Cannabidiol

Introduction Overview

Generic Name

cannabidiol

Brand Name

Epidiolex

Dosage Form

oral solution

Drug Class

Miscellaneous anticonvulsants

Pharmacokinetics

Absorption:
Epidiolex is administered as an oral solution and is absorbed via the gastrointestinal tract. The oral bioavailability of cannabidiol (CBD) is variable due to significant first-pass metabolism in the liver. Studies indicate that CBD has relatively moderate absorption with peak plasma concentrations usually reached within 2.5 to 5 hours after ingestion. The presence of food, particularly high-fat meals, significantly increases the systemic exposure of cannabidiol, raising plasma levels by up to fourfold. Thus, it is recommended that patients take Epidiolex consistently with or without food to maintain stable plasma drug concentrations. Variability in absorption may contribute to fluctuations in therapeutic effect and necessitates careful dose titration.

Distribution:
Cannabidiol is highly lipophilic, which facilitates distribution into highly perfused tissues including the brain, adipose tissue, and hepatic tissue. It exhibits extensive distribution with a large volume of distribution. CBD is approximately 94% protein bound in plasma, primarily to albumin and alpha-1-acid glycoprotein. Due to its lipophilicity, CBD readily crosses the blood-brain barrier, achieving concentrations relevant to its anticonvulsant activity. Distribution can be affected by physiological factors such as age, body fat composition, and concurrent disease states, influencing clinical response.

Metabolism:
The metabolism of cannabidiol is primarily hepatic, involving the cytochrome P450 enzyme system, especially CYP3A4 and CYP2C19 isoenzymes. CBD undergoes extensive first-pass metabolism through hydroxylation and subsequent oxidation to various metabolites, with 7-hydroxy-CBD being a major active metabolite contributing to pharmacological activity. Co-administration of inhibitors or inducers of these enzymes can significantly alter CBD plasma concentrations. For example, concomitant use with strong CYP3A4 inhibitors like ketoconazole can increase serum levels, while inducers like rifampin can reduce CBD exposure. Understanding these interactions is critical for dose adjustments and managing drug-drug interactions.

Elimination:
Cannabidiol and its metabolites are primarily eliminated via feces (approximately 80%) with minor renal excretion (<20%). The elimination half-life ranges considerably based on dose, frequency, and individual patient factors, typically between 18 to 32 hours. CBD is metabolized to more polar inactive metabolites, facilitating biliary and fecal excretion. Because renal clearance is minimal, dose adjustments in mild to moderate renal impairment are generally unnecessary, but caution is advised as clinical studies are limited. Hepatic impairment can markedly reduce clearance leading to increased plasma concentrations, thus dosage modification or increased monitoring is needed in patients with significant liver dysfunction.

Dosage Forms

Available Dosage Forms:
Epidiolex is available exclusively as a strawberry-flavored oral solution. The strength of the preparation is 100 mg/mL cannabidiol. It is supplied in 60 mL and 100 mL bottles.

Dosages for Adults and Adolescents:
- Initial dose for Lennox-Gastaut and Dravet syndromes: 2.5 mg/kg orally twice daily.
- After one week, dose may be increased to 5 mg/kg twice daily.
- Further incremental increases of 2.5 mg/kg twice daily may be made every other day as tolerated.
- Maintenance dose usually ranges between 10 to 20 mg/kg/day divided into two doses.
- Maximum recommended dose: 20 mg/kg/day.

- For treatment of tuberous sclerosis complex:
-- Initial dose: 2.5 mg/kg orally twice daily.
-- Dose may be increased weekly in increments of 2.5 mg/kg twice daily up to a maximum of 12.5 mg/kg twice daily (25 mg/kg/day).
-- Lower doses than 25 mg/kg/day have not been extensively studied for efficacy.

Specific Patient Populations:
- Pediatric patients: Approved for use in patients 1 year of age and older; dosing is weight-based.
- Hepatic impairment: Caution required; monitor liver function tests and consider dose reduction or discontinuation if significant hepatic adverse effects occur.
- Renal impairment: No specific dosage adjustment recommended due to minimal renal clearance, but clinical experience is limited.
- Elderly: Limited data; use with caution due to potential altered pharmacokinetics.
- Food considerations: Take consistently with or without food to minimize plasma concentration fluctuations.

Additional Instructions:
- Epidiolex must be measured precisely using the provided oral dosing syringes (1 mL and 5 mL syringes).
- The oral solution may be administered via non-PVC feeding tubes.
- The solution should be stored at room temperature and used within 12 weeks of opening.

Mechanism Of Action

Epidiolex, containing cannabidiol (CBD) as its active ingredient, exerts its anticonvulsant effects through mechanisms distinct from tetrahydrocannabinol (THC) and other cannabinoids. Unlike THC, CBD does not produce psychoactive effects and its anticonvulsant activity is not primarily mediated via direct activation of cannabinoid receptors CB1 or CB2.

At a molecular level, cannabidiol modulates multiple targets involved in neuronal excitability and neurotransmission. It acts as a negative allosteric modulator of the CB1 receptor, reducing the receptor's response to endogenous cannabinoids, which may contribute to its anticonvulsant properties without eliciting psychoactive effects. Additionally, CBD inhibits the reuptake and enzymatic degradation of the endocannabinoid anandamide, indirectly enhancing endocannabinoid signaling.

CBD's mechanism extends to modulating non-cannabinoid receptors and ion channels involved in epilepsy pathophysiology. It activates transient receptor potential vanilloid (TRPV) channels, particularly TRPV1 and TRPV2, and modulates G protein-coupled receptor 55 (GPR55), which impacts intracellular calcium signaling and neuronal excitability. Moreover, CBD inhibits voltage-gated sodium and calcium channels, stabilizing neuronal membranes and preventing hyperexcitability.

Research also shows that CBD influences intracellular calcium homeostasis and has anti-inflammatory and neuroprotective effects through modulation of adenosine uptake and cytokine production. This multifaceted action results in reduced seizure activity and improved neuronal stability. Clinical evidence from controlled trials in Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex confirms the efficacy of Epidiolex in reducing seizure frequency, corroborating these mechanisms.

Pharmacological Actions

Anticonvulsant activity demonstrated in treatment-resistant epilepsies including Lennox-Gastaut and Dravet syndromes.
Modulation of cannabinoid receptors as a negative allosteric modulator of CB1 receptor.
Enhancement of endocannabinoid signaling through inhibition of anandamide reuptake and degradation.
Activation and modulation of transient receptor potential vanilloid (TRPV) channels influencing neuronal calcium influx.
Inhibition of voltage-gated sodium and calcium channels contributing to neuronal membrane stabilization.
Anti-inflammatory properties reducing neuroinflammation associated with epilepsy.
Neuroprotective effects mediated by modulation of cytokine production and adenosine uptake.
Reduction in seizure frequency and severity in clinical populations.
Minimal psychoactive effects compared to THC, improving patient tolerability.
Potential anxiolytic and mood-stabilizing effects through central nervous system mechanisms.
Interaction with G protein-coupled receptor 55 (GPR55), influencing excitatory neurotransmission.
Oral administration with consistent pharmacokinetics when taken with or without food.
Low potential for abuse or dependence, lacking euphoric effects.
Metabolized mainly via cytochrome P450 enzymes affecting its pharmacological profile.
Contributes to overall seizure management as adjunctive therapy.

Therapeutic Or Clinical Uses

Adjunctive treatment for seizures associated with Lennox-Gastaut syndrome in patients aged 1 year and older.
Adjunctive therapy for seizures associated with Dravet syndrome in children and adults aged 1 year and older.
Treatment for seizures related to tuberous sclerosis complex in pediatric and adult patients aged 1 year and above.
Considered for treatment-resistant epilepsy where conventional therapies have inadequate control.
Reduction of seizure frequency and severity in specific genetic and developmental epileptic encephalopathies.
Use in patients who require cannabidiol-based therapy due to intolerability or contraindications to other anticonvulsants.
Non-psychoactive alternative for epilepsy linked to cannabis-derived compounds.
Treatment option reducing seizure burden and potentially improving quality of life in affected patients.
Potential investigational use in other neurologic or neuroinflammatory disorders, pending research.
Supportive therapy in multisystem genetic disorders like tuberous sclerosis complex with seizure involvement.
Adjunctive agent enabling dose reduction of other antiepileptic drugs due to synergistic effects.
Administered in children as young as one year, extending therapy to early pediatric populations.
May be part of comprehensive epilepsy management including behavioral and developmental support.

Side Or Adverse Effects

Somnolence or increased sleepiness, which may diminish over time.
Decreased appetite leading to potential weight loss in some patients.
Gastrointestinal disturbances including diarrhea and vomiting.
Elevated liver transaminases indicating potential hepatotoxicity, requiring monitoring.
Fatigue and generalized weakness reported during treatment.
Rash or hypersensitivity skin reactions.
Sleep difficulties such as insomnia.
Fever and increased susceptibility to infections.
Rare but serious liver injury potentially requiring drug discontinuation.
Potential for suicidal ideation or behavior, necessitating close psychiatric monitoring.
Risk of allergic reactions, including anaphylaxis and angioedema.
Drowsiness increased by concomitant use of CNS depressants or alcohol.
Withdrawal symptoms or increased seizure frequency if treatment is stopped abruptly.
Possible drug-induced elevations in bilirubin or other liver function abnormalities.
Changes in mood or behavior, including irritability, agitation, or aggression.

Precautions

Conduct baseline and periodic liver function tests due to risk of hepatic enzyme elevations.
Avoid abrupt discontinuation to prevent seizure exacerbation or status epilepticus.
Use caution if patient has a history of depression, mood disorders, or suicidal ideation.
Monitor closely when used concomitantly with other CNS depressants to avoid excessive sedation.
Adjust dosing and monitor patients with hepatic impairment carefully.
Alert patients about potential drowsiness; advise against driving or hazardous activities until response is known.
Be vigilant for signs of allergic reactions and instruct patients to seek immediate care if they occur.
Ensure precise dosing with oral syringes to avoid under- or overdosing.
Advise patients to maintain consistent food intake patterns to reduce fluctuations in drug levels.
Screen for concomitant medications that may affect or be affected by cannabidiol metabolism.
Pregnancy considerations: counsel patients about potential risks to fetus and enrollment in pregnancy registries.
Use with caution in patients with history of substance abuse or dependence.
Educate caregivers to monitor for behavioral changes or mood alterations.
Keep medication out of reach of children to prevent accidental overdose.
Advise against consuming alcohol during treatment to reduce compounded sedative effects.

Warnings

Potential for serious liver injury; monitor liver enzymes especially during the first two months of treatment.
Increased risk of suicidal thoughts and behaviors; monitor mental health and mood symptoms frequently.
Do not discontinue therapy suddenly due to risk of increased seizure frequency or status epilepticus.
May cause somnolence and impair ability to perform hazardous tasks such as driving.
Possible severe allergic reactions including anaphylaxis requiring immediate medical attention.
Concomitant use with clobazam or valproate may increase CNS depressant effects.
Use cautiously in pregnant or breastfeeding women; potential fetal risk detected in animal studies.
Contains sesame seed oil; avoid if patient has allergy to sesame.
Avoid use in patients with severe hepatic impairment until safety is established.
Use within 12 weeks after bottle opening; discard any unused solution to prevent reduced potency.
Drug may cause positive cannabis drug screening results; inform testing personnel accordingly.
Risk of drug interactions that may increase or decrease cannabidiol plasma concentration.
Risk of respiratory depression if combined with other sedatives or opioids.
Monitor for signs of hypersensitivity or rash that may indicate serious dermatologic reactions.
Patients should notify healthcare providers of all concomitant medications to avoid adverse interactions.

Contraindication

Known hypersensitivity to cannabidiol, Epidiolex, sesame seed oil, or any inactive ingredients in the formulation.
History of severe allergic reaction to any cannabinoid-containing product.
Use in patients younger than 1 year of age, due to lack of safety and efficacy data.
Severe hepatic impairment where metabolism and clearance of cannabidiol are compromised.
Concurrent use with other products that may cause additive hepatotoxicity without monitoring.
Patients with active suicidal ideation or untreated psychiatric disorders unless closely monitored.
Known hypersensitivity to any component of the oral solution including flavoring or preservatives.

Drug Interactions

Cannabidiol is metabolized primarily via CYP3A4 and CYP2C19; inhibitors of these enzymes can increase CBD plasma levels.
Concomitant use with clobazam increases sedation due to CYP-mediated increased concentrations of clobazam's active metabolite.
Valproate co-administration can increase risk of elevated liver enzymes and hepatotoxicity.
Inducers of CYP450 enzymes such as rifampin, carbamazepine, and phenytoin can reduce cannabidiol levels, potentially decreasing efficacy.
Inhibitors such as ketoconazole or itraconazole can raise cannabidiol exposure, increasing risk of adverse effects.
Use with CNS depressants including opioids, benzodiazepines, muscle relaxants, and alcohol can potentiate drowsiness and respiratory depression.
Potential for cannabidiol to affect metabolism of other drugs metabolized by CYP450 enzymes, requiring careful monitoring.
Cannabis-based products may have additive or synergistic effects, necessitating careful dose management.
Drugs affecting UDP-glucuronosyltransferase (UGT) enzymes could alter cannabidiol metabolism.
Patients taking blood thinners (e.g., warfarin) may require closer monitoring as cannabidiol might alter anticoagulation effects.
Potential interactions with antiepileptic drugs may require dose adjustments to minimize toxicity or loss of seizure control.
Herbal products like St. John's Wort may reduce cannabidiol plasma levels via enzyme induction.
Co-administration with sirolimus or everolimus requires monitoring due to similar metabolic pathways.
CBD may affect serum levels of certain chemotherapeutic agents, requiring avoidance or close monitoring.
Consult healthcare providers before starting or stopping any new medications to prevent harmful interactions.

Preparations Of The Drug

Epidiolex oral solution contains cannabidiol at a concentration of 100 mg/mL.
Inactive ingredients include dehydrated alcohol, sesame seed oil, sucralose, and strawberry flavoring.
Available in 60 mL and 100 mL amber glass bottles equipped with child-resistant caps.
The formulation is gluten-free and does not contain wheat, barley, or rye.
Supplied with two oral dispensing syringes: 1 mL syringe for doses ≤1 mL and 5 mL syringe for larger doses.
Packaged with a bottle adapter to facilitate accurate dosing.
Strawberry flavoring minimizes medicinal taste and improves palatability.
Contains sesame seed oil as carrier oil; important allergen to note.
Stored at controlled room temperature of 20°C to 25°C (68°F to 77°F).
Should be stored upright to prevent leakage and maintain dosing accuracy.
Must be used within 12 weeks after first opening to maintain potency and sterility.
Not to be frozen; avoid exposure to extreme heat or direct sunlight.
The oral solution is a clear to slightly yellow oily liquid consistent with its composition.
Manufactured by Jazz Pharmaceuticals, ensuring quality control and FDA-approved standards.
Designed for oral administration and can be administered via non-PVC feeding tubes when needed.