Sympazan (clobazam) Oral Film
Date of Approval: November 1, 2018
Company: Aquestive Therapeutics, Inc.
Treatment for: Lennox-Gastaut Syndrome
Sympazan (clobazam) is an oral film benzodiazepine formulation indicated for the adjunctive treatment of seizures associated with Lennox-Gastaut Syndrome.
WARREN, N.J., Nov. 2, 2018 /PRNewswire/ -- Aquestive Therapeutics, Inc. (NASDAQ: AQST), a specialty pharmaceutical company, today announced that the U.S. Food and Drug Administration (FDA) approved Sympazan™ (clobazam) oral film for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients 2 years of age or older.1 Sympazan is the first and only oral film FDA-approved to treat seizures associated with LGS. Previously, clobazam was marketed as ONFI® and offered in two formulations – either tablet or oral suspension.2
"Aquestive Therapeutics is pleased to bring Sympazan to the LGS community," said Keith J. Kendall, Chief Executive Officer of Aquestive Therapeutics. "Treating LGS can be difficult; patients may have a hard time swallowing oral medications. We're optimistic Sympazan can help address unmet medical needs and be an important treatment option for this patient population."
LGS is a severe form of epilepsy that begins in early childhood and is characterized by multiple types of seizures and intellectual disability.3 LGS patients often have difficulty swallowing pills and large volume suspensions due to physical limitations, behavioral or cognitive impact.4,5 Challenges with treatment administration can lead to uncertain and inconsistent dosing, and increase the burden of care, particularly for patients that may be combative or resistant to treatment.5-8
Since FDA approval in 2011, clobazam tablets and oral suspension (brand name ONFI®) have been a trusted adjunctive treatment for LGS. In a Phase 3, randomized, double-blind, placebo-controlled study of 238 LGS patients, clobazam tablets significantly reduced the frequency of drop seizures (which involve falls) compared to baseline by 41 percent (low dose) to 68 percent (high dose) vs. 12 percent for placebo (p<0.05 for all doses vs. placebo).2,9 Please see more Important Safety Information below, including the Boxed Warning on the risks associated with concomitant use of opioids.
"Many LGS patients have a hard time swallowing pills and suspensions. This can make administering medication hard for caregivers," says Christina SanInocencio, Executive Director of the LGS Foundation. "We believe Sympazan will be welcomed by patients and caregivers impacted by LGS and searching for treatment solutions."
Sympazan is a formulation based on Aquestive's proven PharmFilm® technology. Multiple pharmacokinetic studies were conducted to compare Sympazan with ONFI. Based on the studies, Sympazan oral film was demonstrated to be bioequivalent to clobazam tablets and have comparable safety profiles.1 Aquestive's clinical development of Sympazan followed the 505(b)(2) regulatory pathway.
"Sympazan is the beginning of a meaningful CNS franchise for Aquestive," Kendall says. "We are actively working to advance more redesigned, proprietary treatments that can offer meaningful improvements for patients and caregivers who live with epilepsy and other complex conditions."
Aquestive plans to commercialize Sympazan in November, and has engaged Ashfield Healthcare, a company specializing in commercialization services, to build and train a highly qualified, national sales force. The sales force will focus on pediatric neurologists and epileptologists.
Sympazan oral film is berry flavored and offered in 5 mg, 10 mg, and 20 mg dosages to meet a range of LGS patient and caregiver needs.1
About Aquestive Therapeutics
Aquestive Therapeutics is a specialty pharmaceutical company committed to identifying, developing and commercializing differentiated products to address unmet medical needs. Aquestive Therapeutics has a late-stage proprietary product pipeline focused on the treatment of CNS diseases, and is working to advance orally-administered complex molecules that it believes can be alternatives to invasively-administered standard of care therapies. As the leader in developing and delivering drugs via its PharmFilm® technology, Aquestive Therapeutics also collaborates with pharmaceutical partners to bring new molecules to market in differentiated and highly-marketable dosage forms.
IMPORTANT SAFETY INFORMATION
BOXED WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS
Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death.
· Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
· Limit dosages and durations to the minimum required.
· Follow patients for signs and symptoms of respiratory depression and sedation.
CONTRAINDICATIONS
Sympazan is contraindicated in patients with a history of hypersensitivity to the drug or its ingredients. Hypersensitivity reactions have included serious dermatological reactions.
WARNINGS AND PRECAUTIONS
Potentiation of Sedation from Concomitant Use with Central Nervous System (CNS) Depressants
Sympazan has a CNS depressant effect. Caution patients and/or caregivers against simultaneous use with other CNS depressants or alcohol as the effects of other CNS depressants or alcohol may be potentiated.
Somnolence or Sedation
Sympazan causes dose-related somnolence and sedation, which generally begins within the first month of treatment and may diminish with continued treatment. Monitor patients for somnolence and sedation, particularly with concomitant use of other CNS depressants. Caution patients against engaging in hazardous activities requiring mental alertness, i.e., operating dangerous machinery or motor vehicles, until the effect of Sympazan is known.
Withdrawal Symptoms
Abrupt discontinuation of Sympazan should be avoided. The risk of withdrawal symptoms is greater with higher doses. Withdraw Sympazan gradually to minimize the risk of precipitating seizures, seizure exacerbation, or status epilepticus.
Serious Dermatological Reactions
Serious skin reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported with clobazam in both children and adults. Discontinue Sympazan at the first sign of rash, unless the rash is clearly not drug-related.
Physical and Psychological Dependence
Patients with a history of substance abuse should be under careful surveillance when receiving Sympazan.
Suicidal Behavior and Ideation
AEDs, including Sympazan, increase the risk of suicidal thoughts or behavior in patients. Patients treated with Sympazan should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Inform patients, their caregivers, and families of the increased risk of suicidal thoughts and behaviors. Advise them to be alert for and report immediately to healthcare providers any emergence or worsening signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts of self-harm.
ADVERSE REACTIONS
Adverse reactions (≥10% and more frequently than placebo) included constipation, somnolence or sedation, pyrexia, lethargy, and drooling.
DRUG INTERACTIONS
The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression. Limit dosage and duration of concomitant use of benzodiazepines and opioids and follow patients closely for respiratory depression and sedation. Concomitant use of Sympazan with other CNS depressants, including alcohol, may increase the risk of sedation and somnolence. Caution patients and/or caregivers against simultaneous use with other CNS depressants or alcohol, as effects of other CNS depressants or alcohol may be potentiated. Hormonal contraceptives that are metabolized by CYP3A4; effectiveness may be diminished when given with Sympazan. Additional non-hormonal forms of contraception are recommended when using Sympazan. Dose adjustment may be necessary of drugs metabolized by CYP2D6 and of Sympazan when co-administered with strong CYP2C19 inhibitors (e.g., fluconazole, fluvoxamine, ticlopidine).
ONFI片可整片，或压碎和混在苹果酱中给药。
癫痫临床试验中比临床试验对精神病或其它情况自杀想法或行为相对风险较高，但对癫痫和精神病适应证绝对风险差别是相似的。
每ONFI片含5 mg，10 mg，或20 mg clobazam。片还含无活性成分：玉米淀粉，乳糖一水合物，硬脂酸镁，二氧化硅，和滑石粉。分子式是C16H13O2N2Cl和分子量为300.7。
图2. 对ONFI和安慰剂按类别跌倒癫痫发作反应 (研究1)
ONFI片可整片，或压碎和混在苹果酱中给药。
癫痫临床试验中比临床试验对精神病或其它情况自杀想法或行为相对风险较高，但对癫痫和精神病适应证绝对风险差别是相似的。
每ONFI片含5 mg，10 mg，或20 mg clobazam。片还含无活性成分：玉米淀粉，乳糖一水合物，硬脂酸镁，二氧化硅，和滑石粉。分子式是C16H13O2N2Cl和分子量为300.7。
图2. 对ONFI和安慰剂按类别跌倒癫痫发作反应 (研究1)