Budding Therapies: Medical Cannabis and its Uses

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1 Budding Therapies: Medical Cannabis and its Uses MARIAH CADAVOS, PHARMD & VIVIAN NGUYEN, PHARMD PGY1 PHARMACY PRACTICE RESIDENTS FEBRUARY 10,

2 Disclosures & Disclaimer Both presenters have nothing to disclose This CE will cover the FDA-approved indication and utilization of a medication. Since patients may utilize cannabis regardless of legal standing and medical support, it is important for health care professionals to be aware of appropriate uses and interactions with pharmacotherapy. 2

3 Objectives Identify potential indications for medical cannabis Describe current literature on the clinical uses of cannabis Given a patient case, demonstrate whether cannabis is clinically appropriate 3

4 Cannabis vs. Cannabinoids Cannabis = plant Cannabinoids = substances in bud/flower of the plant that causes effect Extracted or synthetic Cannabidiol (Epidiolex) Dronabinol (Marinol, Syndros) Nabilone (Cesamet) Lafaye G, et al. Dialogues Clin Neurosci

5 THC vs. CBD DELTA-9-TETRAHYDROCANNABINOL (THC) Partial agonist of endocannabinoid receptors CB1 and CB2 CB1: G-protein coupled receptors modulate neurotransmitter release CB2: immunosuppressive response CANNABIDIOL (CBD) Low affinity for endocannabinoid receptors Blocks human T-type voltage gated calcium channels (VGCC) Gaston TE, et al. Epilepsy Behav

6 Pre-Assessment Questions 1. Which of following is not subject to control as a schedule II (C-II) drug? A. Dronabinol (capsules) (Marinol) B. Cannabidiol (Epidiolex) C. Nabilone (Cesamet) 2. Which of the following is a labeled FDA indication for a cannabinoid product? A. Anxiety B. Chronic neuropathic pain C. Chemotherapy-induced nausea/vomiting 6

7 Cannabinoids Comparison Chart Generic (Brand) Schedule FDA-Approved Indication Nabilone (Cesamet) CII THC analogue CINV Cannabidiol (Epidiolex) CV Extracted CBD Seizures (Lennox-Gastaut, Dravet syndrome in > 2 yo) Dronabinol (Marinol/Syndros) Syndros = CII Marinol = CIII Synthetic THC CINV AIDS-related anorexia AIDS = acquired immune deficiency syndrome CINV = chemotherapy induced nausea/vomiting FDA and Marijuana

8 Proposed Uses of Cannabis Chemotherapy induced nausea/vomiting (CINV) Seizures in Lennox-Gastaut & Dravet syndrome Spasticity of multiple sclerosis or spinal cord injury Chronic neuropathic pain Cachexia/anorexia associated with AIDS 8

9 Chemotherapy Induced Nausea/Vomiting (CINV) Purpose was to evaluate the effectiveness and tolerability of cannabis-based medications for CINV Smith LA, et al. Cochrane Database Syst Rev

10 Methods Nabilone and Dronabinol used monotherapy or adjunct to conventional dopamine antagonists Patients 18 years and older with any type of cancer receiving chemotherapeutic treatment Primary outcome: complete control of N/V in acute phase (within 24 hours of chemotherapy treatment) and in the delayed phase (after 24 hours of chemotherapy treatment) Nabilone 2 mg BID Dronabinol 10 mg/m 2 BID to 15 mg/m 2 BID Smith LA, et al. Cochrane Database Syst Rev

11 Cannabinoids vs. Placebo Eight trials; N = 552 # of RCTs N Results RR (95% CI) 2 96 No difference 2 (0.19 to 21) Cannabinoid>Placebo 5.7 (2.6 to 13) Cannabinoid>Placebo 2.9 (1.8 to 4.7) Smith LA, et al. Cochrane Database Syst Rev

12 Cannabinoids vs. Prochlorperazine Nine trials; N = 881 # of RCTs N Results RR (95% CI) No difference 1.5 (0.67 to 3.2) No difference 1.1 (0.86 to 1.4) No difference 2 (0.74 to 5.4) Smith LA, et al. Cochrane Database Syst Rev

13 Dronabinol (Marinol) Marinol [package insert]. North Chicago, IL: AbbVie Inc.;

14 Nabilone (Cesamet) Cesamet [package insert]. Costa Mesa, CA: Valeant Pharmaceuticals International;

15 Patient Case AB is a 34 year old female with breast cancer undergoing chemotherapy. She has been experiencing acute phase nausea and vomiting with her chemotherapy regimen. She has not tried any antiemetic medications. Would you consider cannabinoids for this patient? Same case, but patient has tried other antiemetics and nothing seems to work. Would you consider cannabinoids for this patient? 15

16 Proposed Uses of Cannabis Chemotherapy induced nausea/vomiting (CINV) Seizures in Lennox-Gastaut & Dravet syndrome Spasticity of multiple sclerosis or spinal cord injury Chronic neuropathic pain Cachexia/anorexia associated with AIDS 16

17 Office of the Commissioner

18 Lennox-Gastaut & Dravet Syndrome: Background LENNOX-GASTAUT Rare epileptic syndrome that manifests as several seizure types with severe cognitive impairment Spike-and-wave pattern of the brain depicted on an electroencephalogram (EEG) Impaired mental abilities DRAVET SYNDROME Previously known as severe myoclonic epilepsy of infancy (SMEI) Epilepsy syndrome begins in infancy or early childhood Focal or generalized convulsive seizures Lennox-Gastaut syndrome. NLM Gatew Dravet Syndrome Information Page

19 Cannabinoids for Seizures in Lennox- Gastaut & Dravet Syndrome Phase 3, multicenter, randomized, double-blind, placebo-controlled trial Purpose was to demonstrate the efficacy and safety of cannabidiol in conjunction with a regimen of conventional antiepileptic medications to treat drop seizures Devinsky O, et al. New Engl J Med

20 Study Methods Primary outcome: percent change from baseline in frequency of drop seizures (average per 28 days) during treatment period 20 mg CBD group (N = 76) 10 mg CBD group (N = 73) Placebo group (N = 76) Inclusion Between 2-55 years of age Electroencephalogram with spike and wave complexes At least 2 types of generalized seizures for at least 6 months Taking 1-4 antiepileptic drugs At least 2 drop seizures/week at baseline Devinsky O, et al. New Engl J Med

21 Baseline Characteristics Similar between all groups Average age ~15.5 years Median attempted antiepileptic drugs: 6 Most common antiepileptic drug used: clobazam Median # seizure at baseline (in 28 days) Placebo (N=76) 10 mg CBD arm (N=73) 20 mg CBD arm (N=76) Drop seizures Non-drop seizures Total seizures (all types) Devinsky O, et al. New Engl J Med

22 Results Median % reduction from baseline in drop seizure frequency Median % reduction difference from placebo (95% CI, P-value) 20 mg CBD group 10 mg CBD group Placebo 41.9% 37.2% 17.2% 21.6% (6.7 to 34.8; p=0.005) 19.2% (7.7 to 31.2; p=0.002) Devinsky O, et al. New Engl J Med

23 Safety Occurrence of adverse events experienced in: 77 of 82 patients (94%) in 20 mg CBD arm 56 of 67 (84%) in 10 mg CBD arm 55 of 76 (72%) in placebo arm Adverse event 20 mg CBD arm (%) 10 mg CBD arm (%) Placebo (%) Somnolence 25 (30) 14 (21) 4 (5) Decreased appetite 21 (26) 11 (16) 6 (8) Diarrhea 12 (15) 7 (10) 6 (8) Devinsky O, et al. New Engl J Med

24 Cannabidiol (Epidiolex) Epidiolex [package insert]. Carlsbad, CA: GW Pharmaceuticals, plc.;

25 Proposed Uses of Cannabis Chemotherapy induced nausea/vomiting (CINV) Seizures in Lennox-Gastaut & Dravet syndrome Spasticity of multiple sclerosis or spinal cord injury Chronic neuropathic pain Cachexia/anorexia associated with AIDS 25

26 Spasticity of Multiple Sclerosis Meta-analysis 3 trials Randomized, double blind, placebo-controlled, parallel-group Purpose: Efficacy of Sativex (nabiximols) in the alleviation of spasticity in people with MS Wade DT, et al. Mult Scler

27 Nabiximols (Sativex) NOT currently approved for use in the US 1:1 THC/CBD oromucosal spray Approved in adult patients with moderate to severe spasticity due to multiple sclerosis who have no responded adequately to other anti-spasticity medications and who demonstrate clinically significant improvement in spasticity related symptoms during an initial trial of therapy Wade DT, et al. Mult Scler

28 Study Methods Primary Outcome: Improved patient perception of spasticity, 30% improvement in spasticity ( responder ) mm Visual Analogue Scale (VAS) or 0-10 Numerical Rating Scale (NRS), Global impression of change (GIC) Intervention: Nabiximols vs. Placebo N = 363 vs. 303 Treatment period: 6 weeks Wade DT, et al. Mult Scler

29 Results Pooled analysis of individual spasticity assessment Adjusted mean change from baseline Analysis at study endpoint Analysis at week 6 Nabiximols Placebo Nabiximols Placebo N=356 N=296 N=356 N= Treatment difference Standard error of difference % CI for difference -0.61, , P-value Wade DT, et al. Mult Scler

30 Results Responder analysis (>30% reduction from baseline in spasticity assessment) Global Impression of Change (GIC) Analysis at study endpoint Analysis at week 6 Nabiximols Placebo Nabiximols Placebo 130/356 (37%) 77/296 (26%) 123/356 (35%) 73/296 (25% 169/329 (51%) 105/276 (38%) Wade DT, et al. Mult Scler

31 Safety 79.3% patients with nabiximols experienced >1 event vs. 55.% placebo Mild-moderate severity Most common A/E: dizziness (32% vs 11%) Adverse Event Nabiximols Placebo Nervous system GI Administration site reactions Psychiatric Ear/Labyrinth 7.4% 2.3% Wade DT, et al. Mult Scler

32 Proposed Uses of Cannabis Chemotherapy induced nausea/vomiting (CINV) Seizures in Lennox-Gastaut & Dravet syndrome Spasticity of multiple sclerosis or spinal cord injury Chronic neuropathic pain Cachexia/anorexia associated with AIDS 32

Chronic Neuropathic Pain Systematic review and meta-analysis (SR-MA) 11 RCTs Purpose: Determine analgesic efficacy and safety of selective cannabinoids compared to conventional management or placebo

33 Chronic Neuropathic Pain Systematic review and meta-analysis (SR-MA) 11 RCTs Purpose: Determine analgesic efficacy and safety of selective cannabinoids compared to conventional management or placebo for chronic NP Cannabinoids included: dronabinol, nabilone, nabiximols Conventional management: pharmacotherapy, physical therapy, combination Follow up period: > 2 weeks Primary outcome: Intensity of pain after > 2 weeks after initiation of selective cannabinoid Meng H, et al. Anesth Analg

34 Study Methods >18 years of age Inclusion Neuropathic pain for > 3 months Pain intensity: moderate or severe NRS: > 4 VAS > 40/100 Exclusion Severe concomitant illness Seizures History of substance abuse Allowed for patients to be on other analgesics Pain level/doses needed to be stable before study enrollment Meng H, et al. Anesth Analg

35 Results N = 1219 (614 vs. 605) Mean N patients: RCTs total 5 trials central neuropathic pain (multiple sclerosis (4), avulsion injuries to brachial plexus (1)) 4 trials peripheral neuropathic pain (diabetes (2)) 2 trials both central and peripheral neuropathic pain (chemotherapy (1)) Meng H, et al. Anesth Analg

36 Results Primary Outcome: pain scores 6 studies showed superiority of cannabinoids > placebo Significant reduction, but clinically small, reduction of pain scores Meng H, et al. Anesth Analg

37 Proposed Uses of Cannabis Chemotherapy induced nausea/vomiting (CINV) Seizures in Lennox-Gastaut & Dravet syndrome Spasticity of multiple sclerosis or spinal cord injury Chronic neuropathic pain Cachexia/anorexia associated with AIDS 37

38 Dronabinol (Marinol) Marinol [package insert]. North Chicago, IL: AbbVie Inc.;

39 Cachexia Limited evidence in HIV/AIDS 1 RCT, double- blind, placebo-controlled (N = 139) Trend towards improved body weight Beal JE, et al. J Pain Symptom Manage

40 Cachexia Review of 10 studies since 1995 Change in total body weight (TBW) only ranged from -2.0 to 3.2 kg Further studies needed Standard definitions of HIV-associated weight loss Robust sample sizes Associated virologic/immunologic outcomes Badowski, M, et al. HIV/AIDS Research and Palliative Care

41 Adverse Events Somnolence Decreased appetite Diarrhea Dizziness Dysphoria Sedation Increased LFTs Hyperemesis Hypercoagulability 41

42 Potential Harms Cannabis Hyperemesis Syndrome Cannabinoid-Associated Coagulopathy Drug-Drug Interactions Enzyme THC CBD CYP1A2 Induces --- CYP2C9 Inhibits Inhibits CYP2C Inhibits CYP2D6 --- Inhibits CYP3A4 Inhibits Inhibits Glucuronidation --- Inhibits UGT 1A9 & 2B7 42

43 Patient Case MJ is a 34 year old female PMH: anxiety, depression, HTN, type 2 diabetes, GERD and back pain Home meds: fluoxetine, omeprazole, losartan, hydrochlorothiazide, metformin, glipizide, lidocaine patches, oxycodone and acetaminophen as needed She reports increasing pain that is not relieved by her current therapy. She has a friend who suggested cannabis to help. MJ comes to your clinic because she wants to know if cannabis will affect her current therapy. Which pain medications would interact with cannabis use? A. Lidocaine patches B. Oxycodone C. Acetaminophen D. All of above 43

44 Take Home Points Read articles and evaluate them Small populations Type of cannabinoid Varying study periods And more Start low, go slow Informed consent and patient education 44

45 Post-Assessment Questions 1. Which of following is not subject to control as a schedule II (C-II) drug? A. Dronabinol (capsules) (Marinol) B. Cannabidiol (Epidiolex) C. Nabilone (Cesamet) 2. Which of the following is a labeled FDA indication for a cannabinoid product? A. Anxiety B. Chronic neuropathic pain C. Chemotherapy-induced nausea/vomiting 45

46 Questions? 46

47 References 1. Lafaye, G., Karila, L., Blecha, L., et al. Cannabis, cannabinoids, and health. Dialogues Clin Neurosci (3), Gaston TE and Friedman D. Pharmacology of cannabinoids in the treatment of epilepsy. Epilepsy Behav. 2017;70(Pt B): doi: /j.yebeh Smith LA, Azariah F, Lavender VTC, et al. Cannabinoids for nausea and vomiting in adults with cancer receiving chemotherapy. Cochrane Database Syst Rev. 2015, Issue 11. Art. No.: CD doi: / CD pub2. 4. Marinol [package insert]. North Chicago, IL: AbbVie Inc.; Cesamet [package insert]. Costa Mesa, CA: Valeant Pharmaceuticals International; Lennox-Gastaut syndrome. Genetics Home Reference. NLM Gatew. (2019). Retrieved from 7. Dravet Syndrome Information Page. (2018). Retrieved from 8. Office of the Commissioner. (2018). Press Announcements FDA approves first drug comprised of an active ingredient derived from marijuana to treat rare, severe forms of epilepsy. Retrieved from 9. Devinsky O, Patel AD, Cross H, et al. Effect of cannabidiol on drop seizures in the Lennox-Gastaut Syndome. New Engl J Med. 2018; 378: doi: /NEJMoa Epidiolex [package insert]. Carlsbad, CA: GW Pharmaceuticals, plc.; Wade DT, Collin C, Stott C, et al. Meta-analysis of the efficacy and safety of Sativex (nabiximols), on spasticity in people with multiple sclerosis. Mult Scler. 2010; 16(6): Meng H, Johnston B, Englesakis M, et al. Selective cannabinoids for chronic neuropathic pain: a systematic review and meta-analysis. Anesth Analg. 2017; 125(5): Beal JE, Olson R, Laubenstein L, et al. Dronabinol as a treatment for anorexia associated with weight loss in patients with AIDS. J Pain Symptom manage. 1995;10(2): Badowski M, Perez S. Clinical utility of dronabinol in the treatment of weight loss associated with HIV and AIDS. HIV/AIDS Research and Palliative Care. 2016:; 8:

James McCormack BSc (Pharm), PharmD Professor Faculty of Pharmaceutical Sciences University of British Columbia Vancouver, BC, Canada

James McCormack BSc (Pharm), PharmD Professor Faculty of Pharmaceutical Sciences University of British Columbia Vancouver, BC, Canada My Agenda Discuss the best available evidence Put the evidence into