PharmD candidate at UConn School of Pharmacy

Jillian Barrack

In June, the  FDA approved cannabidiol oral solution (COS; Epidiolex, GWPharmaceuticals) for treatment of seizures associated with Lennox-Gastaut syndrome (LGS) or Dravet  syndrome (DS) in patients 2 years and older.

 LGS and DS are rare forms of severe epilepsy that emerge in early childhood. Patients often experience treatment-resistant seizures despite taking multiple antiseizure medications.

 COS is the first approved medication that contains a purified drug derived from marijuana, and the first approved drug for DS.

Approval of COS was based on data from three randomized double-blind placebo-controlled trials of 516 patients with either LGS or DS. Treatment with COS 20 mg/kg/day was tested in both LGS and DS patients (Studies 1, 2, and 3), and COS 10 mg/kg/day was tested in LGS patients (Study 2).

In LGS patients, COS was associated with a significant (p<0.01) reduction in total seizure frequency. The median percent reduction (per 28 days) was 41% in patients treated with 20 mg/kg/day versus 14% in placebo patients in Study 1 and 36% in the 10 mg/kg/day group, 38% in the 20 mg/kg/day group versus 18% in the placebo group in Study 2. Additionally, a greater improvement on the subject/caregiver global impression of change was reported in patients treated with COS compared with placebo in Studies 1 and 2.

In DS patients, COS was associated with a significant (p=0.01) reduction in total seizure frequency. The median percent reduction (per 28 days) was 39% in patients treated with COS 20 mg/kg/dayversus 13% in placebo patients in Study 3.

The most common adverse effects(>10%) were elevated transaminases (16%), decreased appetite (22%), diarrhea (20%), somnolence (25%), fatigue (12%),  insomnia (11%), infection (41%), and rash (13%).

COS caused dose-related elevations of liver transaminases (alanine aminotransferase [ALT] and/or aspartate aminotransferase[AST]). The majority of ALT elevation occurred in patients also taking valproate, and to a lesser extent, clobazam.

Patients with baseline Transaminase elevation experienced higher rates of transaminase elevation while on COS. Obtain serum transaminases and total bilirubin levels prior to treatment initiation, and at 1, 3, and 6 months after initiation, as well as 1 month after dose change or addition/discontinuation of any drug that affects the liver. If a patient develops clinical signs or symptoms of hepatic dysfunction, interrupt or discontinue treatment.1 As with most antiepileptic drugs, COS increases the risk of suicidal thoughts or behavior. Monitor patients for the emergence or worsening of depression or any unusual changes in mood or behavior.1

COS should be withdrawn gradually to avoid increased seizure frequency and status epilepticus. No contraindications with COS are known other than hypersensitivity to any ingredient. Insufficient information exists on the risks of COS on a fetus or breastfeeding infant.1

The recommended starting dose of COSis 2.5 mg/kg twice daily (5 mg/ kg/day). After1week, the dose can be increased to a maintenance dose of 5 mg/kg twice daily(10 mg/kg/day). If further seizure control is warranted, the dose can be increased to the maximum recommended maintenance dosage of 10 mg/kg twice daily (20 mg/kg/day). Dose adjustment is recommended for patients with moderate or severe hepatic impairment.1 Epidiolex is supplied as a 100 mL bottle of 100 mg/mL solution.

 Feature image: Manufacturing Epidiolex, courtesy of GWPharmaceuticals 

Epidiolex (cannabidiol) Package insert. Carlsbad, CA: Greenwich Biosciences, Inc.; June 2018.

Lennox-Gastaut syndrome. Genetics Home Reference. 

. Published July 17, 2018. Accessed July 23, 2018.

Genetic epilepsy with febrile seizures plus. Genetics Home Reference. 

FDA. FDA approves first drug comprised of an active ingredient derived from marijuana to treat rare, severe forms of epilepsy. http://bit.ly/2LZ9vLT Published June 25, 2018. Accessed July 23, 2018.

GW Pharmaceuticals. GW Pharmaceuticals plc and its U.S. subsidiary Greenwich Biosciences announce FDA approval of EPIDIOLEX

 (cannabidiol) oral solution – the first plant-derived cannabinoid prescription medicine. 

. Published June 25, 2018. Accessed July 23, 2018.

Articles

The FDA recently approved cannabidiol oral solution to treat seizures.

What Pharmacists Need to Know About Epidiolex

In November 2017, the FDA approved emicizumab-kxwh (Hemlibra, Genentech) for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A with factor VIII inhibitors. Replacement of factor VIII with plasma-derived or recombinant factor VIII products can prevent bleeding episodes in Hemophilia A patients.

However, inhibitory antibodies to factor VIII may develop during treatment.

 These inhibitors bind factor VIII and prevent its ability to participate in the coagulation cascade, leading to a bleeding risk and increased morbidity.

 Emicizumab-kxwh is a bispecific monoclonal antibody that brings together factors IXa and X to restore the function of the missing activated factor VIII and the blood clotting process.

Approval of emicizumab-kxwh was based on data from HAVEN 1, a multicenter open-label single-arm randomized phase 3 clinical trial of 109 adult and adolescent males with hemophilia A with factor VIII inhibitors who had previously received treatment with bypassing agents.

 Patients were randomized 2:1 to weekly emicizumab-kxwh prophylaxis (3 mg/kg administered subcutaneously once weekly for the first 4 weeks followed by 1.5 mg/kg once weekly) or no prophylaxis.

For patients receiving prophylaxis, the annualized bleeding rate (ABR) requiring treatment with coagulation factors was 2.9 compared with 23.3 for patients not receiving prophylaxis, corresponding to an 87% ABR reduction (p<0.0001). In addition, patients receiving prophylaxis reported improvements in hemophilia-related symptoms and physical functioning.

The most common adverse reactions (≥ 10%) were injection site reactions (19%), headache (15%), and arthralgia (10%).

 Injection site reactions were reported as mild to moderate intensity and 88% resolved without treatment.

The product labeling includes a boxed warning about thrombotic microangiopathy and thromboembolism. If activated prothrombin complex concentrate (aPCC) is coadministered, the patient should be monitored for the development of thrombotic microangiopathy and thrombotic events; aPCC should be discontinued if symptoms occur.

 The decision to resume emicizumab-kxwh following complete resolution of thrombotic microangiopathy should be based on clinical judgment.

Emicizumab-kxwh can interfere with some laboratory coagulation tests, including activated partial thromboplastin time (aPTT), Bethesda assays (clotting-based) for factor VIII inhibitor titers, aPTT-based activated protein C resistance (APC-R), activated clotting time (ACT), and one-stage aPTT-based single-factor assays.

No contraindications with emicizumab-kxwh are known to exist. Insufficient information exists on the risks of emicizumab-kxwh on the fetus.

 Females of child-bearing potential should be advised to use effective contraception during treatment.

The recommended dose of emicizumab-kxwh is 3 mg/kg administered subcutaneously once weekly for the first 4 weeks followed by 1.5 mg/kg once weekly.

 If a dose is missed, administer the dose as soon as possible before the day of the next scheduled dose, and then resume usual weekly dosing. The medication is supplied as 30 mg/mL, 60 mg/0.4 mL, 105 mg/0.7 mL, and 150 mg/mL injections. The average wholesale price is not yet available.

1. Kempton CL, White II GC. How we treat a hemophilia A patient with a factor VIII inhibitor. 

. Wolters Kluwer Heath, Inc. Riverwoods, IL. Available at: http://online.lexi.com. Accessed November 20, 2017.

3. Hemlibra (emicizumab-kxwh) Package insert. San Francisco, CA: Genentech, Inc.; November 2017.

4. Oldenburg J, Mahlangu JN, Kim B, et al. Emicizumab prophylaxis in hemophilia A with inhibitors. 

, 2017; 377: 809-818. doi: 10.1056/NEJMoa1703068

Emicizumab-kxwh brings together factors IXa and X to restore the function of the missing activated factor VIII and the blood clotting process.