Drug information of Cannabidiol

Cannabidiol

Drug group: Anticonvulsants

Cannabidiol is used to treat seizures in people with Lennox-Gastaut syndrome or Dravet syndrome. Cannabidiol is for use in adults and children who are at least 2 years old.

Mechanism of effect

Purified cannabidiol (CBD); the exact mechanism by which CBD produces its anticonvulsant effects is unknown.

Cannabidiol is a structurally novel anticonvulsant; it does not appear to exert its anticonvulsant effects through CB1 receptors, nor through voltage-gated sodium channels.

CBD may exert a cumulative anticonvulsant effect, modulating a number of endogenous systems including, but not limited to, neuronal inhibition (synaptic and extrasynaptic GABA channels), modulation of intracellular calcium (TRPV, VDAC, GPR55), and possible anti-inflammatory effects (adenosine).

Pharmacodynamic

Although the exact mechanism and magnitude of effects of THC and CBD are not fully understood, CBD has been shown to have analgesic, anticonvulsant, muscle relaxant, anxiolytic, neuroprotective, anti-oxidant, and anti-psychotic activity. This wide variety of effects is likely due to it's complex pharmacological mechanisms. In addition to binding to CB1 and CB2 receptors of the endocannabinoid system, there is evidence that CBD activates 5-HT1A serotonergic and TRPV1–2 vanilloid receptors, antagonizes alpha-1 adrenergic and µ-opioid receptors, inhibits synaptosomal uptake of noradrenaline, dopamine, serotonin and gaminobutyric acid and cellular uptake of anandamide, acts on mitochondria Ca2 stores, blocks low-voltage-activated (T-type) Ca2 channels, stimulates activity of the inhibitory glycine-receptor, and inhibits activity of fatty amide hydrolase (FAAH) .

Pharmacokinetics

Peak plasma time, steady-state: 2.5-5 hr

Food: High-fat/high-calorie meal increased peak plasma concentration by 5-fold, AUC by 4-fold, and reduced the total variability compared with healthy volunteers

Protein bound, including metabolites: >94%

Vd: 20,963-42,849 L

Metabolism:Metabolized in the liver and the gut (primarily in the liver) by CYP2C19 and CYP3A4 enzymes, and UGT1A7, UGT1A9, and UGT2B7 isoforms.

After repeat dosing, 7-OH-CBD (active metabolite), has a 38% lower AUC than the parent drug.

The 7-OH-CBD metabolite is converted to 7-COO-CBD, which has ~40-fold higher AUC than the parent drug.

Based on preclinical models of seizure, the 7-OH-CBD metabolite is active; however, the 7-COOH-CBD metabolite is not active.

Half-life: 56-61 hr

Clearance: 1111 L/hr (single 1500-mg dose)

Excretion: Mainly feces; minor renal clearance

Drug indications

Indicated for seizures associated with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), or tuberous sclerosis complex (TSC) in patients aged ≥1 yr

Dosage

-LGS or DS

  • 2.5 mg/kg PO BID initially; after 1 week, may increase to maintenance dose of 5 mg/kg BID  
  • If 5 mg/kg BID tolerated and further seizure reduction required, patient may benefit from a dosage increase up to a maximum recommended maintenance dosage of 10 mg/kg BID (ie, 20 mg/kg/day)
  • Increasing to 10 mg/kg BID may be achieved by increased weekly increments of 2.5 mg/kg BID, as tolerated
  • If a more rapid titration from 10 mg/kg/day to 20 mg/kg/day is warranted, the dosage may be increased no more frequently than every other day
  • Administration of the 20-mg/kg/day dosage resulted in somewhat greater reductions in seizure rates than the recommended maintenance dosage of 10 mg/kg/day, but with an increase in adverse reactions

-TSC

  • Starting dose: 2.5 mg/kg PO BID
  • Increase dose in weekly increments of 2.5 mg/kg BID as tolerated, to recommended maintenance dose of 12.5 mg/kg BID
  • If a more rapid titration is warranted, the dosage may be increased no more frequently than every other day
  • Effectiveness of doses <12.5 mg/kg BID has not been studied in patients with TSC

-Dosage Modifications in Hepatic impairment

·         Moderate (LGS or DS)
  • Starting dose: 1.25 mg/kg BID
  • Maintenance dose range: 2.5-5 mg/kg BID
·         Severe (LGS or DS)
  • Starting dose: 0.5 mg/kg BID
  • Maintenance dose range: 1 mg/kg BID
·         Moderate (TSC)
  • Starting dose: 1.25 mg/kg BID
  • Maintenance dose: 6.25 mg/kg BID
·         Severe (TSC)
  • Starting dose: 0.5 mg/kg BID
  • Maintenance dose: 2.5 mg/kg BID

 

 

 

Drug contraindications

Hypersensitivity to this drug

Hypersensitivity to cannabidiol or any of the product ingredients

Side effects

anemia , sleep disorder , Infection , Diarrhea , weight decrease , abdominal pain , fungal infection , pneumonia , weakness , difficulty urinating , skin rush , tiredness , Abdominal discomfort , Insomnia

Drowsiness , lethargy , sedation , fatigue , malaise , insomnia ,sleep disorder ,sleep disturbance ,Skin rash ,Weight loss ,Decreased appetite , diarrhea ,Anemia ,Increased serum alanine aminotransferase , increased serum transaminases ,Infection , viral infection ,Asthenia ,Agitation , irritability ,aggressive behavior , outbursts of anger , drooling , abnormal gait ,Gastroenteritis ,sialorrhea , abdominal distress , abdominal pain ,Fungal infection ,Pneumonia , hypoxia ,respiratory failure ,Decreased hematocrit, decreased hemoglobin,Increased serum aspartate aminotransferase, increased serum transaminases (>20x ULN),Hypersensitivity reaction,Increased serum creatinine,Angioedema, erythema, pruritus

Interactions

Medroxyprogesterone , Butalbital and Acetaminophen , Tasimelteon , Secobarbital , Tolcapone , Temazepam , Treprostinil , atovaquone/proguanil , Quazepam , Lopinavir and Ritonavir , Cariprazine , Opium , Ethchlorvynol , Gefitinib , Amiodarone , Aprepitant , Erythromycin , Esomeprazole , Estrogen cojugated , Olanzapine , Dronabinol , Esketamine , tucatinib , Netupitant , ropivacaine , nafcillin , mestranol , butalbital , st. john's wort , Eslicarbazepine acetate , nateglinide , Crizotinib , SULFISOXAZOLE , Ceritinib , riociguat , conivaptan , quinupristin and dalfopristin , Iloperidone , Dexlansoprazole , Ramelteon , Apalutamide , Metaxalone , Flibanserin , Nicardipine , cobicistat , Sofosbuvir and velpatasvir , Fostamatinib , Letermovir , Butabarbital , Efavirenz , Celecoxib , Tipranavir , lumacaftor and Ivacaftor , Etravirine , Dabrafenib , Fosphenytoin , Idelalisib , Torsemide , Abiraterone , ospemifene , Pirfenidone , Indinavir , Rosiglitazone , Ribociclib , Carisoprodol , chlorpropamide , Armodafinil , Palonosetron , dasabuvir , ombitasvir , pomalidomide , Tofacitinib , Lopinavir , paritaprevir , Fosamprenavir , Tolbutamide , glyburide , selexipag , Mifepristone , ritonavir , saquinavir , nelfinavir , nevirapine , mitotane , Mirtazapine , Amobarbital , fluvastatin , rasagiline , morphine , Nefazodone , dronedarone , Pioglitazone , Ketamine , Glipizide , Tamoxifen , Grapefruit , Pentobarbital , Cyclobenzaprine , Rifapentine , Atazanavir , Darunavir , Trimethoprim , Pentamidine , Clotrimazole , Clozapine , Clomipramine , Enzalutamide , Bicalutamide , escitalopram , Carbamazepine , Carvedilol , Ketoconazole , Clarithromycin , Chloramphenicol , Clobazam , Montelukast , Miconazole , Haloperidol , Warfarin , Verapamil , Voriconazole , Lorazepam , Losartan , Lidocaine , Methadone , Modafinil , Mexiletine , Phenytoin , Glimepiride , Lamotrigine , Lansoprazole , Lapatinib , Loratadin , Flutamide , Fluvoxamine , Fluoxetine , Fluconazole , Phenobarbital , Fenofibrate , Sertraline , Selegiline , Sulfadiazine , Citalopram , Cyclosporine , Cyclophosphamide , Rabeprazole , Repaglinide , Ropinirole , Rifampin , Riluzole , Zafirlukast , Desipramine , Duloxetine , Doxepin , Diazepam , Diltiazem , Diclofenac , Thiothixene , Ticlopidine , Gemfibrozil , Dapsone , Dacarbazine , Doxycycline , Tetracycline , Tranylcypromine , Tretinoin , Trifluoperazine , Trimipramine , Tizanidine , Propofol , Pantoprazole , Posaconazole , Paclitaxel , Pimozide , Theophyline , Imatinib , Imipramine , Bupropion , Bortezomib , Bosentan , Propranolol , Oxecarbazepin , Itraconazole , Irinotecan , Isotretinoin , Isoniazid , Ifosfamide , ambrisentan , ethotoin
diazepam intranasal-erythromycin base-erythromycin ethylsuccinate-erythromycin lactobionate-erythromycin stearate-estrogens conjugated synthetic-lesinurad-methsuximide-paclitaxel protein bound-progesterone intravaginal gel-progesterone micronized-schisandra-voxilaprevir

Alerts

-Can cause somnolence and sedation that is dose-related; clobazam and other CNS depressants, including alcohol, may potentiate this adverse effect.

-Antiepileptic drugs (AEDs), including cannabidiol, increase risk of suicidal thoughts or behavior in patients taking these drugs for any indication.

-May cause hypersensitivity reactions (eg, pruritus, erythema, angioedema).

-As with other AEDs, cannabidiol should generally be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus.

-A decrease in hemoglobin and hematocrit reported with no effect on red blood indices

-Elevation of serum creatinine reported within 2 weeks of initiating therapy that was reversible in healthy adults; mechanism not determined.

--Existing transaminase elevations >3 x ULN in presence of elevated bilirubin without alternative explanation are important predictors of severe liver injury and should be evaluated before initiating cannabidiol

-Dose-related liver transaminases (ALT and/or AST) elevations reported, typically within the first 2 months of treatment.

-Majority of ALT elevations occurred when coadministered with valproate and, to a lesser extent, with clobazam.

 

Points of recommendation

-monitor for somnolence and sedation and advise patients not to drive or operate machinery until they have gained sufficient experience on drug to gauge whether it adversely affects their ability to safely drive or operate machinery.

-patients should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, or any unusual changes in mood or behavior.

-Therapy can cause weight loss, which may be dose-related.

-Discontinue with transaminase levels >3 x ULN and bilirubin levels >2 x ULN.

-Without bilirubin elevation: Discontinue treatment with sustained transaminase elevations of >5 x ULN

-Because of the risk of hepatocellular injury, obtain serum transaminases (ALT and AST) and total bilirubin levels in all patients before initiating and at 1 month, 3 months, and 6 months, and periodically thereafter or as clinically indicated

 

Pregnancy level

use with caution

There are no adequate data on the developmental risks in pregnant women; developmental toxicity was observed in animals at maternal plasma exposures similar or greater than expected in humans.

Breast feeding warning

-There are no data on the effects of this drug on the breastfed infant or its effects on milk production.
-The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for this drug and any potential adverse effects to the breastfed infant from the drug or from the underlying maternal condition.

Drug forms

Epidiolex

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