Effective Date

Date of Origin 

07-01-2024            

01-01-2021

Fintepla®

(fenfluramine)

Oral solution

Treatment of seizures associated with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) in patients 2 years of age and older

1

Dravet Syndrome

Dravet syndrome (DS) is a severe form of epilepsy characterized by frequent, prolonged seizures and neurodevelopmental problems beginning in infancy. Mutations in the alpha-1 subunit of the voltage-gated sodium channel (SCN1A) gene are identified in 70-85% of patients with DS. Status epilepticus, or a seizure lasting longer than 5 minutes and sometimes 30 minutes or more, is common. Additional seizure types, including myoclonic, atypical absence, and complex partial seizures, appear before age 5 years. Mortality in DS is elevated above that found in the general epilepsy population, with an estimated mortality of 15-20% by adulthood. First-line treatment is typically valproate, with clobazam added if needed. Additional agents include stiripentol, topiramate, cannabidiol, and fenfluramine. For patients with symptoms refractory to drug therapy, ketogenic diet and vagal nerve stimulation may be beneficial.(2,3,4,9)

The mechanisms by which fenfluramine exerts its therapeutic effects in the treatment of seizures associated with DS are unknown. Fenfluramine and its metabolite, norfenfluramine, increase extracellular levels of serotonin through interaction with serotonin transporter proteins, and exhibit agonist activity at serotonin 5HT-2 receptors.(1)

Lennox-Gastaut Syndrome

Lennox-Gastaut syndrome (LGS) is a severe form of epilepsy that typically becomes apparent during infancy or early childhood. The syndrome has many causes, including genetic disorders, cortical malformations, tumors, encephalopathies following hypoxic-ischemic insults, meningitis, and head injuries. Affected children experience several different types of seizures; atonic, clonic, and atypical absence seizures are the most common. Children with LGS may develop cognitive dysfunction, delays in reaching developmental milestones, and behavioral problems. LGS is difficult to treat because no specific therapy is effective in all cases, and the disorder has proven particularly resistant to most therapeutic options. Valproate is generally considered first-line therapy, and if monotherapy is ineffective another drug such as lamotrigine or rufinamide is added to valproate therapy. Alternative adjunctive antiseizure medications include topiramate, clobazam, cannabidiol, fenfluramine, or felbamate. Additional therapies combined with drug therapy, for patients who do not respond, include the ketogenic diet and vagal nerve stimulation.(7,8)

Efficacy

The effectiveness of fenfluramine for the treatment of seizures associated with Dravet syndrome in patients 2 years of age and older was established in two randomized, double-blind, placebo-controlled trials in patients 2 to 18 years of age. Study 1 (N = 117) compared a 0.7 mg/kg/day and a 0.2 mg/kg/day dose of fenfluramine with placebo in patients who were NOT receiving stiripentol. Study 2 (N = 85) compared a 0.4 mg/kg/day dose of fenfluramine with placebo in patients who were receiving stiripentol and either clobazam, valproate, or both. In both studies, patients had a clinical diagnosis of Dravet syndrome and were inadequately controlled on at least one antiepileptic drug (AED) or other antiseizure treatment including vagal nerve stimulation or a ketogenic diet. In Study 1, 98% of patients were taking 1-4 concomitant AEDs; in Study 2, 100% were taking 2-4 concomitant AEDs.(1,5,6)

The primary efficacy endpoint in both studies was the change from baseline in the frequency of convulsive seizures per 28 days during the treatment period. For Study 1, the percent reduction in monthly convulsive seizure frequency was 70% for the 0.7 mg/kg/day dose (p less than 0.001) and 31.7% for the 0.2 mg/kg/day dose (p=0.043); for Study 2 it was 59.5% reduction (p less than 0.001). A reduction in convulsive seizures was observed within 3-4 weeks of starting fenfluramine, and the effect remained generally consistent over the 14- or 15-week treatment period.(1,5,6)

A secondary endpoint was longest seizure-free interval, for which the median longest seizure-free intervals in the 0.7 mg/kg/day, 0.4 mg/kg/day, and 0.2 mg/kg/day groups were 25 days, 22 days, and 15 days, respectively.(5,6)

The effectiveness of fenfluramine for the treatment of seizures associated with LGS in patients 2 years of age and older was established in a randomized, double-blind, placebo-controlled trial in patients 2 to 35 years of age. Study 3 (N=263) compared a 0.7 mg/kg/day and a 0.2 mg/kg/day dose of fenfluramine with placebo in patients with a diagnosis of LGS who were inadequately controlled on at least one antiepileptic drug (AED) or other antiseizure treatment including vagal nerve stimulation and/or a ketogenic diet.(1)

The primary efficacy endpoint was the median percent change from baseline (reduction) in the frequency of seizures per 28 days during the treatment period. The median percent change from baseline (reduction) in the frequency of seizures per 28 days was significantly greater for the 0.7 mg/kg/day group compared with placebo (80%; p=0.0037). The effect remained generally consistent over the 14-week treatment period.(1)

Safety

Fintepla carries a boxed warning for valvular heart disease and pulmonary arterial hypertension. There is an association between serotonergic drugs with 5-HT2B receptor agonist activity, including fenfluramine, and valvular heart disease and pulmonary arterial hypertension. Echocardiogram assessments are required before, during, and after treatment with Fintepla; benefits versus risks of initiating or continuing must be considered based on echocardiogram findings. Because of these risks, Fintepla is available only through the Fintepla REMS program.(1)

Fintepla has the following contraindications:(1)

• Concomitant use of, or within 14 days of the administration of, monoamine oxidase inhibitors because of an increased risk of serotonin syndrome.
• Hypersensitivity to fenfluramine or any of the excipients in Fintepla.

1

Fintepla prescribing information. Zogenix, Inc. January 2023.

2

Wirrell EC, Laux L, Donner E, et al. Optimizing the Diagnosis and Management of Dravet Syndrome: Recommendations from a North American Consensus Panel. Pediatr Neurol. 2017;68:18-34.

3

Sullivan J, Knupp K, Wirrell E. Dravet Syndrome. National Organization for Rare Disorders (NORD). Last updated 2020. Available at https://rarediseases.org/rare-diseases/dravet-syndrome-spectrum/. 

4

Andrade DM, Nascimento FA, et al. Dravet Syndrome: Management and Prognosis. UpToDate. Literature review current through November 2022. Last updated December 2022. 

5

Lagae L, Sullivan J, Knupp K, et al. Fenfluramine Hydrochloride for the Treatment of Seizures in Dravet Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial. Lancet. 2019;394(10216):2243-2254.

6

Nabbout R, Mistry A, Zuberi S, et al. Fenfluramine for Treatment-Resistant Seizures in Patients with Dravet Syndrome Receiving Stiripentol-Inclusive Regimens: A Randomized Clinical Trial. JAMA Neurol. 2020;77(3):300-308.

7

Wheeless JW. Lennox-Gastaut Syndrome. National Organization for Rare Disorders (NORD). Last updated 2020. Available at https://rarediseases.org/rare-diseases/lennox-gastaut-syndrome/.

8

Wilfong A, et al. Epilepsy Syndromes in Children. UpToDate. Last updated June 2022. Literature review current through December 2022.

9

International Consensus on Diagnosis and Management of Dravet Syndrome. Epilepsia. 2022 Jul;63(7):1761-1777.

Fintepla

fenfluramine hcl oral soln

2.2 MG/ML

M ; N ; O ; Y

N

Fintepla

Fenfluramine HCl Oral Soln 2.2 MG/ML

2.2 MG/ML

360

mLs

30

DAYS

Fintepla

fenfluramine hcl oral soln

2.2 MG/ML

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Fintepla

Fenfluramine HCl Oral Soln 2.2 MG/ML

2.2 MG/ML

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Initial Evaluation

Target Agent(s) will be approved when ALL of the following are met:

1. ONE of the following:
   1. BOTH of the following:
      1. ONE of the following:
         1. The patient has been treated with the requested agent (starting on samples is not approvable) within the past 90 days OR
         2. The prescriber states the patient has been treated with the requested agent (starting on samples is not approvable) within the past 90 days AND is at risk if therapy is changed AND
      2. The patient has an FDA labeled indication for the requested agent OR
   2. BOTH of the following:
      1. ONE of the following:
         1. If the patient has a diagnosis of Dravet syndrome (DS), then ONE of the following:
            1. The patient has tried and had an inadequate response to TWO generic antiseizure agents used in the treatment of DS (e.g., valproate, clobazam, stiripentol, topiramate) OR
            2. The patient has an intolerance or hypersensitivity to therapy with generic antiseizure agents used in the treatment of DS OR
            3. The patient has an FDA labeled contraindication to ALL generic antiseizure agents used in the treatment of DS OR
         2. If the patient has a diagnosis of Lennox-Gastaut syndrome (LGS), then ONE of the following:
            1. The patient has tried and had an inadequate response to TWO generic antiseizure agents used in the treatment of LGS (e.g., valproate, lamotrigine, rufinamide, topiramate, clobazam, felbamate) OR
            2. The patient has an intolerance or hypersensitivity to therapy with generic antiseizure agents used in the treatment of LGS OR
            3. The patient has an FDA labeled contraindication to ALL generic antiseizure agents used in the treatment of LGS OR
         3. The patient has another FDA labeled indication for the requested agent and route of administration AND
      2. If the patient has an FDA labeled indication, then ONE of the following:
         1. The patient’s age is within FDA labeling for the requested indication for the requested agent OR
         2. There is support for using the requested agent for the patient’s age for the requested indication AND
2. If the patient has a diagnosis of seizures associated with Dravet syndrome (DS) or Lennox-Gastaut syndrome (LGS), the requested agent will NOT be used as monotherapy for seizure management AND
3. An echocardiogram assessment will be obtained before and during treatment with the requested agent to evaluate for valvular heart disease and pulmonary arterial hypertension AND
4. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., neurologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
5. The patient does NOT have any FDA labeled contraindications to the requested agent

Length of Approval:  12 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

Renewal Evaluation

Target Agent(s) will be approved when ALL of the following are met:

1. The patient has been previously approved for the requested agent through the plan’s Prior Authorization process [Note: patients not previously approved for the requested agent will require initial evaluation review] AND
2. The patient has had clinical benefit with the requested agent AND
3. If using for seizure management associated with Dravet syndrome (DS) or Lennox-Gastaut syndrome (LGS), the requested agent will NOT be used as monotherapy AND
4. An echocardiogram assessment will be obtained during treatment with the requested agent to evaluate for valvular heart disease and pulmonary arterial hypertension AND
5. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., neurologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
6. The patient does NOT have any FDA labeled contraindications to the requested agent

Length of Approval:  12 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

Quantity limit for the Target Agent(s) will be approved when ONE of the following is met:

1. The requested quantity (dose) does NOT exceed the program quantity limit OR
2. ALL of the following:
   1. The requested quantity (dose) exceeds the program quantity limit AND
   2. The requested quantity (dose) does NOT exceed the maximum FDA labeled dose for the requested indication AND
   3. The requested quantity (dose) cannot be achieved with a lower quantity of a higher strength that does NOT exceed the program quantity limit

Length of Approval: up to 12 months