What You Need to Know About Cannabidiol for Rare Forms of Epilepsy

In June 2018, the FDA approved cannabidiol (CBD; Epidiolex, GW Pharmaceuticals) for 2 rare types of epilepsy, Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS).¹

LGS is a form of epilepsy characterized by frequent seizures in early childhood that can cause a multitude of symptoms, from uncontrollable muscle contracts to complete loss of consciousness. LGS is estimated to affect 1 out of every 50,000 to 100,000 children, leading to a prevalence of 4% of all childhood epilepsies.²

DS is another rare form of epilepsy associated with frequent and prolonged seizures. DS is estimated to affect 1 out of every 75,000 individuals, 80% of whom have an SCN1A gene mutation.³

Dosing and Administration

CBD is initially administered at 2.5 mg/kg orally twice a day. After the first week, the dose of CBD can be increased to 5 mg/kg twice a day. Additional dose increases can be made to a maximum of 10 mg/kg twice a day to reduce seizure frequencies. Dose increases should be done at weekly increments of 2.5 mg/kg. Dosage increases can be done every other day for patients who need more rapid titration.⁴

High-fat and high-calorie meals increase CBD’s maximum concentration and bioavailability compared with no food. CBD needs to be taken consistently with or without food. Measure out the dose with the calibrated oral syringe (1 ml or 5 ml) provided with CBD. Do not use a household teaspoon or tablespoon.

Serum transaminases (ALT and AST) and total bilirubin levels must be obtained prior to treatment because of the risk of hepatocellular injury.

Moderate and severe hepatic impairment require dose adjustments (Child-Pugh B or C). Mild hepatic impairment does not require dose adjustments (Child-Pugh A).

Table 1. Dose Adjustments for Moderate and Severe Hepatic Impairment

Hepatic Impairment

Initial Dose

Maintenance Dose

Maximum Recommended Dose

Moderate

1.25 mg/kg twice a day

2.5 mg/kg twice a day

5 mg/kg twice a day

Severe

0.5 mg/kg twice a day

1 mg/kg twice a day

2 mg/kg twice a day

Discontinuation of seizure medications, including CBD must be tapered gradually to avoid increased seizure frequency and status epilepticus.

Pharmacology

CBD does not exert its anticonvulsant effects through the cannabinoid receptors. The exact mechanism is unknown.⁴

Method of Supply

CBD is a colorless to yellow solution supplied in an amber glass bottle containing 100 ml of oral solution. Each ml of solution contains 100 mg of cannabidiol. CBD comes with two 5-

ml calibrated oral dosing syringes and a bottle adapter. The pharmacy can provide 1 ml calibrated oral dosing syringes, if required.⁴

Storage

Store CBD at 20-25°C (68-77°F) with a permitted range between 15-30°C (59-86°F). Do not refrigerate or freeze the medication and keep the cap tightly closed. CBD must be used within 12 weeks for opening the bottle. Discard any medication remaining past 12 weeks.⁴

Drug Interactions and Contraindications

CBD is metabolized by CYP3A4 and CYP2C19. Co-administration with moderate or strong CYP3A4 or CYP2C19 inhibitors can increase CBD concentration and may require a dose reduction. Co-administration with a strong CYP3A4 or CYP2C19 inducer decreases CBD concentration and may require a dose increase.⁴

CBD also may increase concentrations of CYP2C19 substrates (diazepam). Clobazam, when co-administered with CBD, had a 3-fold increase in plasma concentrations of its active metabolite. Dose reductions for CYP2C19 substrates may be needed when administered together with CBD.

In vitro data suggests that CBD might have drug-drug interactions with CYP1A2 substrates (eg, theophylline, caffeine), CYP2B6 substrates (eg, bupropion, efavirez), UGT1A9 substrates (eg, diflunisal, fenofibrate, propofol), UGT2B7 substrates (eg, gemfibrozil, lamotrigine, lorazepam, morphine), CYP2C8 and CYP2C9 substrates (phenytoin). A reduction in the dose of UGT1A9, UGT2B7, CYP2C8, and CYP2C9 may be required to avoid adverse reactions. Dose adjustments for CYP1A2 and CYP2B6 substrates may also be required.

Valproate taken with CBD increase liver enzyme elevations and may increase hepatotoxicity. Discontinuation or reduction of CBD or valproate should be considered. There is no data on other hepatotoxic drugs.

Increased risk of sedation was observed when CBD was used with central nervous system (CNS) depressants or alcohol.

CBD is contraindicated in any patient with an allergic reaction to CBD or any of its components.

Warnings and Precautions

CBD can cause elevated liver transaminase (ALT/AST) that can result in hospitalization. In one-third of cases, transaminase elevations returned to normal without therapy changes. In two-thirds of cases transaminase elevations resolved upon discontinuation of CBD, reduction in dose of CBD and/or valproate. The risk of elevated liver transaminase is higher in patients also taking valproate or clobazam; dose adjustments may be needed. The risk is also higher with higher doses of CBD (20 mg/kg/day vs 10 mg/kg/day) and patients with higher than normal baseline transaminase levels.⁴

Serum transaminase levels and total bilirubin levels should be obtained prior to initiation of therapy, at 1 month, 3 months, 6 months, and when clinically indicated after initiation of treatment. Serum transaminase levels and total bilirubin levels should also be obtained within 1 month of dosage changes of CBD or other medications known to affect the liver. More frequent monitoring may be needed in patients with elevated liver enzymes at baseline, taking valproate, or experiencing clinical signs or symptoms of liver dysfunction (dark urine, jaundice).

Discontinue CBD in patients with elevated transaminase levels 3 times the upper limit of normal (ULN) and bilirubin levels 2 times the ULN, or if there is sustained transaminase levels 5 times the ULN.

A dose-related incidence of sedation or somnolence was observed in patients on CBD, with higher rates in patients also taking clobazam or other CNS depressants, including alcohol. Sedation/somnolence usually occurs early in therapy and lessens after continued use. Patients should be advised not to operate machinery or drive until they have enough time to know if CBD will cause drowsiness.

CBD can cause suicidal thoughts or behavior, hypersensitivity reactions, and increased risk of seizure frequency and status epilepticus if not gradually withdrawn. Rapid discontinuation should only be considered in the case of a serious adverse event.

Adverse Reactions

Common adverse reactions, regarded as an incidence rate of ≥10%, are listed in the table below.⁴

Table 2. Adverse Reactions From Placebo-Controlled Clinical Trials

Adverse Reactions

CBD 10 mg/kg/day Percentages

CBD 20 mg/kg/day Percentages

Infection (all)

41%

40%

Somnolence

23%

25%

Decreased appetite

16%

22%

Diarrhea

9%

20%

Fatigue, malaise, asthenia

11%

12%

Insomnia, sleep disorder, poor sleep quality

11%

5%

Transaminase elevations

8%

16%

Rash

7%

13%

CBD can also cause dose-related weight loss, decreases in hemoglobin and hematocrit, and increases in creatinine.

Pregnancy and Lactation

There is no human data on pregnancy or lactation. When CBD was given to rabbits and rats, there was evidence of embryofetal mortality in rats and decreased fetal body weights, decreased growth, neurobehavioral changes, and delayed sexual maturation in rabbits.⁴ Pregnant women are encouraged to enroll in the North American Antiepileptic Drug Pregnancy Registry at www.aedpregnancyregistry.org.

Pediatric and Geriatric Use

The safety and efficacy of CBD is proven in patients 2 years of age and older. Geriatric patients (55 years or older) may need to take lower doses of CBD.

Clinical Trials

The effectiveness of CBD for Lennox-Gastaut Syndrome (LGS) was shown in 2 randomized placebo-controlled trials. In the first study, patients with LGS who were inadequately controlled on at least 1 antiepileptic drug, received either CBD 20 mg/kg/day or placebo. Median percent change from baseline in the frequency of seizures was significantly greater in the CBD group compared with placebo (41% vs 14%). In the second study, patients with LGS received CBD 20 mg/kg/day, CBD 10 mg/kg/day, or placebo. The median percent reduction in total seizure frequency was 36%, 38%, and 18% for CBD 10 mg/kg/day, CBD 20 mg/kg/day, and placebo, respectively. An overall condition scale, Subject/Caregiver Global Impression of Change (S/CGIC) score also showed improvements in both CBD groups compared with placebo.⁴

The effectiveness of CBD for Dravet syndrome (DS) was proven in one randomized, placebo-controlled trial, comparing CBD 20 mg/kg/day with placebo. Patients enrolled were diagnosed with treatment-resistant DS and were inadequately controlled with at least 1 antiepileptic drug. Patients taking CBD had significantly greater convulsive seizure frequency reductions compared with placebo.

Costs and Availability

CBD was previously a Schedule I controlled substance, meaning it was not approved for sale. It underwent DEA review based on FDA recommendations and clinical study results, and was rescheduled by the DEA to a Schedule V substance.⁵

Patient Counseling

CBD is a cannabinoid used to treat seizures associated with LGS or DS in people 2 years or older. CBD is slowly titrated from a starting dose of 2.5 mg/kg orally twice daily (5 mg/kg/day), up to a maximum maintenance dose of 20 mg/kg/day. Do not abruptly stop CBD as that may cause seizures or status epilepticus. CBD should be stored at room temperature in its original bottle and must be used within 12 weeks of first opening the bottle. Do not refrigerate or freeze the medication.⁴

CBD is known to cause adverse events including sleepiness, decreased appetite, diarrhea, rash, insomnia, fatigue, infections, and increased transaminase levels. Do not drive or operate heavy machinery until the effects of CBD are known. CBD is known to be potentially hepatotoxic. Liver enzyme levels will need to be obtained at set intervals and then periodically as clinically mandated. Any signs of liver damage such as jaundice, or darkening urine must be reported to the clinician immediately.

CBD may interact with some medications, including CYP3A4 and CYP2C19 inhibitors and inducers. Inhibitors may increase CBD serum concentrations and require dose reductions, while inducers may decrease CBD serum concentrations and require dose increases. CBD has also been shown to interact with CNS depressants, including alcohol, which may increase sedation.

There have not been any studies done for CBD on pregnant or lactating women. Dose adjustments may be needed in patients with hepatic impairment or are taking drugs that are hepatotoxic such as valproate.

Directions for Use

1. Remove the child-resistant cap by pushing down while turning the cap to the left.
2. Push the bottle adapter into the bottle and make sure that it is fully inserted.
3. Use the appropriate syringe (1ml or 5ml) and push the plunger all the way down and insert the oral syringe into the bottle adapter.
4. Turn the bottle upside down and pull the plunger of the oral syringe to withdraw the dose needed (if there are air bubbles, keep the bottle upside down, and push the plunger so that the liquid returns to the bottle and re-draw the dose).
5. When the correct dose of CBD is measured, turn the bottle right side up.
6. Remove the oral syringe from the bottle adapter.
7. Place the tip of the oral syringe against the inside of the cheek and push the plunger all the way to administer the dose.
8. Screw back the child-resistant cap back onto the bottle over the bottle adapter.
9. Clean the oral syringe by drawing water in and out of the syringe using the plunger.
10. Remove the plunger from the barrel and rinse both parts. Allow them to dry.

REFERENCES

1. FDA approves

first drug comprised of an active ingredient derived from marijuana to treat rare, severe forms of epilepsy [press release]. Silver Spring, MD: FDA; June 25, 2018. www.fda.gov/newsevents/newsroom/pressannouncements/ucm611046.htm. September 4, 2018.

2. Lennox-Gastaut syndrome. Genetics Home Reference. ghr.nlm.nih.gov/condition/lennox-gastaut-syndrome#statistics. Accessed September 4, 2018.

3. What is Dravet syndrome? Dravet Syndrome Foundation. www.dravetfoundation.org/what-is-dravet-syndrome/. Accessed September 4, 2018.

4. CBD [prescribing information]. Carlsbad, California: Greenwich Biosciences; 2018. www.accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf. Accessed August 23, 2018.

5. GW Pharmaceuticals plc and its U.S. Subsidiary Greenwich Biosciences Announce the DEA has Rescheduled EPIDIOLEX® (cannabidiol) Oral Solution to Schedule V [press release]. London, UK; Carlsbad, CA: GW Pharma. Published September 27, 2018. http://ir.gwpharm.com/news-releases/news-release-details/gw-pharmaceuticals-plc-and-its-us-subsidiary-greenwich-0?rel=0" . Accessed September 27, 2018.