingredients of Diacomit”
.
Using other medicines
If your child needs to use other medicines, please see above
“Take special care with Diacomit”
.
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.
Taking Diacomit with food and drink
Your child should take Diacomit with food, it should NOT be taken on an empty stomach. Do NOT
take Diacomit with milk or dairy products (yoghurt, soft cream cheeses, etc), fruit juice, fizzy drinks
or food and drinks that contain caffeine or theophylline (for example cola, chocolate, coffee, tea and
energy drinks).
Pregnancy
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.
Ask your child’s doctor or pharmacist for advice before taking any medicine.
Breast-feeding
Breast-feeding is not recommended during treatment with this medicine.
Ask your child’s doctor or pharmacist for advice before taking any medicine.
Driving and using machines
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.
Important information about some of the ingredients of Diacomit
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 some sugars, contact your doctor
before taking this medicinal product.
3.
HOW TO TAKE DIACOMIT
Your child should always take the contents of each sachet exactly as your child’s doctor has told you.
You should check with your child’s doctor or pharmacist if you are not sure.
Dosage
The dose is adjusted by the doctor according to your child’s condition, generally 50 mg per kg
bodyweight and per day.
57
How to take the Diacomit powder for oral suspension
The powder should be mixed in a glass of water and should be taken immediately after mixing during
the meal. For food and drinks to be avoided, see the section “
Taking Diacomit with food and drink
”
above.
When to take Diacomit
Your child should take this medicine two or three times a day at regular intervals as directed by your
child’s doctor.
Dose adjustment
Any increase in dose should be gradual over 3 days while the dose of the other antiepileptic
medicine(s) is reduced at the same time. Your child’s doctor will tell you the new dose 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 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 doctor.
If your child takes more Diacomit than he or she should
Contact your child’s doctor if you know or think your child has taken more medicine than he or she
should have.
If 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 product, ask your child’s doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Diacomit can cause side effects, although not everybody gets them.
Very common side effects
(more than one in 10 patients):
•
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
(muscle disorders).
Common side effects
(between one in 100 patients and one in 10 patients):
•
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);
58
•
sleep disorders (abnormal sleeping);
•
hyperkinesis (exaggerated movements);
•
nausea, vomiting;
•
a low number of a type of white blood cells.
Uncommon side effects
(between one in 1,000 patients and one in 100 patients):
•
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).
To eliminate these side effects, your child’s doctor may have to change the dose of concomitant
medicines, or the dosage of Diacomit.
If any of these side effects persists or gets serious, or if you notice any side effects not listed in this
leaflet, please tell your child’s doctor or pharmacist.
5.
HOW TO STORE DIACOMIT
•
Keep out of the reach and sight of children.
•
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.
•
Store in the original package in order to protect from light.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Diacomit 250 mg contains
•
The active substance is stiripentol. Each sachet contains 250 mg of stiripentol.
•
The other ingredients in this medicine are povidone K29/32, sodium starch glycolate type A,
glucose liquid (spray dried), erythrosine (E127), titanium dioxide (E171), aspartame (E951),
tutti frutti flavour (contains sorbitol), carmellose sodium, hydroxyethylcellulose.
What Diacomit 500 mg contains
•
The active substance is stiripentol. Each sachet contains 500 mg of stiripentol.
•
The other ingredients in this medicine are povidone K29/32, sodium starch glycolate type A,
glucose liquid (spray dried), erythrosine (E127), titanium dioxide (E171), aspartame (E951),
tutti frutti flavour (contains sorbitol), carmellose sodium, hydroxyethylcellulose.
What Diacomit 250 mg looks like and contents of the pack
This medicine is a pale pink powder supplied in sachets.
Cartons contain either 30, 60, or 90 sachets. Not all pack sizes may be marketed.
Diacomit is also available as 250 mg and 500 mg capsules for oral use and 500 mg powder for oral
suspension in sachets.
What Diacomit 500 mg looks like and contents of the pack
This medicine is a pale pink powder supplied in sachets.
Cartons contain either 30, 60, or 90 sachets. Not all pack sizes may be marketed.
Diacomit is also available as 250 mg and 500 mg capsules for oral use and 250 mg powder for oral
suspension in sachets.
6/
Marketing Authorisation Holder
7 avenue Gallieni - 94250 Gentilly - France
Tel: + 33 1 41 24 30 00 - e-mail: webar@biocodex.fr
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
AT/BE/BG/CZ/CY/EE/EL/ES/FR/HU/IE/IS/IT/LT/LU/LV/MT/NL/PL/PT/RO/SI/SK/UK
7 avenue Gallieni - F-94250 Gentilly
Tél/Tel.: + 33 (0)1 41 24 30 00
e-mail: webar@biocodex.fr
DE
Desitin Arzneimittel GmbH
Weg beim Jäger 214
D-22335 Hamburg
Tel: +49 (0)40 59101 525
e-mail: epi.info@desitin.de
DK
Desitin Pharma AS
Havnegade 55, st. tv.
1058 Kopenhagen K
Denmark
Tel: 0045-33-73 00 73
e-mail: desitin@desitin.dk
NO
Desitin Pharma AS
Niels Leuchs vei 99
1359 Eiksmarka
Norway
Tel: 0047 67 15 92 30
e-mail: firmapost@desitin.no
FI/SE
Desitin Pharma AB
Krokslätts Torg 5
43137 Mölndal
Sweden
Tel: 0046-31-20 23 10
e-mail: info@desitin.se
This leaflet was last approved in
This medicine has been given “conditional approval”. This means that there is more definitive
evidence to come about this medicine for the treatment of this form of epilepsy when stiripentol is
used in conjunction with clobazam and valproate. The European Medicines Agency (EMA) will
review new information on the medicine every year and this leaflet will be updated as necessary.
Detailed information on this medicine is available on the European Medicine Agency (EMA) website:
http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments.
60
1
Areas: Quality, Non-clinical, Clinical, Pharmacovigilance
2
Due date for the follow-up measure or for the first interim report if a precise date cannot be committed to
61
Source: European Medicines Agency
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