Before introducing FFA as an add-on therapy, a review should be performed of the prior ASMs administered in terms of their efficacy in previous courses of treatment. A polytherapy that includes more than three to five medications should be avoided; therefore, ASMs with lower efficacies should be gradually discontinued before the introduction of a new medication. Special attention should be given to combinations with stiripentol because FFA is metabolized via multiple CYP enzymes (in particular CYP1A2, CYP2B6, and CYP2D6) and drugs that inhibit any of these enzymes may increase serum concentrations of FFA. This interaction can enhance its therapeutic effect but also its side effects, as is the case with stiripentol. Therefore, the FFA dose must be reduced when used concurrently with stiripentol (Table 3). Moreover, it should be considered that drugs that induce corresponding enzymes (e.g., phenobarbital) can reduce the plasma level of FFA and consequently its efficacy.

Table 3 Potential interactions between antiseizure medications: effects of add-on medications on serum concentrations of existing antiseizure medicationsDosage regimen for patients not taking stiripentol

The initial dose of FFA is 0.1 mg/kg twice daily (0.2 mg/kg bw/day). If further epileptic seizures occur and FFA is well tolerated, the dose can be increased to 0.2 mg/kg twice daily (0.4 mg/kg bw/day) after 7 days and to a maximum of 2 × 0.35 mg/kg daily (0.7 mg/kg bw/day) after a further 7 days. Please note that this is the maximum mg/kg bw daily dose. For patients requiring a more rapid titration, the dose may be increased every 4 days. The maximum total daily dose of 26 mg FFA (13 mg twice daily, equivalent to 2 × 6.0 mL) should not be exceeded.

This dosing regimen is not suitable for all patients as tolerability varies greatly among individuals. Side effects of fatigue or ataxia may require slower dosage increases, particularly in patients with higher body weights, as the starting dose of 0.2 mg/kg bw/day might not be well tolerated and can lead to adverse effects such as fatigue and loss of appetite. Patients who are more sensitive to side effects could be given a slower up-dosing. In these cases, we recommend starting with 0.1 mg/kg/day divided into two doses and increasing the dose by 0.1 mg/kg/day at 7‑ to 14-day intervals. If significant side effects occur, the last dose increase should be reversed. After a stabilization period, slower subsequent dose increases may facilitate tolerance. In the respective dosage tables, the recommended amounts are given according to body weight (Supplementary Table S1 A).

Dosage regimen for patients taking stiripentol

The initial dose and the increased dose after 7 days are as indicated in the previous section. A maximum total daily dose of 17 mg (8.6 mg twice daily, equivalent to 2 × 4.0 ml) or maximum 0.4 mg/kg bw daily dose should not be exceeded in patients taking stiripentol. A reduced starting dose in patients with higher body weights is recommended. To avoid side effects, smaller incremental dosage increases should be chosen. The doses in milliliters for twice-daily administration can be found in Supplementary Table S1 B.

General dosage regimen recommendations

For a calculated dose of 3.0 mL or less, the green-printed 3‑mL syringe should be used, and for a dose greater than 3.0, the purple-printed 6‑mL syringe should be used. The calculated dose should be rounded to the nearest scaling step.

For an intermediate dosage increase, increments of 0.2 mg/kg bw/day every 14 days are reasonable. If adverse effects occur, these increments can be extended to monthly intervals (0.2 mg/kg bw/day increment per month). In cases of low seizure frequency, a slower titration with increases of 0.2 mg/kg bw/day every 3 months may be considered. The oral solution is administered in two divided doses. The studies and the CUP identified patients who became seizure-free at a low dose of 0.2 mg/kg bw. In adolescents and adults with body weight of 45 kg and over, increases of 1–2 mL per week may increase tolerability. Adequate observation periods between increments ensure that the lowest dose that leads to seizure freedom is used. In general, we recommend adjusting the individual dosage according to the general rule for all ASMs: as much as necessary, as little as possible.

Infobox Interactions between FFA and other antiseizure medications: with a focus on FFA serum levels 1.

Clobazam mono: no dose adjustment of clobazam or FFA

2.

Valproic acid mono: no dose adjustment of valproic acid or FFA

3.

Stiripentol mono: no dose adjustment of stiripentol

but FFA daily maximum dose is 0.4 mg/kg bw/day or 17 mg/day (instead of 0.7 mg/kg bw/day or 26 mg/day)

4.

Combined treatment of stiripentol, valproic acid, and clobazam: no dose adjustment

but FFA daily maximum dose is 0.4 mg/kg bw/day or 17 mg/day (instead of 0.7 mg/kg bw/day or 26 mg/day)

5.

Cannabidiol: no dose adjustment of cannabidiol or FFA

6.

Bromide: dose adjustment of bromide with FFA, data unpublished; clinical experience shows that serum levels of bromide can increase with corresponding clinical signs

7.

Topiramate, levetiracetam, brivaracetam, zonisamide, and clonazepam: no data available

8.

Phenobarbital: dose adjustment for FFA

Serum levels of antiseizure co-medications should be checked periodically in patients treated with FFA.

Ketogenic diet and fenfluramine

The FFA solution contains small amounts of glucose, which could affect a ketogenic diet and other dietary approaches; however, no interactions were reported in the CUP (experience of the authors). According to the drug information, FFA is compatible with a ketogenic diet.

Withdrawal in cases of intolerance or ineffectiveness

In the randomized controlled trials (Table 1), FFA was discontinued within 8 days. This rapid dose reduction can cause seizure activation or status epilepticus; therefore, smaller steps must be taken if the seizure situation worsens.

Side effects

Supplementary Table S2 summarizes the adverse reactions to FFA therapy according to the organ system and the frequency reported in the placebo-controlled clinical trials for DS. Frequencies are defined as very common (≥ 1/10) or common (≥ 1/100 to < 1/10).

The most common side effects were:

1.

Weight reduction: The effect is not surprising considering the initial development and use of the compound as an appetite suppressant. The authors recommend monitoring the absolute body weight and body mass index (BMI) of children. Children experience growth spurts and the change in weight in relation to height should be considered to detect a slow body weight increase at an early stage. This is especially crucial for young children. Weight reduction of greater than 10% is cause for concern. Therefore, the BMI at the start of treatment is particularly important, since weight loss in cases with initial adiposity is less critical than that in the lower percentile range before the start of therapy. If there is significant weight loss, early nutritional counselling may be helpful. An initial loss of appetite may normalize in the course of therapy or through the reduction of other ASMs such as topiramate, which also has decreased appetite as an adverse event. Of note, a reduced height and weight growth trend has been reported as part of the natural course of DS [41].

2.

Fatigue/somnolence: Fatigue and somnolence are common side effects that can lead to hospitalization. These adverse effects should be treated with a dose reduction since fatigue can trigger an increased seizure frequency.

3.

Increase in seizure frequency: Increases in generalized tonic–clonic seizures or epileptic states may require dose reductions, and if the worsening is related to dose changes in co-medication, the concentrations of the relevant ASMs must be determined. The first step can be dose reduction; however, with an unfavorable benefit–risk assessment, FFA medication should be discontinued.

4.

Lower blood glucose levels: In the regulatory studies, these levels had little clinical relevance and could be related to a decrease in appetite or erroneous measurements caused by long shipment times or suboptimal sample handling.

5.

Movement disorders: In cases with pre-existing ataxic movement disorders, a worsening of symptoms may be observed, which is reversed upon a reduction of the FFA dose. Hyperkinetic movement disorders have also been reported.

Follow-up intervals Laboratory.

It is good clinical practice that serum concentrations of ASMs should be determined before starting any new therapy. First clinical follow-ups are advised after 1 and 3 months. Common laboratory parameters and ASM serum concentrations should be analyzed to detect interactions (Fig. 3). Currently, routine FFA concentration determinations are not available.

Fig. 3

Recommendations for introducing fenfluramine into therapy with antiseizure medications

Cardiological follow-ups.

Echocardiographic examinations at 6‑month intervals for the first 2 years after starting the therapy and annually thereafter are mandatory. ECG recordings were performed during the study check-ups with normal findings; therefore, they are no longer recommended.

Electroencephalogram.

Electroencephalography should be performed on the basis of clinical progression, including before starting FFA therapy and after reaching the first target dose. Systematic evaluations of EEG monitoring during FFA therapy are currently not available. However, in our experience, hypersynchronous activities shown in EEGs often decrease with improvement of the seizure situation. Some patients showed an increase in background activity, which is typically slow in DS and LGS.