Reviews/Evaluations Dronabinol Background Claims Data Summary of Clinical Evidence

Reviews/Evaluations

Dronabinol

Background

Dronabinol (Marinol®) is a schedule III controlled substance that contains delta-9-tetrahydrocannabinol (THC), a major active ingredient found in marijuana. Dronabinol is approved for appetite stimulation in AIDS-related anorexia and treatment of chemotherapy- induced nausea and vomiting in patients who have failed to respond to conventional anti-emetic therapies.(1) Medicinal applications of dronabinol have expanded beyond its approved indications due to various anecdotal reports and clinical studies. This drug evaluation review will evaluate the available literature on the medical uses of dronabinol, examine its current utilization in the Oregon Medicaid fee-for-service members and develop a recommendation for its appropriate clinical uses based on the literature review.

Claims Data

Prescription claims for dronabinol in the Oregon Medicaid fee-for- service members from 1/1/2001 - 12/31/2001 were reviewed. There were a total of 1679 claims for dronabinol, at a cost of $919,000. Medicaid data showed that dronabinol was prescribed for less than 140 patients in Oregon in 2001; about 68% of these patients have a documented diagnosis of HIV infection. There were a total of 171 prescribers for the 1679 claims.

The average claim for dronabinol was $547. There were 248 prescription claims for over $1000 including 24 with claims between $2000 and $4000 and two with claims of $4158. It is difficult to delineate the indications that dronabinol has been prescribed for in these patients based on prescription claims. However, given that doses of 2.5 mg bid and 5 mg/m2 for 4-6 doses/day, respectively, were used in clinical trials for AIDS-related anorexia and treatment of chemotherapy-induced nausea and vomiting, then the monthly costs should be in the region of $210 per month. Some patients needed higher doses in the studies, thus increasing the threshold price to ~$800 per month.

Summary of Clinical Evidence

AIDS-related anorexia - Clinical trials showed that dronabinol increases appetite, but findings on weight increase are inconsistent. The weight gain is primarily an accumulation of water (sometimes fat), but not of lean body mass. Furthermore, the weight gain produced by dronabinol was not shown to be associated with an improved immunologic status or clinical outcome. Studied patients usually noted a delayed onset of effect and reported complaints of getting "too stoned".(2,3) Adding dronabinol to another appetite stimulant, such as megestrol produces no benefit.(4) Lastly, the duration of treatment in these studies was relatively short, 5 weeks to 12 months in length. See Table 1 for summary of clinical trials. Chemotherapy-induced nausea and vomiting - The efficacy of THC for chemotherapy-induced emesis has been evaluated since the mid-1970s. Tramer et al(8) performed a systematic review of 30 randomized clinical trials (1975-1997), a total of 1366 evaluable patients with average trial size of 46 patients. Patients mainly received low emetogenic chemotherapy. Cannabinoids in different dosage forms and formulations were evaluated (oral nabilone, 16 trials; oral dronabinol, 13 trials; intra-muscular injection levonantradol, 1 trial). The most common comparator controls were prochlorperazine (12 trials) and placebo (10 trials). There were no comparison studies of cannabinoids with serotonin, 5-HT3 antagonists (e.g. ondasetron). Across all trials, cannabinoids were slightly more effective than active comparators and placebo for completely relieving nausea and vomiting in the first 24 hours of chemotherapy. However, cannabinoids therapy was associated with increased neuropsychiatric adverse effects. In 19 trials, the number of patients who withdrew from the study due to intolerable side effects was significantly more with cannabinoids therapy than the comparators. See Table 2 for summary of clinical studies.

Cancer-associated anorexia - Dronabinol has been evaluated as an appetite stimulant in anorexia / cachexia associated with advanced cancer. See Table 3 for summary of clinical trials.

Multiple Sclerosis - Animal model of multiple sclerosis (MS) studies have suggested that cannabinoid agonists may improve spasticity.(13) Killestein et al(14) has completed the largest randomized clinical trial of cannabinoids use in patients with MS to date. 16 patients with progressive MS were enrolled this randomized, double-blinded, placebo-controlled, twofold crossover study. Treatment arms included THC, cannabis sativa plant extract and placebo. THC was initiated at 2.5 mg bid for 2 weeks and increased to 5 mg bid for the later 2 weeks if tolerable. Compared with placebo, neither THC nor plant-extract treatment reduced spasticity. However, the study was not powered for efficacy. Other smaller clinical trials have reported significant improvement on spasticity or other MS symptoms (tremor, ataxia) based on investigator's interpretation of video recordings or subjects' self-assessment of symptoms.(15,16) A phase III clinical trial of cannabis, THC and placebo is underway in United Kingdom. The study is recruiting 660 patients with MS.(17)

Dystonia - Studies of cannabinoids for dystonic movement disorders have involved the use of nabilone or cannabidiol, the other active cannabinoid constituents of marijuana. Both products are not available in the US. Fox et al(18) treated 15 subjects with primary dystonia with a single dose of nabilone (0.03 mg/kg) in a double-blinded, randomized, placebo-controlled, crossover study. The study showed no significant difference in dystonia movement scale scores between nabilone and placebo. Consroe P et al(19) enrolled 5 patients with dystonic movement disorders in an open label study. Oral doses of cannabidiol was started at 100 mg/day and subsequently increased weekly by 100 mg/day to a maximum of 600 mg/day. Three patients took antidystonic medication concurrently in the study. Symptomatic improvement ranged from 20-50% in patients with both focal and generalized forms of dystonia, using a standard dystonic movement scale.

Migraine - No randomized clinical trials of dronabinol use has been conducted in patients with migraine. El-Mallakh(20) reported 3 patients with common migraine headache that had appeared shortly after abrupt discontinuation of long-term marijuana smoking use. All three cases responded to conventional treatment of migraine attack.

Pain - Studies of cannabinoids on pain are few and usually involves small subject numbers. Campbell et al(21) performed a systematic review of randomized clinical trials. Nine trials were included, 5 trials related to cancer pain, 2 to chronic non-malignant pain, and 2 to acute postoperative pain. The number of subjects in treatment groups ranged from 1 to 37. Seven studies were single dose evaluations of the analgesic effectiveness of the cannabinoids. The authors concluded that cannabinoids, as oral THC 5-20 mg, oral synthetic nitrogen analogue of THC 1 mg, or IM levonantradol 1.5-3 mg were found to be as effective as codeine 50-120 mg, but have depressant effects on CNS that limit their use. Two studies reported that 20 mg THC was roughly equivalent to 120 mg codeine. However, the THC 20 mg was highly sedating and produced mental effects prohibiting its use.

Clermont-Gnamien et al(22) conducted an open-label study to assess the efficacy and safety of oral dronabinol in the treatment of refractory neuropathic pain in 7 patients. Patients received dronabinol titrated to the maximum dose of 25 mg/day. The mean daily dose was 15 mg while the average duration of therapy was 55.4 days. Pain assessment using visual analog scale and health-related quality of life were evaluated. Oral dronabinol did not show any significant efficacy in these patients. Authors concluded that the unfavorable side effect profile might have been the limiting factor to a favorable efficacy result.

Glaucoma - Smoking marijuana may cause the reduction of intraocular pressure (IOP) on average, by about 25% (range, -45% to +5%). Duration of its effect on IOP reduction is about 3 to 4 hours, by which time the IOP approaches the presmoking level. Studies in patients with primary open-angle glaucoma indicated a reduction of IOP in 60% to 65% of the population after marijuana smoking or delta-9-THC ingestion. However, the systemic routes of administration has caused undesirable side effects; therefore, researchers are focused on ophthalmic administration of cannabinoids.(2)

Based on the comprehensive review of published literature here, the evidence to support the use of dronabinol outside of its approved indications is lacking. Dronabinol is highly abusable and high cost. Long-term use of cannabinoids has been associated with disorders of motivation, judgment, and cognition. In addition to its psychoactive effects, dronabinol can cause significant cardiovascular effects such as palpitations, tachycardia or hypotension.(1,2) It is recommended that dronabinol to be restricted to its approved indications with a maximum claim value allocated to its use by prior authorization. Indication for dronabinol use should be obtained along with the dose and quantity in the prior authorization process.

Recommended dose Maximum FDA Indication or recommended Approved dose used in trials dose AIDS-related 2.5 mg bid 10 mg bid Yes anorexia 5mg/m2 1-3 hrs Chemotherapy- before chemo; then 15mg/m2 per induced nausea & q2-4h after chemo for Yes dose vomiting a total of 4-6 doses/day Multiple Sclerosis 2.5 mg bid 5 mg bid No Dystonic Not studied No Disorders

Migraine Not studied No Pain 5 mg/day 25 mg/day No Glaucoma Not studied No Cancer-associated 2.5 mg bid 5 mg bid No anorexia

REFERENCE

1. Dronabinol. Drugdex Drug Evaluations. Micromedex. Accessed 5/10/2002. 2. Workshop on the Medical Utility of Marijuana: www.nih.gov/news/medmarijuana/MedicalMarijuana.htm. Accessed 5/10/2002. 3. Bagshaw SM. Medical Efficacy of Cannabinoids and Marijuana: a Comprehensive Review of the Literature. J Palliat Care 2002;18(2):111-122. 4. Timpone JG, Wright DJ, Li N, Egorin MJ, Enama ME, Mayers J et al. The Safety and Pharmacokinetics of Single-Agent and Combination Therapy with Megestrol Acetate and Dronabinol for the Treatment of HIV Wasting Syndrome. AIDS Res Hum Retroviruses 1997;13(4):305-315. 5. Beal JE, Olson R, Laubenstein L, Morales JO, Bellman P, Yangco B et al. Dronabinol as a Treatment for Anorexia Associated with Weight Loss in Patients with AIDS. J Pain Symptom Manage 1995;10:89-97. 6. Beal JE, Olson R, Lefkowitz L, Laubenstein L, Bellman P, Yangco B et al. Long-Term Efficacy and Safety of Dronabinol for Acquired Immunodeficiency Syndrome-Associated Anorexia. J Pain Symptom Manage 1997;14(1):7-14. 7. Struwe M, Kaempfer SH, Geiger CJ, Pavia AT, Plasse TF, Shepard KV et al. Effect of Dronabinol on Nutritional Status in HIV Infection. Ann Pharmacother 1993;27:827-31. 8. Tramer MR, Carroll D, Campbell FA, Reynolds DJM, Moore RA, McQuay HJ. Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review. BMJ 2001;323:16-21. 9. Sallan SE, Cronin C, Zelen M, Zinberg NE. Antiemetics in Patients Receiving Chemotherapy for Cancer: A Randomized Comparison of Delta-9- Tetrahydrocannabinol and Prochlorperazine. New Eng J Med 1980;302(3):135-138. 10. Gonzalez-Rosales F, Walsh D. Intractable Nausea and Vomiting Due to Gastrointestinal Mucosal Metastases Relieved by Tetrahydrocannabinol (Dronabinol). J Pain Symptom Manage 1997;14(5):311-314. 11. Plasse TF, Gorter RW, Krasnow SH, Lane M, Shepard KV, Wadleigh RG. Recent Clinical Experience With Dronabinol. Pharmacol Biochem Behav 1991;40:695-700. 12. Jatoi A, Windschitl HE, Loprinzi CL, Sloan JA, Dakhil SR, Mailliard JA et al. Dronabinol Versus Megestrol Acetate Versus Combination Therapy for Cancer-Associated Anorexia: A North Central Cancer Treatment Group Study. J Clin Oncol 2002;20(2):567-573. 13. Pertwee RG. Cannabinoids and multiple sclerosis. Pharmacol Therapeutics 2002;95:165-174. 14. Killestein J, Hoogervosrt ELJ, Reif M, Kalders NF, Van Loenen AC, Staats PGM et al. Safety, tolerability, and efficacy of orally administered cannabinoids in MS. Neurol 2002;58:1404-1407. 15. Petro DJ, Ellenberger C. Treatment of Human Spasticity with delta-9-Tetrahydrocannabinol. J Clin Pharmacol 1981;21:413S-416S. 16. Clifford DB. Tetrahydrocannabinol for Tremor in Multiple Sclerosis. Ann Neurol 1983;13:669-671. 17. Thompson AJ, Baker D. Cannabinoids in MS: Potential useful but not just yet! Neurol 2002; 58(9):1323-1324. 18. Fox HS, Kellett M, Moore AP, Crossman AR, Brotchie JM. Movement Disorders 2002;17(1):145-149. 19. Consroe P, Sandyk R, Snider SR. Open Label Evaluation of Cannabidiol in Dystonic Movement Disorders. Intern J Neuroscience 1986;30:277-282. 20. El-Mallakh RS. Marijuana and Migraine. Headache 1987;27:442-443. 21. Campbell FA, Tramer MR, Carroll D, Reynolds DJM, Moore RA, McQuay HJ. Are cannabinoids an effective and safe option in the management of pain? A qualitative systematic review. BMJ 2001;323:13-16. 22. Clermont-Gnamien S, Atlani S, Attal N, Le Mercier F, Guirimand F, and Brasseur L. The therapeutic use of D9-tetrahydrocannabino (dronabinol) in refractory neuropathic pain. Presse Med 2002;31(39):1840-5.

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