PART 3 - THE DEBATE: HINCHEY/ROHRABACHER MEDICAL MARIJUANA AMENDMENT

Mr. WOLF. Mr. Chairman, I yield 2 minutes to the gentleman from Texas (Mr.
Burgess).

Mr. BURGESS. Mr. Chairman, I thank the chairman for yielding me this time.
I actually had not planned on speaking on this issue this evening, but
after sitting in my office and hearing some of the other arguments, I felt
compelled to come over and at least, if I could, perhaps provide some
illumination on this subject.

The last speaker, in fact, talked about science, common sense, and human
decency as dictating that we must make marijuana available to our sickest
patients.

But why, indeed, would we want to make a substance available that is widely
recognized as a gateway drug which could lead to greater drug use?

My friend from Arizona pointed out that drug use amongst our youth and our
children is increasing at a rapid rate, and we need to do what we can to
stop that. I do not believe that making marijuana generally available, even
for medicinal purposes, is going to further that curtailment of drug use in
children or young people.

But, Mr. Chairman, the fact remains that if we want to legally prescribe
medication to deal with our patients' suffering, that is, anorexia, Marinol
is available today; and I believe it is legal in all States, not just 10
states. What is Marinol? Marinol is a synthetic
delta-9-tetrahydrocannabinol. Delta-9-tetrahydrocannabinol is also the
naturally occurring compound of Cannabis sativa, or marijuana.

So you see, Mr. Chairman, our physicians already have the active ingredient
in marijuana available to prescribe to their patients today; and, in fact,
I will include for the RECORD the package insert from Marinol which details
the double-blind placebo studies that show that Marinol has been useful as
an appetite stimulant and an antiemetic, that is, it inhibits nausea and
vomiting in individuals who are suffering from terminal HIV/AIDS and
individuals who are undergoing chemotherapy. And perhaps the beauty of
using Marinol is your patient does not have to be terminally ill, they just
have to be ill, because Marinol can be used for a short term. In fact, that
is what it is recommended, to be used over the short term to deal with
those two adverse consequences of chemotherapy.

Mr. Chairman, compassionate care is available in this country. Our doctors
are providing compassionate care. It is approved by the Food and Drug
Administration. It is approved by the DEA.

Marinol (Dronabinol) Capsules

DESCRIPTION

Dronabinol is a cannabinoid designated chemically as
(6aR-trans)-6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]py
ran-1-ol.

Dronabinol, the active ingredient in Marinol Capsules, is synthetic
delta-9-tetrahydrocannabinol (delta-9-THC). Delta-9-tetrahydrocannabinol is
also a naturally occurring component of Cannabis sativa L. (Marijuana).

Dronabinol is a light yellow resinous oil that is sticky at room
temperature and hardens upon refrigeration. Dronabinol is insoluble in
water and is formulated in sesame oil. It has a pKa of 10.6 and an
octanol-water partition coefficient: 6,000:1 at pH 7.

Capsules for oral administration: Marinol Capsules is supplied as round,
soft gelatin capsules containing either 2.5 mg, 5 mg, or 10 mg dronabinol.
Each Marinol Capsule is formulated with the following inactive ingredients:
FD&C Blue No. 1 (5 mg), FD&C Red No. 40 (5 mg), FD&C Yellow No. 6 (5 mg and
10 mg), gelatin, glycerin, methylparaben, propylparaben, sesame oil, and
titanium dioxide.

CLINICAL PATHOLOGY

Dronabinol is an orally active cannabinoid which, like other cannabinoids,
has complex effects on the central nervous system (CNS), including central
sympathomimetic activity. Cannabinoid receptors have been discovered in
neural tissues. These receptors may play a role in mediating the effects of
dronabinol and other cannabinoids.

Pharmacodynamics: Dronabinol-induced sympathomimetic activity may result in
tachycardia and/or conjunctival injection. Its effects on blood pressure
are inconsistent, but occasional subjects have experienced orthostatic
hypotension and/or syncope upon abrupt standing.

Dronabinol also demonstrates reversible effects on appetite, mood,
cognition, memory, and perception. These phenomena appear to be
dose-related, increasing in frequency with higher dosages, and subject to
great interpatient variability.

After oral administration, dronabinol has an onset of action of
approximately 0.5 to 1 hours and peak effect at 2 to 4 hours. Duration of
action for psychoactive effects is 4 to 6 hours, but the appetite stimulant
effect of dronabinol may continue for 24 hours or longer after administration.

Tachyphylaxis and tolerance develop to some of the pharmacologic effects of
dronabinol and other cannabinoids with chronic use, suggesting an indirect
effect on sympathetic neurons. In a study of the pharmacodynamics of
chronic dronabinol exposure, healthy male volunteers (N = 12) received 210
mg/day dronabinol, administered orally in divided doses, for 16 days. An
initial tachycardia induced by dronabinol was replaced successively by
normal sinus rhythm and then bradycardia. A decrease in supine blood
pressure, made worse by standing, was also observed initially. These
volunteers developed tolerance to the cardiovascular and subjective adverse
CNS effects of dronabinol within 12 days of treatment initiation.

Tachyphylaxis and tolerance do not, however, appear to develop to the
appetite stimulant effect of Marinol Capsules. In studies involving
patients with Acquired Immune Deficiency Syndrome (AIDS), the appetite
stimulant effect of Marinol Capsules has been sustained for up to five
months in clinical trials, at dosages ranging from 2.5 mg/day to 20 mg/day.
The elimination phase of dronabinol can be described using a two
compartment model with an initial (alpha) half-life of about 4 hours and a
terminal (beta) half-life of 25 to 36 hours. Because of its large volume of
distribution, dronabinol and its metabolites may be excreted at low levels
for prolonged periods of time.

Metabolites: Dronabinol undergoes extensive first-pass hepatic metabolism,
primarily by microsomal hydroxylation, yielding both active and inactive
metabolites. Dronabinol and its principal active metabolite,
11-OH-delta-9-THC, are present in approximately equal concentrations in
plasma. Concentrations of both parent drug and metabolite peak at
approximately 2 to 4 hours after oral dosing and decline over several days.
Values for clearance average about 0.2 L/kg-hr, but are highly variable due
to the complexity of cannabinoid distribution.

Elimination: Dronabinol and its biotransformation products are excreted in
both feces and urine. Biliary excretion is the major route of elimination
with about half of a radio-labeled oral dose being recovered from the feces
within 72 hours as contrasted with 10 to 15% recovered from urine. Less
than 5% of an oral dose is recovered unchanged in the feces.

Following single dose administration, low levels of dronabinol metabolites
have been detected for more than 5 weeks in the urine and feces.

In a study of Marinol Capsules involving AIDS patients, urinary
cannabinoid/creatinine concentration ratios were studied bi-weekly over a
six week period. The urinary cannabinoid/creatinine ratio was closely
correlated with dose. No increase in the cannabinoid/creatinine ratio was
observed after the first two weeks of treatment, indicating that
steady-state cannabionoid levels had been reached. This conclusion is
consistent with predictions based on the observed terminal half-life of
dronabinol.

Special Populations: The pharmacokinetic profile of Marinol Capsules has
not been investigated in either pediatric or geriatric patients.

CLINICAL TRIALS

Appetite Stimulation: The appetite stimulant effect of Marinol (Dronabinol)
Capsules in the treatment of AIDS-related anorexia associated with weight
loss was studied in a randomized, double-blind, placebo-controlled study
involving 139 patients. The initial dosage of Marinol Capsules in all
patients was 5 mg/day, administered in doses of 2.5 mg one hour before
lunch and one hour before supper. In pilot studies, early morning
administration of Marinol Capsules appeared to have been associated with an
increased frequency of adverse experiences, as compared to dosing later in
the day. The effect of Marinol Capsules on appetite, weight, mood, and
nausea was measured at scheduled intervals during the six-week treatment
period. Side effects (feeling high, dizziness, confusion, somnolence)
occurred in 13 of 72 patients (18%) at this dosage level and the dosage was
reduced to 2.5 mg/day, administered as a single dose at supper or bedtime.

As compared to placebo, Marinol Capsules treatment resulted in a
statistically significant improvement in appetite as measured by visual
analog scale (see figure). Trends toward improved body weight and mood, and
decreases in nausea were also seen.

After completing the 6-week study, patients were allowed to continue
treatment with Marinol Capsules in an open-label study, in which there was
a sustained improvement in appetite.

Antiemetic: Marinol (Dronabinol) Capsules treatment of chemotherapy-induced
emesis was evaluated in 454 patients with cancer, who received a total of
750 courses of treatment of various malignancies. The antiemetic efficacy
of Marinol Capsules was greatest in patients receiving cytotoxic therapy
with MOPP for Hodgkin's and non-Hodgkin's lymphomas. Marinol Capsules
dosages ranged from 2.5 mg/day to 40 mg/day, administered in equally
divided doses every four to six hours (four times daily). Escalating the
Marinol Capsules dose above 7 mg/mg 2 Capsules dose above 7 mg/m 2
increased the frequency of adverse experiences, with no additional
antiemetic benefit.

Combination antiemetic therapy with Marinol Capsules and a phenothiazine
(prochlorperazine) may result in synergistic or additive antiemetic effects
and attenuate the toxicities associated with each of the agents.

INDIVIDUALIZATION OF DOSAGES

The pharmacologic effects of Marinol (Dronabinol) Capsules are dose-related
and subject to considerable interpatient variability. Therefore, dosage
individualization is critical in achieving the maximum benefit of Marinol
Capsules treatment.

Appetite Stimulation: In the clinical trials, the majority of patients were
treated with 5 mg/day Marinol Capsules, although the dosages ranged from
2.5 to 20 mg/day. For an adult:

1. Begin with 2.5 mg before lunch and 2.5 mg before supper. If CNS symptoms
(feeling high, dizziness, confusion, somnolence) do occur, they usually
resolve in 1 to 3 days with continued dosage.

2. If CNS symptoms are severe or persistent, reduce the dose to 2.5 mg
before supper. If symptoms continue to be a problem, taking the single dose
in the evening or at bedtime may reduce their severity.

3. When adverse effects are absent or minimal and further therapeutic
effect is desired, increase the dose to 2.5 mg before lunch and 5 mg before
supper or 5 and 5 mg. Although most patients respond to 2.5 mg twice daily,
10 mg twice daily has been tolerated in about half of the patients in
appetite stimulation studies.

The pharmacologic effects of Marinol Capsules are reversible upon treatment
cessation.

Antiemetic: Most patients respond to 5 mg three or four times daily. Dosage
may be escalated during a chemotherapy cycle or at subsequent cycles, based
upon initial results. Therapy should be initiated at the lowest recommended
dosage and titrated to clinical response. Administration of Marinol
Capsules with phenothiazines, such as prochlorperazine, has resulted in
improved efficacy as compared to either drug alone, without additional
toxicity.

Pediatrics: Marinol Capsules is not recommended for AIDS-related anorexia
in pediatric patients because it has not been studied in this population.
The pediatric dosage for the treatment of chemotherapy-induced emesis is
the same as in adults. Caution is recommended in prescribing Marinol
Capsules for children because of the psychoactive effects.

Geriatrics: Caution is advised in prescribing Marinol Capsules in elderly
patients because they are generally more sensitive to the psychoactive
effects of drugs. In antiemetic studies, no difference in tolerance or
efficacy was apparent in patients 55 years old.

INDICATIONS AND USAGE

Marinol (Dronabinol) Capsules is indicated for the treatment of:

1. anorexia associated with weight loss in patients with AIDS; and

2. nausea and vomiting associated with cancer chemotherapy in patients who
have failed to respond adequately to conventional antiemetic treatments.

CONTRAINDICATIONS

Marinol (Dronabinol) Capsules is contraindicated in any patient who has a
history of hypersensitivity to any cannabinoid or sesame oil.

WARNINGS

Patients receiving treatment with Marinol Capsules should be specifically
warned not to drive, operate machinery, or engage in any hazardous activity
until it is established that they are able to tolerate the drug and to
perform such tasks safely.