Oral liquid cannabidiol (Epidyolex) for Dravet syndrome

• On 1 May 2021, oral liquid cannabidiol (Epidyolex) was listed on the PBS for Dravet syndrome – also known as severe myoclonic epilepsy in infancy (SMEI).
  It is the first medicinal cannabis product to be listed on the PBS.
• The PBS listing is for patients with generalised tonic-clonic or generalised clonic seizures associated with Dravet syndrome.
  Seizures must be inadequately controlled despite treatment with at least two antiepileptic medicines.
• Oral liquid cannabidiol for Dravet syndrome can only be prescribed as an adjunctive therapy.
  It is a third-line treatment and must be prescribed in combination with at least two other antiepileptic medicines.
• Initial prescription is restricted to the patient’s treating neurologist.
  General practitioners and paediatricians must consult a neurologist to continue prescribing oral liquid cannabidiol for their patients.
• Prescribers should be aware of flow-on changes to the PBS-listed anticonvulsant stiripentol (Diacomit).
  Clinical criteria for stiripentol are now in line with oral liquid cannabidiol for Dravet syndrome.

On 1 May 2021, oral liquid cannabidiol, 100 mg per mL, 100 mL (Epidyolex) was listed on the PBS General Schedule (Section 85) as Authority Required (immediate assessment) for the treatment of Dravet syndrome – also known as severe myoclonic epilepsy in infancy (SMEI).¹

To be considered for treatment with oral liquid cannabidiol for Dravet syndrome:¹

• the patient must have, or have had, generalised tonic-clonic seizures or generalised clonic seizures that are not adequately controlled with at least two other antiepileptic drugs; and
• the treatment must be as adjunctive therapy to at least two other antiepileptic drugs.

The treatment criteria stipulate that:¹

• the patient must be treated by a neurologist if treatment is being initiated; or,
• the patient must be treated by a neurologist if treatment is being continued/reinitiated; or
• the patient must be treated by a paediatrician in consultation with a neurologist if treatment is being continued; or
• the patient must be treated by a general practitioner in consultation with a neurologist if treatment is being continued.

See the PBS website for complete details

Dravet syndrome is a rare, refractory form of severe myoclonic epilepsy that usually emerges in the first year of life.^1,3 Seizures associated with Dravet syndrome are difficult to control, can lead to status epilepticus and sudden unexplained death in epilepsy (SUDEP), with mortality rates for patients under 18 years of age ranging from 3.7% to 17.5%.^4-6

The main goal of treatment in Dravet syndrome is to reduce the duration and frequency of seizures.⁷ Two recent studies^8,9 reported that oral liquid cannabidiol (10 mg/kg/day or 20 mg/kg/day) in addition to standard care (at least one antiepileptic medicine +/- ketogenic diet and vagal stimulation) can reduce the frequency of seizures associated with Dravet syndrome in children and adolescents aged between 2 and 18 years. Read more about the studies below.

The new listing for oral liquid cannabidiol gives prescribers an additional treatment option to reduce seizure frequency for patients with Dravet syndrome that is resistant to current treatment. Cannabidiol provides for some patients an improvement in efficacy over standard care.¹

Treatment pathway

In Australia, there are no current guidelines recommending a treatment pathway specifically for Dravet syndrome.¹ There is guidance for generalised tonic-clonic and myoclonic seizures. The Australian Medicines Handbook recommends the treatment for these types of seizures is sodium valproate as first line, followed by clobazam as second line.¹⁰

In the UK, the National Institute for Health and Clinical Excellence (NICE) treatment pathway for Dravet syndrome is consistent with their clinical guideline on epilepsy in general, recommending first-line treatment with sodium valproate or topiramate.⁷ If seizures are not adequately controlled, second-line treatments are clobazam or stiripentol.⁷ Stiripentol, an anticonvulsant, was recently listed on the PBS as a third-line treatment for Dravet syndrome and must be in combination with at least two other antiepileptic medicines.^1,11

Evidence for oral liquid cannabidiol in Dravet syndrome

Two randomised, double-blind, placebo-controlled trials (GWPCARE1 and GWPCARE2) evaluated the efficacy of oral liquid cannabidiol for the adjunctive treatment of seizures associated with Dravet syndrome.^8,9

In GWPCARE2,⁸ two maintenance doses of oral liquid cannabidiol (10 mg/kg/day and 20 mg/kg/day) were compared with placebo. In GWPCARE1,⁹ the higher maintenance dosage of 20 mg/kg/day was compared with placebo. Both trials had a follow up of 14 weeks.

GWPCARE2 demonstrated that patients treated with cannabidiol 10 mg/kg/day and 20 mg/kg/day experienced, on average, an additional 29.8% (95% CI 8.4% to 46.2%; p = 0.01) and 25.7% (95% CI 2.9% to 43.2%; p = 0.03) reduction in the frequency of convulsive seizures respectively from baseline, compared to patients treated with placebo.⁸

Several of the most common adverse events, including decreased appetite, diarrhoea, and fatigue, occurred more frequently in the 20 mg/kg/day group, as did serious adverse events, adverse events leading to discontinuation, and elevations of liver transaminase levels of greater than 3 times the upper normal limit of the reference range (among patients taking concomitant valproate).⁸

In GWPCARE1, patients treated with cannabidiol 20 mg/kg/day showed a reduction in both convulsive and non-convulsive seizure frequency compared with placebo. Percentage change in seizure frequency for the cannabidiol group was –38.9 (–100 to 337) compared to the placebo group –13.3 (–91.5 to 230). The adjusted median difference (95% CI) for both groups was –22.8 (–41.1 to –5.4) p = 0.01.⁹

Adverse events occurred more frequently in the cannabidiol group than in the placebo group and included diarrhoea, vomiting, fatigue, pyrexia, somnolence, and elevated liver transaminase levels. greater than 3 times the upper normal limit (among patients taking concomitant valproate). Importantly, liver transaminase levels mostly returned to normal levels for patients who continued with both treatments, suggesting a cannabidiol–valproate interaction that potentially causes transient metabolic stress on liver function.⁹

Clinical trials have shown that oral liquid cannabidiol can reduce the frequency of convulsive and non-convulsive seizures for patients with Dravet syndrome, when compared with usual care.⁷ 

In their July 2020 recommendation, the PBAC considered the appropriate place in therapy for oral liquid cannabidiol is as a third-line treatment, in combination with at least two other antiepileptic medicines.¹ 

International commentary suggests that treatment with oral liquid cannabidiol is likely to be cost-saving for families and carers, considering the risks to patients of severe, refractory seizures, and the stress and cost of repeated hospital admissions.¹²

• The new listing for oral liquid cannabidiol provides an additional treatment option to reduce seizure frequency for patients with refractory Dravet syndrome.
• This is the first cannabidiol product to be listed on the Pharmaceutical Benefits Scheme.
• Approved cannabidiol products are intended to be used as an adjunct to existing antiepileptic therapies rather than replace them.
• Cannabidiol is not suitable for prescribing by nurse practitioners.¹

Dosage

When commencing oral liquid cannabidiol, incremental up-titration is recommended to allow for assessment and monitoring of individual clinical response and tolerability. The maximum daily dose of oral liquid cannabidiol is 20 mg/kg/day.²

The recommended starting and up-titration doses of oral liquid cannabidiol are shown in table 1.

Table 1. Recommended starting and up-titration doses of oral liquid cannabidiol (Epidyolex)²

a Any dose increases above the maintenance dose of 10 mg/kg/day should be made considering individual benefit and risk and should not exceed the maximum daily dose.

Changes to stiripentol (Diacomit)

Flow-on changes to stiripentol (Diacomit) were recommended by the PBAC and the listing is now in line with clinical criteria for oral liquid cannabidiol (Epidyolex). See table 2.

Table 2. Clinical criteria changes for stiripentol (Diacomit)¹

Oral liquid cannabidiol 100mg/mL, 100 mL (Epidyolex) comes as one unit (bottle) with two oral dosing syringes. The maximum allowable prescribed quantity of oral liquid cannabidiol is one unit, with 5 repeats.^2,13

Side effects

Oral liquid cannabidiol can potentially cause drowsiness and sedation, particularly when used alongside clobazam or other central nervous system depressants, including alcohol.

Other common side effects include decreased appetite and weight loss, diarrhoea, vomiting, fever and fatigue.

Oral liquid cannabidiol cannot be excluded from the small increased risk of suicidal behaviour and ideation reported with other antiepileptic drugs.

Patients should be monitored for signs of suicidal behaviour and ideation. Caregivers of older children, adolescent and adult patients should be advised to seek urgent medical advice if any signs of suicidal ideation or self-harming behaviour emerge.^2,13

Liver function

Oral liquid cannabidiol can cause dose-related elevations of liver transaminases (alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST]). This typically occurs in the first 2 months of treatment but can occur up to 18 months after treatment initiation, particularly for patients taking concomitant valproate and to a lesser extent clobazam.

In about one-third of cases, elevated transaminase levels resolve without requiring dose reduction or discontinuation of treatment. The remaining two-thirds of cases will require either discontinuation of oral liquid cannabidiol, reduction of oral liquid cannabidiol and/or reduction of valproate for resolution of transaminase levels.

Oral liquid cannabidiol should be used with caution by patients with severe hepatic impairment. For patients with moderate hepatic impairment, a lower starting dose is recommended.^2,13

Monitoring

Regular monitoring and early identification of elevated transaminase may decrease the risk of severe liver injury. Prior to starting oral liquid cannabidiol, obtain baseline serum transaminases (ALT and AST) and total bilirubin levels. These results will determine the recommended monitoring schedule once treatment has been initiated (see table 3).

Table 3. Recommended monitoring schedule for patients taking oral liquid cannabidiol (Epidyolex)²

b Restart routine monitoring when increasing dose above 10mg/kg/day or if adding other medications that are known to impact the liver.

Interactions

Closely monitor patients taking oral liquid cannabidiol and concomitant antiepileptic drugs, particularly clobazam and valproate, for increased systemic levels of the active substances and an increase in adverse drug reactions.²

Decreasing or discontinuing oral liquid cannabidiol

Oral liquid cannabidiol should be discontinued in any patients with:

• elevations of transaminase levels greater than 3 times the upper limit of normal; and
• bilirubin levels greater than 2 times the upper limit of normal; or
• clinical signs or symptoms suggestive of liver injury (eg, unexplained nausea, vomiting, right upper quadrant abdominal pain, fatigue, anorexia, or jaundice and/or dark urine).

If discontinuing oral liquid cannabidiol, decrease the dose gradually to reduce the risk of increased seizure activity or status epilepticus.

• Dose can be decreased by approximately 10% per day for 10 days.
• Down-titration may be slower or faster at the discretion of the prescriber.²

Oral liquid cannabidiol does not cause what is generally known as a ‘high’ as it does not contain tetrahydrocannabinol (THC).

It is only to be used as prescribed and in combination with other antiepileptic medicines to treat seizures associated with Dravet syndrome.²

How is oral liquid cannabidiol administered?

Oral liquid cannabidiol (Epidyolex) is an oral solution that is administered via an oral dosing syringe.

Each box of oral liquid cannabidiol contains:

• two 1 mL oral syringes graduated in 0.05 mL increments (each 0.05 mL increment corresponds to 5 mg oral liquid cannabidiol)
  • If the calculated dose is ≤ 100 mg (1 mL), the smaller 1 mL oral syringe should be used.
• two 5 mL oral syringes graduated in 0.1 mL increments (each 0.1 mL increment corresponds to 10 mg oral liquid cannabidiol)
  • If the calculated dose is > 100 mg (1 mL), the larger 5 mL oral syringe should be used.
  • Calculated doses should be rounded up to the nearest increment.²

When should oral liquid cannabidiol be taken?

Oral liquid cannabidiol can be taken with or without food.

Taking oral liquid cannabidiol with food – particularly a high fat, high calorie meal – is known to increase the level of cannabidiol in the blood.

Because of this, patients and caregivers need to practice consistency in administering oral liquid cannabidiol. Consistent dosing times help to minimise variability in the way the medicine works.

A schedule for morning or evening dosing and taking oral liquid cannabidiol either with or without food, should be prepared and adhered to.²

Missed doses

In the case of one or more missed doses, the missed doses should not be compensated. Dosing should be resumed at the existing treatment schedule. In the case of more than 7 days’ missed doses, up-titration to the therapeutic dose should be started again.²

Shelf life

An unopened bottle of oral liquid cannabidiol (Epidyolex) has a shelf life of 2 years.

Patients and caregivers should be advised to use the medicine within 8 weeks of first opening the bottle.²

Side effects

Inform patients and caregivers that side effects of cannabidiol can include:

• drowsiness and sedation
  • usually occurs early on in treatment and may diminish as treatment continues
  • is more common with clobazam
  • is potentiated by other central nervous system (CNS) depressants, including alcohol
• decreased appetite and weight loss
• vomiting
• fever
• fatigue.

If the patient is unable to tolerate side effects, inform them and caregivers that the treating neurologist should be consulted.

Educate caregivers of older children and adult patients about the small increased risk of suicidal behaviour and ideation associated with antiepileptic drugs and advise to seek urgent medical advice if any signs emerge.²

Other

Oral liquid cannabidiol (Epidyolex) has been approved by the TGA and adheres to strict quality standards. Dosing recommendations are based on clinical trials conducted with patients with Dravet syndrome.

It is not interchangeable with low-dose over-the-counter (OTC) cannabidiol products.¹⁴

Find out more about low-dose OTC cannabidiol products on the TGA website.

• Applications for authorisation under these restrictions may be made in real time using the Online PBS Authorities system or by phoning Services Australia on 1800 888 333.
• Read the 2017 TGA Guidance for the use of medicinal cannabis in the treatment of epilepsy in paediatric and young adult patients in Australia
• Visit Australian Prescriber for more information about stiripentol for Dravet syndrome