Dravet syndrome Pharmacotherapy Consultation
S: Per mother: “My child currently weight 42 lbs, we tried the keto diet in winter – spring ’06 with no change in seizure control. The seizures he has been having recently are a combination of eye fluttering, chin tucking in to chest, drooling, with occasional myoclonics. He displays this activity for 10-15 sec and will continue about his routine, however, they are occurring every 3-5 minutes. Swiping the VNS may help, but they resolve rapidly on their own so it’s difficult to tell.
His “normal” seizure pattern had been early am (4-5am) seizures lasting 2-3 minutes; mostly absence (staring off) with tonic (posturing). Occasionally he’ll become hypoxic and require oxygen. These had been occurring weekly and continue to do so, but they have not required intervention beyond the VNS. (Unfortunately I do not know the VNS settings, they have not been adjusted since last winter).
Last week, however, he had two seizures (one febrile around midnight) that required Diastat. During the non-febrile seizure (6am) we accessed his port and administered Ativan – 20min total activity absence, tonic.
We have used depakote in the past and he did not respond. It’s been a few years, probably about the time we were on the keto diet.
Cognition wise, he tested at 18-20 months; he has little to no expressive language, toddler babble and bye-bye on occasion. It’s difficult to assess his receptive language because of his lack of expressive. He is 8 years old.
O: Current Medication Regimen as of 12/19
8 AM:
250 mg topirimate
0 .25 mg clonazepam
500 mg stiripentol
2 PM
250 mg topirimate
0.25 mg clonazepam
8 PM
250 mg topirimate
0.25mg clonazepam
750 mg stiripentol
Multi Vitamin plus Iron
1/2 Claritin ( 10mg each ) PRN = 5 mg
Topirimate trough: 27.4 read 12/17/08
TDD topirimate: 750 mg (39.5 mg/kg/day)
TDD stiripentol: 1250 mg (66 mg/kg/day)
TDD clonazepam: 0.75 mg (0.04 mg/kg/day)
A: This child has a clinical diagnosis of Dravet syndrome (Ds) with genetic confirmation. He continues to suffer from frequent seizures despite polypharmacy and VNS. His most recent seizure type is described as an “eye flutter” that has progressed to a chin drop, drooling, +/- myoclonics. In addition, he has weekly early am seizures his mother describes as staring of or tonic “posturing” seizures. EEG observation of this seizure type was not documented by the mother and may not be available. Most likely this eyeflutter/head nod seizure type is an atypical absence or complex partial seizure.
While Ds is notably treatment resistant, Chiron and colleagues have shown significant improvement in seizure control with the combination of stiripentol, valproate, and clobazam. Generalized tonic clonic seizures that are prolonged or are status epilepticus in children under twelve are the most likely seizure type to benefit from the stiripentol/valproate/clobazam cocktail. Stiripentol has received conditional EMA approval when used in conjunction with valproate and clobazam in children with Ds. On November 11, 2008, the FDA designated stiripentol (Diacomit) an orphan drug with more studies required for full approval.
The major concern of the FDA is the utility of stiripentol without clobazam and valproate. When used as monotherapy, stiripentol is ineffective in controlling seizures in Ds. Stiripentol has weak gabaergic activity and the proposed major mechanism of action is the synergistic drug interaction between stiripentol, valproate, and clobazam due to interactions with the CYP450 coenzymes 3A4 and 2C19. Stiripentol substantially increases metabolites of valproate and clobazam. Notably, norclobazam is a potent AED. Five metabolites of clonazepam have been identified; one from the 3A4 or oxidative pathway, the others through reductive pathways. This interaction with the oxidative pathway in clonazepam does not produce significant active metabolite.
Conversely, stiripentol serves to “boost” the AED potential of clobazam, a 1,5 benzodiazepine with less potential for psychomotor slowing than typical benzodiazepines such as clonazepan. The 2C19 hydroxylation of clobazam to norclobazam, a highly active AED, raises norclobazam levels as much as threefold. It is believed that this interaction is responsible for the significant improvement in seizure control for children affected by Ds in clinical studies.
Clobazam received orphan drug designation on January 4 2008 and is undergoing additional required studies. As with stiripentol, clobazam can be obtained on a compassionate use basis.
Topirimate has also proven effective in reducing seizure frequency or length in some children with Ds. The manufacter’s recommended dose is 5-9 mg/kg/day up to 30 mg/kg/day. Dose / blood level relationship is linear; however, blood monitoring is not generally performed as dose/response relationship is poorly correlated.
It is well known that topirimate can cause significant psychomotor and language impairment. Some studies suggest this is dose proportionate.
P: Stiripentol is approved for use with clobazam and valproate as the clinical studies submitted for EMA approval associated this combination for seizure control in Ds. No clinical studies have been published using stiripentol with clonazepam and topirimate. While stiripentol will increase one metabolite of clonazepam, this metabolite is not as active as the parent and synergistic effect is minimal. Stiripentol does not boost the effect of topirimate as topirimate is renally cleared and minimally oxidated by CYP3A4.
This child is on about 66 mg/kg/day, which is with the 50 – 100 mg/kg/day manufacturer recommendation. Since he is not having frequent prolonged GTC seizures, this is an appropriate dose.
Discuss his sleep patterns and ensure he is getting adequate continuous sleep in the appropriate number of hours for his age. Consider sleep pharmacotherapy if is sleep patterns or quality are interrupted. Melatonin 3 mg hs or diphenhydramine 25 mg hs may be considered as first line agents.
Recommended action:
1) Wean clonazepam to clobazam (approx 1:10 dose relation) ; keeping all other pharmacotherapy doses the same
Days 1-3: Clobazam 2.5 mg (1/4 10 mg tablet) at 8 am
Clonazepam 0.25 mg at 2 pm
Clonazepam 0.25 mg at 8 pm
Days 4-6: Clobazam 2.5 mg (1/4 of 10 mg tablet) at 8 am
Clobazam 2.5 mg (1/4 of a 10 mg tablet) at 2 pm
Clonazepam 0.25 mg at 8 pm
Days 7 forward
Clobazam 2.5 mg 8 am
Clobazam 2.5 mg 2 pm
Clobazam 2.5 mg 8 pm
Watch for excessive agitation or insomnia. If this occurs, consider dose reduction. Clobazam with stiripentol may help eyeflutter/headnod seizure type.
2) Wean topirimate slowly – dose is larger than maximum recommended; this child is significantly delayed and has little to no speech. Topirimate is not synergistic to stiripentol, and is not effective for atypical absence seizures.
Day 10 until topirimate is weaned completely or to the lowest acceptable dose based on seizure control:
Decrease dose by 25 mg every 3 days with close monitoring of seizure activity.
3) After topirimate is removed or reduced to lowest possible dose, consider adding valproate for improvement in total seizure control, synergy with stiripentol, and improvement in atypical absence seizures. Lower doses of valproate will be required with stiripentol interaction. Starting dose of 10 mg/kg/day increasing desired effect within therapeutic level as tolerated. In the European clinical studies with stiripentol, valproic acid, and clobazam in Dravet syndrome (STILCO studies), the maximum recommended dose of depakote was 30 mg/kg/day and levels around 30 -50 mg/dL showed better tolerance to medication side effects.
If topirimate is still used due to lack of ability to fully wean, monitor ammonia level as these drugs used in combination can increase ammonia.
4) If valproate does not improve eyeblink, head drop seizures, consider addition of ethosuximide with stiripentol/clobazam/valproate. Stiripentol will not significantly increase ethosuximide levels; however there are pharmacodynamic interactions between depakote and ethosuximide (increased ethosuximide levels when on Depakote).
5) If ethosuximide is added and maximized but eyeblinks/head nods persist, consider removing ethosuximide and adding felbamate 15 mg/kg/day – 45 mg/kg/day. Carefully monitor LFTs and CBC regularly and explain black box warning for Felbamate.
I hope this child’s condition improves and please do not hesitate to contact me if I can be of further assistance.
Best regards,
Harriet Davies, PharmD
References:
Gross-Tsur V et al. Reversibile language regression as an adverse effect of topirimate treatment in children. Neurology 2004;62:299-300
Additional references found on the attached treatment guide.