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January February 2019 Clinical Rx Forum Newsletter.Pub In This Issue Cannabidiol (Epidiolex ))) for Lennox-Gastaut and Dravet Syndrome Stiripentol (Diacomit ®) From the Department of Pharmacy for Dravet Syndrome January/February Issue 2019 Volume 7, Issue 1 Formulary Cannabidiol (Epidiolex ®) for Lennox-Gastaut and Dravet Syndrome Update FDA Medication Safety Alert: Risk of VTE with Test osterone By: Ana Simonyan, Pharm.D. Marcia J. Wyman, Pharm.D., BCPS Background: Lennox-Gastaut Syn- Mechanism of Action: Cannabidiol is Drug Information Pharmacist drome (LGS) is characterized by severe a chemical component of the Cannabis Editor 5 tonic seizures and cognitive dysfunc- sativa plant. Since it does not contain Mandy C. Leonard, Pharm.D., BCPS tion usually occurring in children tetrahydrocannabinol (THC), CBD does System Director, Drug Use Policy and < 8 years of age. 1 Approximately 56% of not exert the same psychoactive effects Formulary Management patients with LGS experience sudden seen with THC. The exact antiepileptic Editor tonic or atonic falls known as drop sei- mechanism of action of CBD is not Meghan K. Lehmann, Pharm.D., BCPS zures. Dravet Syndrome (DS) is charac- known. 4,6 However, it is theorized that Coordinator, Drug Information Services terized by prolonged, convulsive sei- CBD’s anti-seizure activity may be asso- Drug Information Specialist zures. 2 Lennox-Gastaut Syndrome is ciated with its interactions with various Editor estimated to account for 1%-10% of receptors (e.g., opioid, serotonin, gly- 5 Marigel Constantiner, MSc, BCPS, BCGP childhood epilepsies, whereas DS has a cine, GPR55). Drug Information Pharmacist reported incidence of 1 in 15,700. 2,3 Associate Editor Frequently accompanied by a poor Key Clinical Trials: Cannabidiol oral prognosis these rare and severe forms solution received FDA approval based Christopher Snyder, B.S., R.Ph. of epilepsy are difLicult to manage and on three randomized, double-blind, pla- Drug Information Pharmacist cebo-controlled trials in patients with Associate Editor are often refractory to most conven- either LGS or DS. 4 Study 1 (N=171) tional anti-seizure therapies. 1,3 Fortu- Brian Hoffmaster, Pharm.D., BCPS nately, a new medication, cannabidiol evaluated CBD solution at a dose of Student Education Pharmacist (CBD) oral solution (Epidiolex ®; Green- 20 mg/kg/day compared with matching Associate Editor wich Biosciences), was approved by the placebo for 14 weeks in patients with LGS. 7 The primary endpoint was the Benjamin Witt, Pharm.D., MBA, BCPS Food and Drug Administration (FDA) in Drug Information Pharmacist June 2018 for the treatment of seizures percentage change from baseline in the Associate Editor in patients ≥ 2 years of age with LGS monthly frequency of drop seizures 4 (Continued on page 2) Sneha Shah, Pharm.D., BCPS or DS. Drug Information Pharmacist Associate Editor Stiripentol (Diacomit ®) for Dravet Syndrome Scott Knoer, MS, Pharm.D., FASHP By: Amber Daley, Pharm.D. Chief Pharmacy OfPicer Background: Dravet Syndrome (DS) (Diacomit ®; Biocodex), for the treat- is often refractory to the off-label use of ment of seizures associated with DS in conventional antiepileptic therapy (e.g., patients ≥ 2 years of age concurrently valproate, clobazam, topiramate, and receiving clobazam. 4,5 There are no da- levetiracetam) which in some cases ta to support stiripentol as a monother- From the Department of Pharmacy may actually exacerbate DS associated apy for this disease state.5 1-3 Drug Information Service seizures. The lack of effective thera- peutic options highlights the im- Mechanism of Action: Stiripentol’s (216) 444-6456, option #1 5 portance of the June 2018 approval of exact mechanism of action is unknown. cannabidiol solution (Epidiolex ®) by One proposed mechanism is an indirect Comprehensive information about the Food and Drug Administration anticonvulsant effect involving inhibi- medications, biologics, nutrients, (FDA) for the treatment of DS. Shortly tion of Cytochrome P450 (CYP 450) and drug therapy afterwards in August 2018, the FDA activity and clobazam metabolism. This approved another agent, stiripentol (Continued on page 3) (Continued from page 1) during the treatment period. The median percent re- strong inhibitors or inducers of Cytochrome P450 duction in monthly drop seizure frequency from base- (CYP)3A4 and CYP2C19, as well as clobazam and line was 44% in patients receiving CBD solution valproate. Patients should also be told that they may compared to 22% in those receiving placebo test positive for cannabis during urine drug screen ing. (p<0.0135). Study 2 (N=225) evaluated CBD solution Availability and Storage: Cannabidiol 100 mg/mL at 10 mg/kg/day and 20 mg/kg/day compared to pla- is available in an amber glass bottle with a child- cebo in patients with LGS for 14 weeks. 8 The primary resistant closure containing 100 mL of strawberry Lla- outcome was the percentage change from baseline in vored solution (NDC 70127-100-01) and also packaged the frequency of drop seizures. The median reduction in a carton containing two 5 mL calibrated oral dosing in drop seizure frequency from baseline during the syringes and a bottle adapter (NDC 70127-100-10). 4 treatment period was 38% in the 10 mg/kg/day group, Pharmacies are instructed to provide a 1 mL calibrated 42% in the 20 mg/kg/day group, and 17% in the place- oral syringe for doses less than 1 mL. The bottle of can- bo group (p<0.005 for the 20 mg group vs. placebo and nabidiol oral solution should be stored at room tem- p=0.002 for the 10 mg group vs. placebo). Study 3 perature 20°C to 25°C (68°F to 77°F) and used within (N=120) compared CBD solution 20 mg/kg/day with 12 weeks of opening. Cannabidiol oral solution is des- placebo in patients with DS. 9 The primary endpoint ignated as a CV Controlled Substance. was the change in convulsive seizure frequency after 14 weeks of treatment compared with a 4 week base- line period. The percentage of patients who experi- Formulary Status: Cannabidiol oral solution is not enced at least a 50% reduction in convulsive seizure currently on the CCHS Formulary. frequency from baseline was 43% in the CBD group versus 27% in the placebo group (p=0.08). References: 1. Arzimanoglou A, French J, Blume WT, Cross JH, Ernst JP, Feucht M, et Dosing and Administration: The recommended al. Lennox-Gastaut syndrome: a consensus approach on diagnosis, starting dose of CBD solution is 2.5 mg/kg twice daily assessment, management, and trial methodology. Lancet Neurol. (5 mg/kg/day) taken on an empty stomach. 4,6 After 2009;8(1):82-93. 2. Wirrell EC, Laux L, Donner E, Jette N, Knupp K, Meskis MA, et al. Opti- 1 week of treatment, patients can be titrated mizing the diagnosis and management of Dravet Syndrome: recom- to 5 mg/kg twice daily (10 mg/kg/day). Patients who mendations from a North American consensus panel. Pediatr Neurol. 2017;68:18-34. would beneLit from further seizure reduction can be 3. Hancock EC, Cross JH. Treatment of Lennox-Gastaut syndrome. titrated to a maximum dose of 10 mg/kg twice daily Cochrane Database Syst Rev. 2013;2:CD003277. (20 mg/kg/day). Abrupt discontinuation of CBD oral 4. Epidiolex ® [package insert]. Carslbad, CA: Greenwich Biosciences; January 2019. solution should be avoided to minimize the risk of sta- 5. Bih CI, Chen T, Nunn AVW, Bazelot M, Dallas M, Whalley BJ. Molecular tus epilepticus. If CBD solution is to be discontinued, targets of cannabidiol in neurological disorders. Neurotherapeutics. the dose should be decreased gradually. 2015;12(4):699-730. 6. Lexi-Comp Online, Lexi-Drugs Online, Hudson, Ohio: Lexi-Comp Inc;2018:September 6, 2018. 7. Thiele EA, Marsh ED, French JA, Mazurkiewicz-Beldzinskia M, Ben- Safety: Cannabidiol oral solution is associated with badis SR, Joshi C, et al. Cannabidiol in patients with seizures associated dose-related elevations in liver enzymes. 4,6-9 This may with Lennox-Gastaut Syndrome (GWPCARE4): a randomized, double- blind, placebo-controlled phase 3 trial. Lancet. 2018;391(10125): occur within the Lirst 2 months of treatment, especially 1085-96. in patients taking other antiepileptic medications. Pri- 8. Devinsky O, Patel AD, Cross JH, Villanueva V, Wirrell EC, Privitera M, et or to initiating CBD oral solution, serum transaminases al. Effect of cannabidiol on drop seizures in the Lennox-Gastaut Syn- drome. N Engl J Med. 2018;378(2):1888-97. and total bilirubin levels should be obtained. 4 Monitor- 9. Devinsky O, Cross JH, Laux L, Marsh E, Miller I, Nabbout R, et al. Trial ing for liver injury should continue at 1 month, of cannabidiol for drug-resistant seizures in the Dravet Syndrome. N 3 months, and 6 months after initiation, and as clinical- Engl J Med. 2017;376(21):2011-20. ly indicated thereafter. Common adverse reactions associated with CBD 20 mg/kg/day dosage include somnolence (25%), sedation (6%), sleep disturbances (5%), decreased appetite (22%), weight loss (5%) diarrhea (20%), and infections (40%). As with any anti-epileptic treatment, patients taking CBD should be aware of the increased risk for suicidal thoughts or behavior and be monitored appropriately. A dosage adjustment should be made if CBD solution is administered concomitantly with 2 (Continued from page 1) results in an increase in serum concentrations of considered when used concomitantly with strong in- clobazam and its active metabolite, thereby potentiat- ducers of CYP1A2, CYP3A4 or CYP2C19 (e.g., rifampin, ing their anti-seizure activity. 1,5 Stiripentol may also phenytoin, phenobarbital, and carbamazepine). have a direct antiepileptic effect as a weak partial ago- nist of the gamma-amino butyric acid (GABA) A Dosing and Administration: The recommended receptor. 5,6 starting dose of stiripentol is 50 mg/kg/day divided in two or three doses with a maximum of 3000 mg/day.
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