Budding Therapies: Medical Cannabis and its Uses MARIAH CADAVOS, - PowerPoint PPT Presentation

Budding Therapies: Medical Cannabis and its Uses MARIAH CADAVOS, PHARMD & VIVIAN NGUYEN, PHARMD PGY1 PHARMACY PRACTICE RESIDENTS FEBRUARY 10, 2019 1

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

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

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 . 2017 4

THC vs. CBD DELTA-9-TETRAHYDROCANNABINOL (THC) CANNABIDIOL (CBD)  Partial agonist of endocannabinoid receptors  Low affinity for endocannabinoid receptors CB1 and CB2  Blocks human T-type voltage gated calcium  CB1: G-protein coupled receptors modulate channels (VGCC) neurotransmitter release  CB2: immunosuppressive response Gaston TE , et al. Epilepsy Behav . 2017 5

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

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 Syndros = CII Synthetic THC CINV • (Marinol/Syndros) Marinol = CIII AIDS-related anorexia AIDS = acquired immune deficiency syndrome CINV = chemotherapy induced nausea/vomiting FDA and Marijuana. 2018 7

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

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 . 2015 9

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 . 2015 10

Cannabinoids vs. Placebo Eight trials; N = 552 # of RCTs N Results RR (95% CI) 2 96 No difference 2 (0.19 to 21) 3 168 Cannabinoid>Placebo 5.7 (2.6 to 13) 3 288 Cannabinoid>Placebo 2.9 (1.8 to 4.7) Smith LA, et al. Cochrane Database Syst Rev . 2015 11

Cannabinoids vs. Prochlorperazine Nine trials; N = 881 # of RCTs N Results RR (95% CI) 5 258 No difference 1.5 (0.67 to 3.2) 4 209 No difference 1.1 (0.86 to 1.4) 4 414 No difference 2 (0.74 to 5.4) Smith LA, et al. Cochrane Database Syst Rev . 2015 12

Dronabinol (Marinol) Marinol [package insert]. North Chicago, IL: AbbVie Inc.; 2017. 13

Nabilone (Cesamet) Cesamet [package insert]. Costa Mesa, CA: Valeant Pharmaceuticals International; 2006. 14

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

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

Office of the Commissioner. 2018 17

Lennox-Gastaut & Dravet Syndrome: Background LENNOX-GASTAUT DRAVET SYNDROME  Rare epileptic syndrome that manifests as  Previously known as severe myoclonic several seizure types with severe cognitive epilepsy of infancy (SMEI) impairment  Epilepsy syndrome begins in infancy or early  Spike-and-wave pattern of the brain childhood depicted on an electroencephalogram (EEG)  Focal or generalized convulsive seizures  Impaired mental abilities Lennox-Gastaut syndrome. NLM Gatew . 2019 18 Dravet Syndrome Information Page. 2018

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. 2018 19

Study Methods Primary outcome: percent change from Inclusion baseline in frequency of drop seizures  Between 2 - 55 years of age (average per 28 days) during treatment period  Electroencephalogram with spike and wave complexes  20 mg CBD group (N = 76)  At least 2 types of generalized seizures for at  10 mg CBD group (N = 73) least 6 months  Taking 1-4 antiepileptic drugs  Placebo group (N = 76)  At least 2 drop seizures/week at baseline Devinsky O, et al. New Engl J Med. 2018 20

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 Placebo (N=76) 10 mg CBD arm (N=73) 20 mg CBD arm (N=76) baseline (in 28 days) Drop seizures 80.3 86.9 85.5 Non-drop seizures 78 95.7 93.7 Total seizures (all 180.6 165 174.3 types) Devinsky O, et al. New Engl J Med. 2018 21

Results 20 mg CBD group 10 mg CBD group Placebo Median % reduction from baseline in drop 41.9% 37.2% 17.2% seizure frequency Median % reduction difference from 21.6% 19.2% placebo (6.7 to 34.8; p=0.005) (7.7 to 31.2; p=0.002) (95% CI, P-value) Devinsky O, et al. New Engl J Med. 2018 22

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. 2018 23

Cannabidiol (Epidiolex) Epidiolex [package insert]. Carlsbad, CA: GW Pharmaceuticals, plc.; 2018. 24

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

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. 2010 26

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. 2010 27

Study Methods  Primary Outcome: Improved patient perception of spasticity, 30% improvement in spasticity (“responder”)  0-100 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. 2010 28

Results  Pooled analysis of individual spasticity assessment Analysis at study endpoint Analysis at week 6 Nabiximols Placebo Nabiximols Placebo N=356 N=296 N=356 N=296 Adjusted mean change from -1.30 -0.97 -1.27 -0.95 baseline Treatment difference -0.32 -0.32 Standard error of difference 0.145 0.140 95% CI for difference -0.61,-0.04 -0.59, -0.04 P-value 0.026 0.026 Wade DT, et al. Mult Scler. 2010 29

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. 2010 30