(I-Newswire) May 22, 2005 - "Despite the introduction of new chemotherapy treatments and antiemetics since the approval of MARINOL(R) in 1985, there still remains an unmet need for patients suffering from nausea and vomiting," said Harold H. Shlevin, Ph.D., president and CEO of Solvay Pharmaceuticals, Inc. and chairman and CEO of Unimed Pharmaceuticals, Inc. "Solvay Pharmaceuticals continues to invest in research in this important area and strives to provide physicians with current information for their patients. Understanding the role of MARINOL(R) for controlling nausea and vomiting may help doctors better manage patients' symptoms, thus encouraging patients to maintain their chemotherapy schedule."
MARINOL(R) is indicated for the treatment of anorexia associated with weight loss in patients with AIDS and for the treatment of nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments.
Chemotherapy-Induced Nausea and Vomiting
Up to 50 percent of patients experience nausea and vomiting following moderately emetogenic treatment(1). Symptoms occurring on Day 1 following chemotherapy are referred to as acute CINV. Delayed CINV occurs more than 24 hours following chemotherapy treatment and sometimes is a result of poor symptom management of acute CINV.
"While acute symptoms are often more severe, it is the delayed symptoms that can result in hospitalization for dehydration and metabolic disorders," said James J. Vredenburgh, M.D., Division of Medical Oncology at Duke University Medical Center and aco-author of the study. "Delayed symptoms have a significant impact on patients' quality of life."
The severity of CINV contributes to a reluctance to continue chemotherapy in many patients (2,3). In addition to symptoms directly related to CINV, poor symptom management also is associated with fatigue, anorexia, insomnia and a deterioration in physical and cognitive functioning (4). The current therapy regimen for preventing CINV includes serotonin (5-HT3) receptor antagonists, but they appear to be less effective in preventing delayed nausea and vomiting than the acute form (5).
About the Study
The study was designed and conducted by investigators at Bethesda Memorial Hospital in Boynton Beach, Fla., Compassionate Cancer Care in Fountain Valley, Calif., Duke University Medical Center in Durham, N.C., among others, and sponsored by Solvay Pharmaceuticals, Inc.
The frequency and severity of nausea and vomiting was observed in a placebo-controlled, double-blind, parallel group, five-day study of 64 subjects receiving moderate to high emetogenic chemotherapy. Subjects were randomized into four therapy groups for evaluation on Days 2 through 5 (1) MARINOL(R); (2) ondansetron; (3) combination MARINOL(R) and ondansetron and (4) placebo. All groups received a standard pre-chemotherapy antiemetic regimen of dexamethasone (a corticosteroid) and ondansetron. Subjects randomized to active treatment for Days 2 through 5 also received MARINOL(R) in addition to the standard antiemetic regimen, prior to and following chemotherapy on Day 1. Treatment continued through Day 5 with daily symptom assessment.
The primary efficacy evaluation for the delayed CINV study was total response defined as nausea intensity of less than 5 mm on a 100 mm visual analog scale (VAS), no vomiting/retching and no use of a rescue antiemetic. Secondary evaluations included presence or absence of nausea, nausea intensity on the VAS and the number of vomiting/retching episodes. A total of 61 subjects were analyzed for efficacy.
"The results support the potential role of MARINOL(R) for managing delayed CINV," said Lou Barbato, M.D., director of neuroscience clinical development and medical affairs, Solvay Pharmaceuticals, Inc. "The research also reinforces the value of the treatment's unique mechanism of action for preventing nausea and vomiting that follows chemotherapy."
Results on Day 1 (Exploratory Analysis)
On Day 1, all subjects received a standard pre-chemotherapy antiemetic regimen of dexamethasone and ondansetron. In addition, 50 subjects who were randomized to active treatment on Days 2 through 5 also received a 2.5 mg dose of MARINOL(R) before and immediately following chemotherapy. Subjects receiving MARINOL(R) as part of their therapy scored significantly better on three measures of symptom management, compared to subjects receiving only the standard therapy (placebo group; n=13). Total response to antiemetic treatment was observed in 79 percent (n=33/42) of subjects receiving MARINOL(R) compared to 40 percent (n=4/10) of subjects receiving only the standard antiemetic therapy (p=0.024). Absence of nausea was achieved in 79 percent (n=38/48) of subjects who received MARINOL(R), compared to 38 percent (n=5/13) of subjects receiving only standard antiemetic therapy (p=0.013). Mean nausea intensity scored was greater in subjects receiving only the standard antiemetic therapy, compared to subjects who received MARINOL(R) plus standard therapy (30.7 mm vs. 7.7 mm on the VAS, respectively; p=0.029).
Results on Days 2 through 5 (Primary and Secondary Analysis)
For total response, MARINOL(R) was comparable to ondansetron at endpoint (54 percent and 58 percent, respectively). Total response to ondansetron was significantly better than placebo (20 percent) at the end of the study(p=0.04). Subjects receiving MARINOL(R) had fewer vomiting/retching episodes (mean 0.2) compared to other groups (all means approximately 1). Those receiving MARINOL(R) alone had less than half the mean nausea intensity score at endpoint (10 mm) compared to ondansetron (24 mm) and a lower intensity score than the combination treatment group (14 mm). All active treatment groups had significantly less nausea intensity scores as compared to placebo (48 mm). For absence of nausea, all active treatments were significantly better than the placebo group (p less than or equal to 0.05). The data also showed the combination of MARINOL(R) and ondansetron was comparable to either agent alone.
Twenty-four percent of the MARINOL(R) group required rescue medication to treat nausea and vomiting, compared to 43 percent of the placebo group, 31 percent of the ondansetron group and 12 percent of the combination group. The incidence of treatment emergent adverse events was similar among the three active treatment groups. MARINOL(R) had a low incidence of central nervous system side effects compared to the other two active treatment groups. No clinically meaningful abnormalities in lab parameters, vital signs or ECGs were considered related to study medications. Median daily doses were 20 mg for MARINOL(R) and 16 mg for ondansetron.
About MARINOL(R)
MARINOL(R)(dronabinol) CIII Capsules is the only legal cannabinoid approved by the U.S. Food and Drug Administration; it is synthetic delta-9- tetrahydrocannabinol (delta-9-THC). MARINOL(R) is part of a class of compounds called CB1/CB2 receptor agonists. MARINOL(R) and other cannabinoids bind to the CB1 and CB2 receptors in the endogenous cannabinoid system, a unique biological pathway involved in regulating nausea, vomiting, appetite, and other physiologic processes. Concentrations of these receptors exist in many brain regions, including the cerebral cortex, hypothalamus, cerebellum, brainstem and the vomiting center located in the medulla (6).
MARINOL(R) is indicated for the treatment of anorexia associated with weight loss in patients with AIDS and for the treatment of nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments. MARINOL(R) is contraindicated in any patient who has a history of hypersensitivity to any cannabinoid or sesame oil. MARINOL(R) should be used with caution in patients with cardiac disorders; in patients with a history of substance abuse (including alcohol abuse or dependence); in patients with mania, depression, or schizophrenia (along with careful psychiatric monitoring); in patients receiving concomitant therapy with sedatives, hypnotics, or other psychoactive drugs; and in pregnant patients, nursing mothers, or pediatric patients. The most common adverse effects with MARINOL(R) are related to the central nervous system (CNS). Adverse effects probably related to MARINOL(R) (dizziness, euphoria, paranoid reaction, somnolence, thinking abnormal, abdominal pain, nausea and vomiting) occurred in 3 to 5 percent of patients (7).
Solvay Pharmaceuticals, Inc. (http://www.solvaypharmaceuticals-us.com) of Marietta, Ga. (USA) is a research-driven pharmaceutical company that seeks to fulfill unmet medical needs in the therapeutic areas of cardiology, gastroenterology, mental health, women's health and a select group of specialized markets including men's health. It is a part of the global Solvay Pharmaceuticals organization whose core activities consist of discovering, developing and manufacturing medicines for human use. Solvay Pharmaceuticals, Inc. is a subsidiary corporation of the worldwide Solvay Group of chemical and pharmaceutical companies headquartered in Brussels, Belgium. Unimed Pharmaceuticals, Inc., (http://www.unimed.com) is a wholly owned, independently operated subsidiary of Solvay Pharmaceuticals, Inc.
(1) Martin M. The severity and pattern of emesis following different cytotoxic agents. Oncology 1996;53 (Suppl 1):26-31.
(2) Berger AM, et al. In: Cancer: Principles & Practice of Oncology. 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001:2869-2880.
(3) Joy JE, Watson SJ, Benson JA, eds. Marijuana and Medicine: Assessing the Science Base. Washington, DC: National Academy Press; 1999.
(4) Osoba D, et al. Support Care Cancer. 1997;5:307-313.
(5) National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. V.1, 2003.
(6) Martin BR, Wiley JL. Mechanism of action of cannabinoids: how it may lead to treatment of cachexia, emesis, and pain. J Support Oncol. 2004;2:305-316.
(7) MARINOL(R) Package Insert.(C) 2003 Solvay Pharmaceuticals, Inc.
Contact:
Gabrielle Braswell
Solvay Pharmaceuticals, Inc.
(770) 578-5637
Michael Lourie
Edelman
(312) 240-3370
Solvay Pharmaceuticals, Inc.
http://www.solvaypharmaceuticals-us.com
http://www.unimed.com
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