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

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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.

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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

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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)

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Lafaye G, et al. Dialogues Clin Neurosci. 2017

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)

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Gaston TE , et al. Epilepsy Behav. 2017

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

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Cannabinoids Comparison Chart

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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. 2018

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

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Chemotherapy Induced Nausea/Vomiting (CINV)

 Purpose was to evaluate the effectiveness and tolerability of cannabis-based medications for CINV

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Smith LA, et al. Cochrane Database Syst Rev. 2015

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

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Smith LA, et al. Cochrane Database Syst Rev. 2015

Cannabinoids vs. Placebo

Eight trials; N = 552

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# 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

Cannabinoids vs. Prochlorperazine

Nine trials; N = 881

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# 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

Dronabinol (Marinol)

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

Nabilone (Cesamet)

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

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?

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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

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Office of the Commissioner. 2018

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

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Lennox-Gastaut syndrome. NLM Gatew. 2019 Dravet Syndrome Information Page. 2018

Cannabinoids for Seizures in Lennox- Gastaut & Dravet Syndrome

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 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

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

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Devinsky O, et al. New Engl J Med. 2018

Baseline Characteristics

 Similar between all groups  Average age ~15.5 years  Median attempted antiepileptic drugs: 6  Most common antiepileptic drug used: clobazam

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Median # seizure at baseline (in 28 days) Placebo (N=76) 10 mg CBD arm (N=73) 20 mg CBD arm (N=76) Drop seizures 80.3 86.9 85.5 Non-drop seizures 78 95.7 93.7 Total seizures (all types) 180.6 165 174.3

Devinsky O, et al. New Engl J Med. 2018

Results

20 mg CBD group 10 mg CBD group Placebo Median % reduction from baseline in drop seizure frequency 41.9% 37.2% 17.2% Median % reduction difference from placebo (95% CI, P-value) 21.6% (6.7 to 34.8; p=0.005) 19.2% (7.7 to 31.2; p=0.002)

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Devinsky O, et al. New Engl J Med. 2018

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

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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

Cannabidiol (Epidiolex)

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

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

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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

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Wade DT, et al. Mult Scler. 2010

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

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Wade DT, et al. Mult Scler. 2010

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

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Wade DT, et al. Mult Scler. 2010

Results

Analysis at study endpoint Analysis at week 6 Nabiximols Placebo Nabiximols Placebo N=356 N=296 N=356 N=296 Adjusted mean change from baseline

• 1.30
• 0.97
• 1.27
• 0.95

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

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 Pooled analysis of individual spasticity assessment

Wade DT, et al. Mult Scler. 2010

Results

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%)

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 Responder analysis (>30% reduction from baseline in spasticity assessment)  Global Impression of Change (GIC)

Wade DT, et al. Mult Scler. 2010

Safety

 79.3% patients with nabiximols experienced >1 event vs. 55.% placebo

 Mild-moderate severity

 Most common A/E: dizziness (32% vs 11%)

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Adverse Event Nabiximols Placebo Nervous system 54.5 26.4 GI 29.6 19.4 Administration site reactions 29.2 19.1 Psychiatric 18.5 5.6 Ear/Labyrinth 7.4% 2.3%

Wade DT, et al. Mult Scler. 2010

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

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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

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Meng H, et al. Anesth Analg. 2017

Study Methods

Inclusion  >18 years of age  Neuropathic pain for > 3 months  Pain intensity: moderate or severe

 NRS: > 4  VAS > 40/100

Allowed for patients to be on other analgesics

 Pain level/doses needed to be stable before study enrollment

Exclusion  Severe concomitant illness  Seizures  History of substance abuse

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Meng H, et al. Anesth Analg. 2017

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))

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Meng H, et al. Anesth Analg. 2017

Results

Primary Outcome: pain scores

 6 studies showed superiority of cannabinoids > placebo  Significant reduction, but clinically small, reduction of pain scores

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Meng H, et al. Anesth Analg. 2017

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

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Dronabinol (Marinol)

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

Cachexia

 Limited evidence in HIV/AIDS  1 RCT, double- blind, placebo-controlled (N = 139)  Trend towards improved body weight

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Beal JE, et al. J Pain Symptom Manage. 1995.

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

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Badowski, M, et al. HIV/AIDS – Research and Palliative Care. 2016.

Adverse Events

 Somnolence  Decreased appetite  Diarrhea  Dizziness  Dysphoria  Sedation  Increased LFTs  Hyperemesis  Hypercoagulability

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Potential Harms

 Cannabis Hyperemesis Syndrome  Cannabinoid-Associated Coagulopathy  Drug-Drug Interactions

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Enzyme THC CBD CYP1A2 Induces

• CYP2C9

Inhibits Inhibits CYP2C19

• Inhibits

CYP2D6

• Inhibits

CYP3A4 Inhibits Inhibits Glucuronidation

• Inhibits UGT 1A9 & 2B7

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

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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

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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

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Questions?

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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.

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