Results of a new study showed
MARINOL(R) (dronabinol) CIII Capsules helps to reduce delayed chemotherapy-
induced nausea and vomiting (CINV). MARINOL(R) is a synthetic version of
delta-9-tetrahydrocannabinol, which is one of more than 400 compounds found in
the marijuana plant (Cannabis sativa L). The research was presented today at
the American Society of Clinical Oncology's Annual Meeting in Orlando, Fla.
The research also suggested that adding a small dose of MARINOL(R) (2.5
mg) to the standard preventive antiemetic regimen helped relieve CINV on the
day of chemotherapy. On Days 2 through 5 following chemotherapy, the study
concluded that continued treatment with MARINOL(R) alone, or in combination
with ondansetron (a commonly used serotonin receptor antagonist), was more
effective than placebo in reducing delayed CINV and comparable to ondansetron
alone.
"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. (solvaypharmaceuticals-us)
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., (unimed) 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.
solvaypharmaceuticals-us
unimed