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 neurotransmitter release channels (VGCC)  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/m2 BID to 15 mg/m2 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  20 mg CBD group (N = 76) complexes  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 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 54.5 26.4 GI 29.6 19.4 Administration site 29.2 19.1 reactions Psychiatric 18.5 5.6 Ear/Labyrinth 7.4% 2.3%

Wade DT, et al. Mult Scler. 2010 31 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 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. 2017 33 Study Methods Inclusion Exclusion  >18 years of age  Severe concomitant illness  Neuropathic pain for > 3 months  Seizures  Pain intensity: moderate or severe  History of substance abuse  NRS: > 4  VAS > 40/100 Allowed for patients to be on other analgesics  Pain level/doses needed to be stable before study enrollment

Meng H, et al. Anesth Analg. 2017 34 Results  N = 1219 (614 vs. 605)  Mean N patients: 48 11 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. 2017 35 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. 2017 36 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 Dronabinol (Marinol)

Marinol [package insert]. North Chicago, IL: AbbVie Inc.; 2017. 38 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. 1995. 39 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. 2016. 40 Adverse Events  Somnolence  Dysphoria  Decreased appetite  Sedation  Diarrhea  Increased LFTs  Dizziness  Hyperemesis  Hypercoagulability

41 Potential Harms  Cannabis Hyperemesis Syndrome  Cannabinoid-Associated Coagulopathy  Drug-Drug Interactions

Enzyme THC CBD

CYP1A2 Induces --- CYP2C9 Inhibits Inhibits CYP2C19 --- Inhibits CYP2D6 --- Inhibits CYP3A4 Inhibits Inhibits Glucuronidation --- Inhibits UGT 1A9 & 2B7

42 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 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 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 Questions?

46 References

1. Lafaye, G., Karila, L., Blecha, L., et al. Cannabis, cannabinoids, and health. Dialogues Clin Neurosci. 2017. 19(3), 309-316.

2. Gaston TE and Friedman D. Pharmacology of cannabinoids in the treatment of epilepsy. Epilepsy Behav. 2017;70(Pt B):313-318. doi: 10.1016/j.yebeh.2016.11.016.

3. 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.: CD009464. doi: 10.1002/14651858.CD009464.pub2.

4. Marinol [package insert]. North Chicago, IL: AbbVie Inc.; 2017.

5. Cesamet [package insert]. Costa Mesa, CA: Valeant Pharmaceuticals International; 2006.

6. Lennox-Gastaut syndrome. Genetics Home Reference. NLM Gatew. (2019). Retrieved from https://ghr.nlm.nih.gov/condition/lennox-gastaut-syndrome.

7. Dravet Syndrome Information Page. (2018). Retrieved from https://www.ninds.nih.gov/Disorders/All-Disorders/Dravet-Syndrome-Information-Page.

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 https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm611046.htm.

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; 378:1888-1897. doi: 10.1056/NEJMoa1714631.

10. Epidiolex [package insert]. Carlsbad, CA: GW Pharmaceuticals, plc.; 2018.

11. 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):707-14.

12. 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):1638-52.

13. 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):89-97.

14.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:; 8:37-45.

47