Drug and Biologic Coverage Policy

Effective Date ...... 6/1/2020 Next Review Date ...... 6/1/2021 Coverage Policy Number ...... P0085

Clobazam Oral Film

Table of Contents Related Coverage Resources

Coverage Policy ...... 1 FDA Approved Indications ...... 2 Recommended Dosing ...... 2 General Background ...... 3 Coding/Billing Information ...... 4 References ...... 4

INSTRUCTIONS FOR USE The following Coverage Policy applies to health benefit plans administered by Cigna Companies. Certain Cigna Companies and/or lines of business only provide utilization review services to clients and do not make coverage determinations. References to standard benefit plan language and coverage determinations do not apply to those clients. Coverage Policies are intended to provide guidance in interpreting certain standard benefit plans administered by Cigna Companies. Please note, the terms of a customer’s particular benefit plan document [Group Service Agreement, Evidence of Coverage, Certificate of Coverage, Summary Plan Description (SPD) or similar plan document] may differ significantly from the standard benefit plans upon which these Coverage Policies are based. For example, a customer’s benefit plan document may contain a specific exclusion related to a topic addressed in a Coverage Policy. In the event of a conflict, a customer’s benefit plan document always supersedes the information in the Coverage Policies. In the absence of a controlling federal or state coverage mandate, benefits are ultimately determined by the terms of the applicable benefit plan document. Coverage determinations in each specific instance require consideration of 1) the terms of the applicable benefit plan document in effect on the date of service; 2) any applicable laws/regulations; 3) any relevant collateral source materials including Coverage Policies and; 4) the specific facts of the particular situation. Coverage Policies relate exclusively to the administration of health benefit plans. Coverage Policies are not recommendations for treatment and should never be used as treatment guidelines. In certain markets, delegated vendor guidelines may be used to support medical necessity and other coverage determinations. Coverage Policy

Sympazan™ (clobazam oral film) is considered medically necessary when ALL of the following criteria are met: • Individual is 2 years of age or older • For the treatment of ONE of the following: o Documented diagnosis of Dravet syndrome o Documented diagnosis of Lennox-Gastaut syndrome and the following: . Used concomitantly with at least one other antiepileptic drug o Documented diagnosis of treatment-resistant epilepsy and the following: . Used concomitantly with at least one other antiepileptic drug • Prescribed by, or in consultation with, a pediatric neurologist or an adult neurologist with expertise in epilepsy

Coverage for Sympazan (clobazam oral film) varies across plans. Refer to the customer’s benefit plan document for coverage details.

Where coverage requires the use of preferred products, the following criteria apply. For Employer Group Plans: • For use in Dravet Syndrome:

Page 1 of 4 Drug and Biologic Coverage Policy: P0085 o Documented intolerance, inability to swallow or not a candidate (for example, stabilized condition where therapeutic interchange is inappropriate) clobazam tablets AND oral suspension

• For use in Lennox-Gastaut syndrome: o Documented failure / inadequate response, contraindication per FDA label, intolerance, or not a candidate (for example, stabilized condition where therapeutic interchange is inappropriate) for at least TWO other antiepileptic drugs (for example, valproic acid, lamotrigine, rufinamide, topiramate, felbamate)

• For use in Treatment-Resistant Epilepsy: o Documented failure / inadequate response, contraindication per FDA label, intolerance, or not a candidate (for example, stabilized condition where therapeutic interchange is inappropriate) for at least TWO other antiepileptic drugs (for example, valproic acid, lamotrigine, rufinamide, topiramate, felbamate)

Initial authorization is up to 12 months.

Sympazan (clobazam oral film) is considered medically necessary for continued use when BOTH of the following criteria are met: • Initial criteria are met • Evidence of beneficial clinical response as submitted by the provider

Reauthorization for up to 12 months.

When coverage is available and medically necessary, the dosage, frequency, duration of therapy, and site of care should be reasonable, clinically appropriate, and supported by evidence-based literature and adjusted based upon severity, alternative available treatments, and previous response to therapy.

Clobazam oral film (Sympazan) is considered experimental, investigational or unproven for ANY other use.

Note: Receipt of sample product does not satisfy any criteria requirements for coverage.

FDA Approved Indications

FDA Approved Indication Sympazan is a benzodiazepine indicated for adjunctive treatment of seizures associated with Lennox-Gastaut Syndrome (LGS) in patients 2 years of age or older.

Recommended Dosing

FDA Recommended Dosing Dose patients according to body weight. Individualize dosing within each body weight group, based on clinical efficacy and tolerability. Each dose in the table below has been shown to be effective, although effectiveness increases with increasing dose. A daily dose of Sympazan greater than 5 mg should be administered in divided doses twice daily; a 5 mg daily dose can be administered as a single dose. Do not proceed with dose escalation more rapidly than weekly, because serum concentrations of clobazam and its active metabolite require 5 and 9 days, respectively, to reach steady-state.

Recommended Total Daily Dosing by Weight Group 30 kg or Less Body Weight Greater than 30 kg Body Weight Starting Dose 5 mg 10 mg

Page 2 of 4 Drug and Biologic Coverage Policy: P0085 Starting Day 7 10 mg 20 mg Starting Day 14 20 mg 40 mg

General Background

Disease Overview Dravet syndrome is a rare genetic epileptic encephalopathy (dysfunction of the brain) marked with frequent and/or prolonged seizures. It’s been estimated that 1 out of 15,700 infants born in the US are affected with Dravet syndrome. The seizures generally begin in the first year of life in an otherwise healthy infant. Affected individuals can develop many seizure types: myoclonic, tonic-clonic, absence, atypical absence, atonic, focal aware or impaired awareness (previously called partial seizures), and status epilepticus. As the seizures continue, most of the children develop some level of developmental disability and other conditions associated with the syndrome. Two or more antiepileptic drugs (AEDs) are often needed to control the seizures; most of the seizures are refractory to medications. The goals of treatment are cessation of prolonged convulsions, reductions in overall seizure frequency, and minimization of treatment side effects. Some patients respond to the ketogenic diet and/or vagus nerve stimulation. (Dravet Foundation, 2020; Knupp, 2018; Shafer, 2017; Wirrell, 2017)

Lennox-Gastaut syndrome (LGS), a severe epileptic and developmental encephalopathy, is associated with a high rate of morbidity and mortality. LGS most often begins between 3 and 5 years of age and comprises approximately 4% to 10% of childhood epilepsies; the prevalence is 0.26 per 1,000 people (or 26 out of 100,000). Children may develop normally before onset of seizures and then lose previously acquired skills (psychomotor regression), and because the seizures associated with LGS are usually resistant to treatment, intellectual impairment and learning problems may worsen over time. Affected children experience several different types of seizures, most commonly atonic seizures (sudden loss of muscle tone and limpness, also called drop seizures) and tonic seizures (increased muscle tone and muscle stiffness). The three main forms of treatment of LGS are AEDs, dietary therapy (typically the ketogenic diet), and device/surgery (eg. vagus nerve stimulation, corpus callosotomy). None of the therapies are effective in all cases of LGS and the disorder has proven particularly resistant to most therapeutic options. The choice of treatment should take into consideration the patient’s age and other associated conditions. (Sirven, 2017; Cross, 2017; Ostendorf, 2017; Wheless, 2017)

Professional Societies/Organizations Dravet Syndrome Valproic acid and clobazam are considered to be the first-line treatment for Dravet syndrome. If seizure control is suboptimal, stiripentol (not available in the US, but can be obtained from foreign countries) and topiramate are second-line treatment. Ketogenic diet is moderately effective and can also be considered second-line. If control is still inadequate, other therapies to consider are clonazepam, levetiracetam, and zonisamide. Sodium channel blockers (e.g., carbamazepine, oxcarbazepine, lamotrigine, and phenytoin can worsen seizures in Dravet syndrome. Additionally, Sabril® (vigabatrin tablet, oral packet) and tiagabine may increase the frequency of myoclonic seizures and should be avoided. (Dravet Foundation, 2018; Knupp, 2018; Wirrell, 2017)

Lennox-Gastaut Syndrome Currently, the FDA-approved drugs for this condition are felbamate, lamotrigine, Banzel® (rufinamide tablet, oral suspension), topiramate, and clobazam. Despite the lack of level I or level II evidence, valproic acid remains a mainstay in treatment. If valproic acid does not provide adequate seizure control, which is almost always the case, lamotrigine should be added as the first adjunctive therapy. If the combination regimen of valproic acid and lamotrigine does not provide adequate control, then Banzel should be initiated and either valproic acid or lamotrigine should be discontinued. If seizure control is still not achieved, the next adjunctive therapies to consider are topiramate, clobazam, and felbamate. There are limited evidence for the use of levetiracetam, zonisamide, and Fycompa® (perampanel tablet, oral suspension). Where possible, no more than two AEDs should be used concomitantly; use of multiple AEDs raise the risk of side effects and/or drug-drug interactions. (Cherian, 2017; Cross, 2017; LGS Foundation; Ostendorf, 2017; Wheless, 2017)

Page 3 of 4 Drug and Biologic Coverage Policy: P0085 Treatment-Resistant Epilepsy American Academy of Neurology (AAN) and the American Epilepsy Society published a guideline update for treatment-resistant epilepsy (2018) that clobazam is probably effective as add-on therapy for LGS and is possibly effective as add-on therapy for treatment-resistant adult focal epilepsy. (Kanner 2018)

Other Covered Uses AHFS Drug Information 2020 Edition does not support any off-label uses of Sympazan.

Experimental, Investigational, Unproven Uses Compendia and other published clinical studies do not currently support any uses other than the FDA indication. Criteria will be updated as new published data are available.

Coding/Billing Information

Note: Clobazam is typically covered under pharmacy benefit plans. Certain prescription drugs require an authorization for coverage to ensure that appropriate treatment regimens are followed. Medical drug coding and diagnosis codes, however, are generally not required for pharmacy claims submissions, therefore, this section is not in use.

References

1. Aquestive Therapeutics. Sympazan (clobazam) oral film [product information]. Warren, NJ: Aquestive Therapeutics. November 2018. 2. Cherian KA. Lennox-Gastaut syndrome treatment & management. Updated November 2017. Available at: https://emedicine.medscape.com/article/1176735-treatment. Accessed on October 30, 2018. 3. Cross JH, Auvin S, Falip M, et al. Expert opinion on the management of Lennox-Gastaut syndrome: treatment algorithms and practical considerations. Front Neurol. 2017; 8:505. 4. Dravet Foundation – Dravet Syndrome. Available at: https://www.dravetfoundation.org/what-is-dravet- syndrome/. Accessed on February 27, 2020. 5. Kanner AM, Ashman E, Gloss D, et al. Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs II: Treatment-resistant epilepsy. Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2018; 91:82-90. 6. Knupp KG, Wirrell EC. Treatment Strategies for Dravet Syndrome. CNS Drugs. 2018; 32(4):335-350. 7. Lennox-Gastaut Syndrome Foundation – Lennox-Gastaut Syndrome. Available at: http://www.lgsfoundation.org/understanding. Accessed on May 14, 2018. 8. McEvoy GK, ed. AHFS 2020 Drug Information. Bethesda, MD: American Society of Health-Systems Pharmacists, Inc; 2020. 9. Ostendorf AP, Ng YT. Treatment-resistant Lennox-Gastaut syndrome: therapeutic trends, challenges, and future directions. Neuropsych Dis Treatment. 2017; 13:1131-1140. 10. Shafer PO. Epilepsy Foundation – Dravet Syndrome. Updated June 2017. Available at: https://www.epilepsy.com/learn/types-epilepsy-syndromes/dravet-syndrome. Accessed on October 23, 2018. 11. Sirven JI, Shafer PO. Epilepsy Foundation – Lennox-Gastaut Syndrome. Updated June 2017. Available at: https://www.epilepsy.com/learn/types-epilepsy-syndromes/lennox-gastaut-syndrome-lgs. Accessed on October 23, 2018. 12. Wheless JW. National Organization for Rare Diseases (NORD) – Lennox-Gastaut syndrome. Available at: https://rarediseases.org/rare-diseases/lennox-gastaut-syndrome/. Accessed on October 23, 2018. 13. Wirrell EC, Laux L, Donner, et al. Optimizing the diagnosis and management of Dravet syndrome: recommendations from a North American Consensus Panel. Pediatr Neurol. 2017; 68:18-34.

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