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CESAMET
TM
(Nabilone)
Innovations in OmnineuromodulationTM
for Chemotherapy-Induced
Nausea and Vomiting
CesametTM is a trademark of Valeant
Pharmaceuticals International.
©2006 Valeant Pharmaceuticals International.
All Rights Reserved.
Table of Contents
•
CESAMET Product Profile
•
CESAMET Pharmacology
•
CINV Overview
•
CESAMET’s Mechanism of Action
•
CESAMET Clinical Efficacy • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • Slides 25-34
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Slides 4-6
Indications and Usage
Dosage and Administration
•••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••
Slides 7-10
Nabilone Clinical Pharmacology
Pharmacokinetic Overview of Available Cannabinoids
Pharmacology Conclusions
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Slides 11-16
Epidemiology and Risk Factors
Clinical Presentation
Emetogenic Potential for Chemotherapy
Pathophysiology
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Slides 17-24
Distinct Therapeutic Mechanism
Ubiquitous CB1
Omnineuromodulation
Mechanism of Action Conclusions
Pivotal Efficacy Trials
Clinical Trial Design
Composite Efficacy Evaluation
Placebo-Controlled, Fixed-Dose Trials
Active-Controlled, Fixed-Dose Trials
Active-Controlled, Flexible-Dose Trials
Efficacy Conclusions
2
Table of Contents
•
CESAMET Safety and Tolerability
•
Role of CESAMET in Therapy
••••••••••••••••••••••••••••••••••••••••••••••••••••
Slides 35-47
Important Safety Information
Other Nontherapeutic Effects
Most Common Adverse Events
Adverse Events vs. Dose in CESAMET Clinical Trials
Comparative Incidence of Adverse Events in CESAMET Clinical Trials
Drug Interactions
Published Drug Interactions
Pregnancy Category C
Pediatric and Geriatric Use
Safety and Tolerability Conclusions
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Slides 48-51
Role of CESAMET in CINV Therapy and Expected Outcomes
Principles of Emesis Control
Alternate Pharmacological Treatments
•
CESAMET Product Value and Overview
•••••••••••••••••••••••••••••••••••••••••••••
Product Value
Product Overview
3
Slides 52-54
Cesamet (Nabilone) Product Profile
Synthetic Analog of ∆9-THC
•
•
Synthetic cannabinoid for oral administration1
Different mechanism of action (MOA) from conventional antiemetics2,3
•
Efficacious for chemotherapy-induced nausea and vomiting (CINV)1
•
•
Acts as OmnineuromodulatorTM4-9
Favorable safety profile1
Predictable pharmacokinetics1
Convenient and easy to use1
Improved appetite in CINV patients in clinical trials1
No drug interactions were found in clinical trials with cancer patients on a
variety of medications (e.g., antineoplastic, antibiotic, analgestic or antiinflammatory agents)1
1. CESAMETTM (nabilone) Package Insert. Valeant Pharmaceuticals North America. 2. Tramer MR, et al. Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative
systematic review. Br Med J. 2001;323:1-8. 3. National Comprehensive Cancer Network. Antiemesis: Clinical practice guidelines in oncology. 2005;1:page nos?. 4. Data on File, Valeant
Pharmaceuticals North America (The science behind Omnineuromodulation presentation and the trademark work). 5. Howlett AC, et al. Cannabinoid physiology and pharmacology: 30 years of
progress. Neuropharm. 2004;47(suppl 1):345-358. 6. Croxford JL. Therapeutic potential of cannabiniods in CNS disease. CNS Drugs. 2003;17(3):179-202. 7. Joy JE, et al. Marijuana and Medicine:
Assessing the science base. National Academy Press; 1999:156. 8. Howlett AC, et al. International union of pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev.
2002;54(2):161-202. 9. Martin BR. Cellular effects of cannabiniods. Pharmacol Rev. 1986;38(1): 45-47.
4
Indications and Usage1
• CESAMET is indicated for the treatment of nausea and vomiting
associated with cancer chemotherapy (CINV) in patients who have failed
to respond adequately to conventional antiemetic treatments
This restriction is required because a substantial proportion of any group of
patients treated with Cesamet can be expected to experience disturbing
psychotomimetic reactions not observed with other antiemetics
• Additional important information regarding the use of CESAMET for the
treatment of CINV:
Due to its potential to alter mental state, Cesamet should be used under
circumstances that permit close supervision, particularly during initial use
and dose adjustments
CESAMET is controlled as nabilone under Schedule II
of the Controlled Substances Act
Prescriptions should be limited to the amount necessary
for a single cycle of chemotherapy
1. CESAMETTM (nabilone) Package Insert. Valeant Pharmaceuticals North America.
5
Safety Statement1
Cesamet is contraindicated in patients with a hypersensitivity to any
cannabinoid. Patients treated with Cesamet 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. Cesamet has been reported to cause tachycardia and
orthostatic hypotension. Cesamet has the potential to affect the
central nervous system (CNS), which might manifest itself in dizziness,
drowsiness, feeling “high” or relaxed, anxiety, disorientation, depression,
hallucinations and psychosis. The effects of Cesamet may persist for a
variable and unpredictable period of time following its oral
administration. Adverse psychiatric reactions can persist for 48 to 72
hours. Cesamet should not be taken with alcohol, sedatives, hypnotics,
or other psychotomimetic substances. Cesamet should be used with
caution in: the elderly, patients with hypertension or heart disease,
patients with current or previous psychiatric disorders (e.g., manic
depression, schizophrenia), individuals receiving other psychoactive drugs,
patients with a history of substance abuse (e.g., alcohol abuse or
dependence), pregnant patients, nursing mothers, and pediatric patients.
Caution must be used when administering Cesamet in combination with
any CNS depressant. The most frequent adverse events seen with
Cesamet in clinical trials were drowsiness, dizziness/vertigo, dry mouth,
and euphoria.
1. CESAMETTM (nabilone) Package Insert. Valeant Pharmaceuticals North America.
6
Dosage and Administration1
• Convenient B.I.D. dosing
Usual adult dosage: 1 or 2 mg B.I.D.
Lower starting dose is recommended,
with increase in dosage when necessary
Maximum recommended daily dose:
6 mg in divided doses T.I.D.
May be taken with or without food
• Initial dose should be given 1 to 3 hours
before oncolytic agent
1 or 2 mg evening before chemotherapy
may be beneficial
• CESAMET can be administered 2 or 3 times daily
during the entire course of each chemotherapy
cycle and, if needed, for 48 hours after the last
dose of each cycle
1. CESAMETTM (nabilone) Package Insert. Valeant Pharmaceuticals North America.
7
CESAMET Pharmacology
Nabilone Clinical Pharmacology1
• Pharmacodynamics
Long duration of action: 8-12 hours
Dose-related effects:
Single 1 and 2.5 mg doses induced relaxant and sedative effects
Effects of euphoria, dry mouth, tachycardia, or postural hypotension were
minimal after 2.5 mg, and marked after 5 mg (tachycardiac effects were
not significant)
Tolerance developed against adverse events (AEs), such as euphoria
and hypotension, but not against the antiemetic effect
• Pharmacokinetics (PKs)
Peak plasma concentrations occur within 2 hours
Nabilone exhibits dose linearity within its therapeutic range
1. CESAMETTM (nabilone) Package Insert. Valeant Pharmaceuticals North America.
9
Overview of Available Cannabinoids1,2
CESAMETTM (nabilo ne)
MARINO L® (dronabinol)
Control II
Control III
Dosing
1-2 m g two times a day
5 mg/ m2, 1-3 hours before
chemotherapy, then give 5 mg/m2/dose
every 2-4 hours after chemo therapy for
a total of 4-6 doses/day
Source
Synthetic canna binoi d
(THC analog)
Delta-9-THC
Dis tribution Volum e
Liposoluble (very large)
Liposoluble (very large)
Bioavaila bili ty
Around 20% after fi rstpass by the li ver
6-20% after first-pass by the liv er
60-90 minu tes
30-60 minutes
2 h ours
1-4 hours
2 active metabolit es
1 active metabolite and more
than 20 other metabolites
2 h ours
Metabolites: 35 ho urs
Variable: 19-56 hours
Metabolites: 59-53 hours
Schedule
Onset of A ction
T-max
Number of Metabolites
Half-life
Indication
Mariju ana Drug Test
(EMIT)
Nausea and vomiting
associated wi th
chemotherapy treatment
Negative
Nausea and vomiting associated
with chemo therapy treatment
Body wasting syndrome,
anorexia associated with HIV
Positive
1. CESAMETTM (nabilone) Package Insert. Valeant Pharmaceuticals North America. 2. MARINOL® (dronabinol) Package Insert. Solvay Pharmaceuticals, Inc.
10
CESAMET Pharmacology Conclusions
• CESAMET, an oral medication, possesses a long duration of
action, which allows for easy B.I.D. dosing1,2
• Nabilone has predictable pharmacokinetics,1 which may allow
for a more predictable patient response to treatment
1. CESAMETTM (nabilone) Package Insert. Valeant Pharmaceuticals North America. 2. MARINOL® (dronabinol) Package Insert. Solvay Pharmaceuticals, Inc.
11
CINV Overview
CINV Epidemiology and Risk Factors
• CINV occurs in 70% to 80% of all patients receiving
chemotherapy1
Approximately 1.37 million new cancer cases were reported in 20042
• An estimated 30% of patients receiving moderately or highly
emetogenic agents will continue to have acute
nausea/vomiting, even following antiemetic prophylaxis3
• Primary Risk Factor4,5
Emetogenicity of the chemotherapeutic regimen
• Additional Risk Factors5
Female gender
Younger age (age <50 years)
Susceptibility to motion sickness
History of alcoholism
1. Berger, AM, Clark-Snow RA. Adverse Effects of Treatment. Cancer: Principles and Practice of Oncology, 6th ed. Lippincott, Williams and Wilkins;2001:2869-2880.
2. American Cancer Society. http://www.cancer.org, accessed 12/05. 3. Carlson R. Better anti-emetic regimens still needed. Oncology Times 2001; 23: 19-23. 4. National
Comprehensive Cancer Network. Antiemesis: Clinical practice guidelines in oncology. 2005;1:page nos?. 5. National Cancer Institute.
http://www.meds.com/pdq/supportive_pro.html, accessed 6/05.
13
CINV Clinical Presentation1
Emetic Syndromes
Characterization of Nausea and Vomiting
Acute CINV
Occurs within 24 hours of chemotherapy
Delayed CINV
Occurs 24 hours after chemotherapy
Anticipatory CINV
Conditioned response to previous chemotherapy; may occur
before, during, or after chemotherapy
Breakthrough CINV
Occurs despite preventive therapy
Refractory CINV
Persists in subsequent chemotherapy cycles after antiemetic
prophylaxis or rescue therapy has failed
1. Berger, AM, Clark-Snow RA. Adverse Effects of Treatment. Cancer: Principles and Practice of Oncology, 6th ed. Lippincott, Williams and Wilkins;2001:2869-2880.
14
Emetogenic Potential of Chemotherapy1,2
Severe
(>90% )
Cisplatin
Ø
(Platinol -AQ)
Dacarbazine
Ø
(DTIC-Dome )
Streptozocin
Ø
(Zanosar )
Mechlorethamine
Ø
(Mustargen )
Cytarabine - high
Ø
dose (Cytosar )
High
(60%-90%)
Cylcophosphamide
Ø
(Cytoxan )
Carmustine
Ø
(Gliadel )
Semustine
Lomustine
Ø
(CeeNu )
Procarbazine
Ø
(Matulane )
Methotrexate high dose
(TrexallTM)
Dactinomycin
Ø
(Cosmegen )
Ifosfamide
Ø
(Ifex )
Carboplatin
Ø
(Paraplatin )
Moderate
Low
Very Low
(30%-60%)
L-asparaginase
Ø
(Elspar )
Daunorubicin
Ø
(Cerubidine )
Doxorubicin
Ø
(Adriamycin )
Mitomycin-C
Ø
(Mutamycin )
5-Azacytidine
(VidazaTM)
(10%-30%)
Bleomycin
Ø
(Blenoxane )
Cytarabine - low
Ø
dose (Cytosar )
Methotrexate
(TrexallTM)
Hydroxyurea
Ø
(Hydrea )
6-Mercaptopurine
Ø
(Purinethol )
5-Fluorouracil
Ø
(Adrucil )
Vinblastine
Ø
(Velban )
Vincristine
Ø
(Vincasar )
Thiotepa
Progestins
Etoposide
Ø
(Toposar )
Paclitaxel
Ø
(Taxol )
Tamoxifen
Ø
(Nolvadex )
Hexamethylmelamine
Ø
(Hexalen )
Amifostine
Ø
(Ethyol )
Epirubicin
Ø
(Ellence )
(<10% )
Busulfan
Ø
(Myleran )
Androgens
Estrogens
Corticosteroids
Thioguanine
(TabloidØ)
1. National Cancer Institute. http://www.meds.com/pdq/supportive_pro.html, accessed 6/05. 2. National Comprehensive Cancer Network. Antiemesis: Clinical practice
guidelines in oncology. 2005;1:page nos?.
15
CINV Pathophysiology
• Chemotherapy and primary mechanisms of CINV:1,2
Central Nervous System (CNS): Activation of the chemoreceptor
trigger zone (CTZ) in the area postrema causes neurotransmitter
release and stimulation of the brainstem emetic circuitry
Peripheral GI Tract: GI irritation and damage to mucosa causes
neurotransmitter release; impulses from the GI tract also signal
the brainstem emetic circuitry via the vagus and sympathetic nerves
1. Berger, AM, Clark-Snow RA. Adverse Effects of Treatment. Cancer: Principles and Practice of Oncology, 6th ed. Lippincott, Williams and Wilkins;2001:2869-2880.
2. Hornby PJ. Central neurocircuitry associated with emesis. Am J Med. 2001;111(suppl 8A)106-112.
16
CINV Pathophysiology
• Neurotransmitters and receptors involved:
Serotonin (5-HT) and dopamine (DA) acting on 5-HT3 and
D2 receptors are involved in signaling peripheral stimuli to the
brainstem emetic circuitry, which may lead to emesis1,2
5-HT and 5-HT3 receptors play a major role in acute phase CINV1
Substance P, a neuropeptide found in the GI tract and the CTZ,
and its Neurokinin-1 (NK1) receptors are thought to be
important in acute and delayed CINV1
1. Berger, AM, Clark-Snow RA. Adverse Effects of Treatment. Cancer: Principles and Practice of Oncology, 6th ed. Lippincott, Williams and Wilkins;2001:2869-2880.
2. Hornby PJ. Central neurocircuitry associated with emesis. Am J Med. 2001;111(suppl 8A)106-112.
17
CESAMET
Mechanism of Action:
Omnineuromodulation
Distinct Therapeutic Mechanism
• Cesamet has an MOA different from conventional antiemetics
(e.g., 5-HT3 or D2 receptor antagonists)1-3
The antiemetic effect of nabilone is thought to be due to interaction with
cannabinoid CB1 receptors found in neural tissues4
• Cesamet acts as an OMNINEUROMODULATOR5-10
Nabilone is a CB1 agonist that activates omnipresent presynaptic CB1
receptors in the central nervous system (CNS), thereby modulating
neuronal signaling in important brain areas including those that mediate
nausea/vomiting and appetite
• Cesamet may provide antiemetic benefit in patients who fail to respond
adequately to conventional agents
Combining agents with different MOAs may be the optimal approach
to management of CINV3
1. Tramer MR, et al. Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review. Br Med J. 2001;323:1-8. 2. National
Comprehensive Cancer Network. Antiemesis: Clinical practice guidelines in oncology. 2005;1:page nos?. 3. National Cancer Institute.
http://www.meds.com/pdq/supportive_pro.html accessed 6/05. 4. CESAMETTM (nabilone) Package Insert. Valeant Pharmaceuticals North America. 5. Data on File, Valeant
Pharmaceuticals North America (The science behind Omnineuromodulation presentation and the trademark work). 6. Howlett AC, et al. Cannabinoid physiology and
pharmacology: 30 years of progress. Neuropharm. 2004;47(suppl 1):345-358. 7. Croxford JL. Therapeutic potential of cannabiniods in CNS disease. CNS Drugs.
2003;17(3):179-202. 8. Joy JE, et al. Marijuana and Medicine: Assessing the science base. National Academy Press; 1999:156-?. 9. Howlett AC, et al. International union of
pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev. 2002;54(2):161-202. 10. Martin BR. Cellular effects of cannabiniods. Pharmacol Rev.
1986;38(1): 45-47.
19
The Ubiquitous CB1
• Endocannabinoids are a major class of
neuromodulators, acting through CB1
receptors primarily located on CNS
neurons
Levels exceed those of nearly all
neurotransmitter receptors1
• Endocannabinoids also activate CB2
receptors, mainly located on immune
cells in the periphery2
• Exogenous cannabinoids exert their
effects by driving these innate systems,
often mimicking and enhancing their
natural functions
• Antiemetic therapeutic effects are
primarily due to CB1 agonist action in
brain regions that mediate
nausea/vomiting and appetite
1..Martin BR, Wiley JL. Mechanism of action of cannabinoids: how it may lead to treatment of cachexia, emesis, and pain.
J Support Oncol. 2004 Jul-Aug;2(4):305-14; discussion 314-6. 2. Croxford JL. Therapeutic potential of cannabinoids in CNS disease. CNS Drugs 2003; 17: 179-202.
20
Omnineuromodulation
• Cesamet (nabilone) acts
on presynaptic CB1 receptors,
similar to innate or “endo”cannabinoids
Inhibits the release of excitatory
(e.g., glutamate) and inhibitory
(e.g., GABA) neurotransmitters
• The primary effect on neuronal
signaling appears to be inhibitory,
but network effects may be complex
and, hence, modulatory in nature
• Endocannabinoids act in reverse
from classical neurotransmitters by
serving as retrograde synaptic
messengers
21
1. Neurotransmitter (NT)
released from vesicles within
the presynaptic neuron
activates the postsynaptic
neuron
5
4
1
2
2. Activation of the postsynaptic
neuron leads to the
biosynthesis and nonvesicular
release of an endocannabinoid
3
3. The endogenous CB1 ligand
diffuses back to and binds to
the presynaptic CB1 receptor
4. The CB1 receptor activates a
G-protein, which can lead to
a number of presynaptic
events that result in inhibition
of NT release
5. Omnineuromodulators
circumvent this multi-step
process by directly activating
CB1 receptors to stimulate
the endogenous cannabinoid
system, enhancing its function
• The Nucleus of the Solitary
Tract (NTS) receives
information about:
Blood-borne emetics via
the brainstem (BS) CTZ
Abdominal irritants via
vagal afferents
• NTS neurons, in turn, project to
a BS central pattern generator,
which coordinates emesis
behavior
Cortex
Limbic
System
• Higher cortical and limbic
Brainstem
Emetic
Circuitry
Dorsal Vagal
Complex—NTS
regions (governing taste,
smell, sight, pain, memory
and emotion) can suppress
or stimulate nausea and
vomiting through descending
connections to the BS emetic
circuitry
• Cannabinoids are thought to
exert their antiemetic effects
primarily via action on CB1
receptors in the NTS and higher
cortical and limbic regions
Indirect, partial actions on
5-HT and DA signaling via
5-HT3 and D2 receptors are
implicated
• Cannabinoids can stimulate
appetite and increase food
intake by:
Acting on CB1 receptors in the
Hypothalamus, which plays
a key role in homeostatic
regulation of energy balance
Acting on CB1 receptors in the
Nucleus Accumbens and
activating an important
Reward Path that connects
the VTA and Nucleus
Accumbens, which enhances
attractiveness/enjoyment of
food, thus increasing incentive
to eat
Hypothalamus
Feeding
Circuitry
Nucleus
Accumbens
Reward Path
Ventral
Tegmental
Area (VTA)
• Omnineuromodulator
action drives the innate
cannabinoid system in the
hypothalamus to stimulate
feeding, and circumvents
the partial negative control
of the circulating satiety
factor leptin hormone1-2
Leptin Hormone
• Cannabinoids also increase
motivation to eat through
interaction with the
dopamine and opioid
systems in the Reward Path1,3
1. Cota et al, 2003
2. Harrold and Williams, 2003
3. Fride et al, 2005
Mechanism of Action Conclusions
• Cannabinoids, such as nabilone, act as Omnineuromodulators
Cannabinoids act as agonists on presynaptic CB1 receptors
omnipresent in the CNS to modulate neuronal signaling
Different mechanism of action from conventional antiemetics1-3
• Evidence suggests that omnineuromodulator action underlies
their therapeutic role in CINV and appetite stimulation
Occurs primarily through direct activation of CB1 receptors in
important brain regions that mediate nausea/vomiting and appetite
1. Tramer MR, et al. Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review. Br Med J. 2001;323:1-8.
2. National Comprehensive Cancer Network. Antiemesis: Clinical practice guidelines in oncology. 2005;1:page nos?.
3. National Cancer Institute. http://www.meds.com/pdq/supportive_pro.html accessed 6/05.
25
CESAMET
Clinical Efficacy
CINV Reduction and
Appetite Improvement
CESAMET Pivotal Efficacy Trials1
• In Phase III studies in cancer patients receiving various
chemotherapy regimens (N=316), CESAMET demonstrated
superior efficacy to placebo and prochlorperazine in:
Reducing vomiting episodes
Decreasing severity of nausea
Improving investigators’ global impression of efficacy2
1. CESAMETTM (nabilone) Package Insert. Valeant Pharmaceuticals North America. 2. Data on File: Protocol 20 and 28. Valeant Pharmaceuticals North America.
27
Double-blind, Crossover Clinical Trial Design1,2
• Double-blind, crossover clinical trials with optional continuation
into CESAMET* open-label therapy:
6 PLACEBO-controlled studies: fixed-dose (N=129)
3 PROCHLORPERAZINE-controlled studies: fixed-dose (N=75)
2 PROCHLORPERAZINE-controlled studies: flexible-dose (N=112)
CESAMET
CESAMET
Control Drug
Control Drug
1-5 days
Chemotherapy 1
2-6 weeks
1-5 days
Chemotherapy 2
Optional
Open-label
*The most frequent dose regimen of CESAMET was 2 mg B.I.D., except in the 2 flexible-dose studies, where daily doses of >4 mg were frequent.
1. CESAMETTM (nabilone) Package Insert. Valeant Pharmaceuticals North America. 2. Data on File: Protocol 7, 9, 20, 28. Valeant Pharmaceuticals North America.
28
Composite Efficacy Evaluation1
Placebo-Controlled, Fixed-Dose Trials
10.8
Active-Controlled, Fixed-Dose Trials
CESAMET
10
10
Placebo
8
8
6
6
4
*
4.5
0
1.3
†
‡
5.3
1.1
Nausea
Severity
‡ 1.8
2
1.3
0.6
0
Vomit
Frequency
Prochlorperazine
4
† 2.2
2
CESAMET
9.6
Food Intake
N=129
*P ≤0.01
†P ≤0.001
Vomit
Frequency
Values plotted are based on the means of the average daily scores by the patient’s observations.
1. CESAMETTM (nabilone) Package Insert. Valeant Pharmaceuticals North America.
29
Nausea
Severity
§
1.0 0.9
Food Intake
N=75
‡P ≤0.007
§P ≤0.012
Placebo-Controlled, Fixed-Dose Trials1
Primary Endpoint: Patient-Rated Efficacy Criteria
Both Cycles Combined
Frequency of Vom its
CESAM ET
Investigator 01
Investigator 02
Investigator 03
Investigator 04
Investigator 05
Investigator 06
Composite
Placebo
Investigator 01
Investigator 02
Investigator 03
Investigator 04
Investigator 05
Investigator 06
Composite
Severity of Nause a
Food Intake
Average
Day 1
Average
Day 1
Average
Day 1
8.55
4.16
10.27
2.33
2.97
4.53
4.51
8.55
5.58
15.20
2.33
2.97
4.53
5.09
2.29
1.19
1.73
1.75
1.03
1.25
1.31
2.27
1.45
2.00
1.75
1.03
1.25
1.39
0.55
0.84
1.20
1.00
1.28
1.33
1.10
0.55
0.75
1.20
1.00
1.28
1.33
1.09
13.73
13.05
34.60
14.83
7.47
6.87
10.81
13.73
15.03
36.80
14.83
7.47
6.86
11.43
2.89
2.08
2.67
2.75
2.25
2.06
2.25
2.91
2.39
2.80
2.75
2.25
2.06
2.34
0.38
0.63
0.40
0.63
0.50
0.92
0.64
0.36
0.61
3.40
0.63
0.50
0.92
0.64
Number of vomits
Nausea severity: 0=none, 1=mild, 2=moderate, 3=severe
Food intake: 0=none, 1=less than usual, 2=usual amount or average, 3=more than usual
1. Data on File: Protocol 28. Valeant Pharmaceuticals North America.
30
Placebo-Controlled, Fixed-Dose Trials1
• 77% of evaluable patients preferred nabilone treatment
• 12% preferred placebo treatment
• 12% indicated no preference
Primary Endpoint: Investigator-Related Efficacy and Adverse Events
Inve stigators
CESAMET
Investigator 301
Investigator 302
Investigator 306
Composite
Prochlorperazine
Investigator 301
Investigator 302
Investigator 306
Composite
Global Impres sions
Efficacy
Safety
2.31
1.64
2.14
1.97
0.94
1.03
1.00
0.99
3.22
3.00
3.14
3.11
0.50
0.56
0.57
0.53
Efficacy: 1=very good, 2=good, 3=fair, 4=poor, 5=very poor
Safety: Based on the frequency of adverse events
1. Data on File: Protocol 28. Valeant Pharmaceuticals North America.
31
Active-Controlled, Fixed-Dose Trials1
Primary Endpoint: Patient-Rated Efficacy Criteria
Both Cycles Combined
Frequency of Vom its
CESAM ET
Investigator 301
Investigator 302
Investigator 306
Composite
Prochlorperazine
Investigator 301
Investigator 302
Investigator 306
Composite
Severity of Nause a
Food Intake
Average
Day 1
Average
Day 1
Average
Day 1
7.85
3.24
7.00
5.43
7.85
6.47
7.00
7.07
1.38
1.29
1.29
1.33
1.38
1.58
1.29
1.47
1.16
0.99
0.86
1.05
1.16
1.06
0.86
1.08
7.96
9.08
20.33
9.64
7.96
12.59
20.33
11.42
1.72
1.78
1.71
1.75
1.72
1.94
1.71
2.83
1.00
0.80
0.71
0.88
1.00
0.86
0.71
0.91
Number of vomits
Nausea severity: 0=none, 1=mild, 2=moderate, 3=severe
Food intake: 0=none, 1=less than usual, 2=usual amount or average, 3=more than usual
1. Data on File: Protocol 20. Valeant Pharmaceuticals North America.
32
Active-Controlled, Fixed-Dose Trials1
• 73.3% of evaluable patients preferred CESAMET treatment
• 20% preferred prochlorperazine treatment
• 6.7% indicated no preference
Primary Endpoint: Investigator-Rated Efficacy and Safety
Inve stigators
CESAM ET
Investigator 301
Investigator 302
Investigator 306
Composite
Prochlorperazine
Investigator 301
Investigator 302
Investigator 306
Composite
Global Impres sions
Efficacy
Safety
2.31
1.64
2.14
1.97
0.94
1.03
1.00
0.99
3.22
3.00
3.14
3.11
0.50
0.56
0.57
0.53
Efficacy: 1=very good, 2=good, 3=fair, 4=poor, 5=very poor
Safety: Based on the frequency of adverse events
1. Data on File: Protocol 20. Valeant Pharmaceuticals North America.
33
Active-Controlled, Flexible-Dose Trial1
Primary Endpoint: Patient-Rated Efficacy Criteria
Frequency of Vom its
Average
Day 1
CYCLE 1
CESA MET
SD
Prochlorperazine
SD
CYCLE 2
CESA MET
SD
Prochlorperazine
SD
BOTH CYCLES
CESA MET
SD
Prochlorperazine
SD
Severity of Nause a
Average
Day 1
Food Intake
Average
Day 1
1.96
1.80
6.50
7.62
5.23
5.65
9.79
8.76
1.29
0.89
1.70
0.90
1.82
1.19
2.12
0.99
1.20
0.57
0.85
0.52
1.21
0.66
0.86
0.68
5.59
7.65
6.93
6.11
9.55
8.06
11.46
8.50
1.43
0.95
2.07
0.86
2.24
0.82
2.51
0.85
0.95
0.59
0.83
0.51
0.91
0.75
0.97
0.64
3.84
5.90
6.71
6.89
7.47
7.29
10.59
8.63
1.36
0.92
1.88
0.90
2.04
1.03
2.31
0.94
1.06
0.59
0.84
0.52
1.05
0.72
0.91
0.66
Number of vomits
Nausea severity: 0=none, 1=mild, 2=moderate, 3=severe
Food intake: 0=none, 1=less than usual, 2=usual amount or average, 3=more than usual
1. Data on File: Protocol 9. Valeant Pharmaceuticals North America.
34
Efficacy Conclusions
• Cesamet is effective in controlling CINV, and was shown to
increase food intake by cancer patients in clinical trials1-4
• Cesamet is superior to prochlorperazine in controlling CINV1,3,4
• Majority of patients prefer Cesamet over placebo2 and
prochlorperazine3
• Cesamet is effective in patients receiving cisplatin,1-4
which has severe emetogenic potential5
1. CESAMETTM (nabilone) Package Insert. Valeant Pharmaceuticals North America. 2. Data on File: Protocol 28. Valeant Pharmaceuticals North America.
3. Data on File:Protocol 20. Valeant Pharmaceuticals North America. 4. Data on File: Protocol 9. Valeant Pharmaceuticals North America. 5. National Cancer
Institute. http://www.meds.com/pdq/supportive_pro.html, accessed 6/05.
35
CESAMET
Safety and Tolerability
Important Safety Information1
• Cesamet is contraindicated in patients with a history of hypersensitivity
to any cannabinoid
• Patients should be warned not to drive, operate machinery, or engage in
any hazardous activity until it is established that they are able to
tolerate Cesamet and can perform such tasks safely
• Cesamet has been reported to cause tachycardia and orthostatic
hypotension
• Cesamet has the potential to affect the CNS, which might manifest itself
in dizziness, drowsiness, feeling “high” or relaxed, anxiety,
disorientation, depression, hallucinations, and psychosis
• Effects of Cesamet may persist for a variable/unpredictable time period
Adverse psychiatric reactions can persist for 48 to 72 hours
Patients should be supervised during initial use of Cesamet and during dose
adjustments
• CESAMET should not be taken with alcohol, sedatives, hypnotics,
or other psychotomimetic substances
1. CESAMETTM (nabilone) Package Insert. Valeant Pharmaceuticals North America.
37
Important Safety Information1
• The risk/benefit ratio of Cesamet should be evaluated in
patients with the following medical conditions due to individual
variation in response to and tolerance of drug effects
• Cesamet should be used with caution in elderly patients and
patients with hypertension or heart disease
Cesamet can elevate supine and standing heart rates and cause
postural hypotension
• Cesamet should be used with caution in patients with current
or previous psychiatric disorders (e.g., manic depression,
schizophrenia)
Symptoms of these disease states may be unmasked
1. CESAMETTM (nabilone) Package Insert. Valeant Pharmaceuticals North America.
38
Important Safety Information1
• Cesamet should be used with caution in patients receiving other
psychoactive drugs
• Cesamet should be used with caution in patients with a history
of substance abuse, including alcohol abuse or dependence
• Cesamet should be used with caution in pregnant patients,
nursing mothers, or pediatric patients since it has not been
studied in these populations
1. CESAMETTM (nabilone) Package Insert. Valeant Pharmaceuticals North America.
39
Other Nontherapeutic Effects1
• Cesamet may produce psychological dependence
• Cesamet has complex CNS effects; mental state effects are similar
to those of cannabis
May be more common with higher doses
• Experience with cannabis suggests that chronic cannabinoid use may
be associated with various untoward effects on motivation, cognition,
and judgment
• Cesamet has several systemic actions, the most prominent being dry
mouth and hypotension
• Cesamet may decrease airway resistance
This effect has not been observed in asthmatic patients
1. CESAMETTM (nabilone) Package Inser. Valeant Pharmaceuticals North America.
40
Most Common Adverse Events1
• In Cesamet clinical trials, nearly all patients experienced at least
one adverse event (AE)
• The most frequent AEs were:
Drowsiness
Dizziness/vertigo
Dry mouth
Euphoria
• Most AEs were of mild to moderate severity
• Clinical studies have shown development of tolerance against
some AEs, such as drowsiness, euphoria and hypotension, but not
against the antiemetic therapeutic effect
1. CESAMETTM (nabilone) Package Insert. Valeant Pharmaceuticals North America.
41
Adverse Events vs. Dose
in CESAMET Clinical Trials1
•
Frequency of patients reporting drowsiness, vertigo, and depression
increased with CESAMET >4.0 mg/day
•
Duration of reported AEs, such as drowsiness and vertigo, increased
with doses >4.0 mg
Average Daily Dose
Adverse Event
Frequency
Percentage
2.0 mg
(n = 49)
2.01-4.0 m g
(n = 251 )
>4.0 m g
(n = 68)
>70%
—
—
Drowsiness, Vertigo
50.1-70%
Drowsiness, Vertigo
Drowsiness
—
20.1-50%
Dry Mouth
Dry Mouth, Vertigo
Dry Mouth, Depression
10-20%
Ataxia, Decreased
Concentration, Vision
Disturbance, Asthenia
Headache, Sleep
Disturbance
Ataxia
Ataxia, Decreased
Concentration, Vision
Disturbance
Depression,
Depersonalization
Depression,
Decreased
Concentration, Vision
Disturbance, Asthenia,
Headache, Sleep
Disturbance,
Depersonalization,
Euphoria
Asthenia, Headache,
Sleep Disturbance,
Euphoria
<10%
1. CESAMETTM (nabilone) Package Insert. Valeant Pharmaceuticals North America.
42
Comparative Incidence of Adverse Events
in CESAMET Clinical Trials1
Incidence of Adverse Events in Placebo-Controlled Studies
Adverse Event
Vertigo
Drowsiness
Dry Mouth
Ataxia
Euphoria
Sleep Disturbance
Dysphoria
Headache
Nausea
Disorientation
Depersonalization
Nabilone (n=132)
Pla cebo (n=119)
Patients
Percent
Patients
Percent
69
69
47
19
14
14
12
8
5
3
2
52
52
36
14
11
11
9
6
4
2
2
3
6
2
0
1
1
0
0
0
0
1
3
5
2
0
1
1
0
0
0
0
1
1. CESAMETTM (nabilone) Package Insert. Valeant Pharmaceuticals North America.
43
Comparative Incidence of Adverse Events
in CESAMET Clinical Trials1
Incidence of Adverse Events in Active-Controlled Studies
Adverse Event
Drowsiness
Vertigo/Dizziness
Euphoria
Dry Mouth
Depression
Ataxia
Visual Disturbance
Concentration Difficulties
Hypotension
Asthenia
Anorexia
Headache
Sedation
Increased Appetite
Nabilone (n=250)
Prochlorperazine (n=232)
Patients
Percent
Patients
Percent
165
147
95
54
35
32
32
31
20
19
19
18
7
6
66
59
38
22
14
13
13
12
8
8
8
7
3
2
108
53
12
11
37
4
9
3
3
10
22
14
2
2
47
23
5
5
16
2
4
1
1
4
9
6
1
1
1. CESAMETTM (nabilone) Package Insert. Valeant Pharmaceuticals North America.
44
Drug Interactions1
• During clinical trials, no drug interactions were observed in cancer
patients co-administered Cesamet with a wide range of medications
(e.g., antineoplastic, antibiotic, analgesic, and anti-inflammatory
agents)
• Nevertheless, cannabinoids may interact with other drugs through
both metabolic and pharmacodynamic mechanisms
• Caution must be used when co-administering nabilone with any
CNS depressant (e.g., diazepam, sodium secobarbital, or
codeine), due to potential for additive effects
Cesamet should not be taken with alcohol, sedatives, hypnotics, other
psychotomimetic substances, or barbiturates
• When co-administering nabilone with highly protein-bound
drugs, physicians should monitor for a need for dosage
modification of all agents
Nabilone is purportedly highly bound to plasma proteins, and therefore,
might displace other protein-bound drugs
1. CESAMETTM (nabilone) Package Insert. Valeant Pharmaceuticals North America.
45
Published Drug Interactions1
Concomitant Drug
Clinical Effect(s)
Amphetamines, cocaine, other sympathomimetic agents
Additive hypertension, tachycardia, possibly cardiotoxicity
Atropine, scopolamine, antihistamines, other anticholinergic
agents
Additive or super-additive tachycardia, drowsiness
Amitriptyline, amoxapine, desipramine, other tricyclic
antidepressants
Additive tachycardia, hypertension, drowsiness
Barbiturates, benzodiazepines, ethanol, lithium, opioids,
buspirone, antihistamines, muscle relaxants, other CNS
depressants
Additive drowsiness and CNS depression
Disulfiram
A reversible hypomanic reaction was reported in a 28 yearold man who smoked marijuana; confirmed by dechallenge
and rechallenge
Fluoxetine
A 21 year-old female with depression and bulimia receiving
20 mg/day fluoxetine x4 wks became hypomanic after
smoking marijuana; symptoms resolved after 4 days
Antipyrine, barbiturates
Decreased clearance of these agents, presumably via
competitive inhibition of metabolism
Theophylline
Increased theophylline metabolism reported with smoking of
marijuana; effect similar to that following smoking tobacco
Opioids
Cross-tolerance and mutual potentiation
Naltrexone
Oral THC effects were enhanced by opioid receptor blockade
Alcohol
Increase in the positive subjective mood effects of smoked
marijuana
1. CESAMETTM (nabilone) Package Insert. Valeant Pharmaceuticals North America.
46
Pregnancy Category C1
• No adequate and well-controlled studies in pregnant women
• Rat and rabbit studies showed no evidence for a teratogenic
potential of nabilone (doses 16x and 3x human dose based
upon body surface area)
• Rat and rabbit studies did show dose-related developmental
toxicity
• Because animal data cannot rule out the possibility of harm,
CESAMET should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus
1. CESAMETTM (nabilone) Package Insert. Valeant Pharmaceuticals North America.
47
Pediatric and Geriatric Use1
• CESAMET safety and efficacy have not been specifically
established in patients <18 years or ≥65 years of age
• Caution is recommended in prescribing CESAMET to children,
due to psychoactive effects
• CESAMET should be used with caution in patients ≥65 years old
Generally more sensitive to psychoactive effects of drugs
CESAMET can elevate supine and standing heart rates and cause
postural hypotension
• In general, CESAMET therapy should be initiated at the low end
of the dosing range in elderly patients and titrated to achieve
desired effect
1. CESAMETTM (nabilone) Package Insert. Valeant Pharmaceuticals North America.
48
Safety and Tolerability Conclusions1
• Cesamet is safe for the treatment of CINV in cancer patients
receiving a wide range of chemotherapy regimens, including lowdose cisplatin
Most AEs were mild or moderate, with the most common being
drowsiness, dizziness/vertigo, dry mouth, and euphoria
• Antiemetic effect of CESAMET is not diminished with repeat use
• No drug interactions were found in clinical trials with cancer
patients on a variety of medications (e.g., antineoplastic,
antibiotic, analgestic or anti-inflammatory agents)
• Nabilone and prochlorperazine may be co-administered
Co-administration reduced nabilone-associated CNS effects1
1. CESAMETTM (nabilone) Package Inser. Valeant Pharmaceuticals North America.
49
Role of CESAMET
in Therapy
Role of CESAMET in CINV Therapy
and Expected Outcomes1
• Second-line therapy
CESAMET should be used as an additive, second-line agent
in patients who fail to respond adequately to first-line
antiemetic regimens
• Expected outcomes of CESAMET therapy
Clinically effective treatment of CINV
CESAMET may also improve appetite in CINV patients
1. CESAMETTM (nabilone) Package Insert. Valeant Pharmaceuticals North America.
51
Principles of Emesis Control
• First-line antiemetic therapy is not always effective in preventing
acute emesis1
• Knowledge of anticipated severity of emesis and use of algorithms that
determine emetogenicity of chemotherapeutic regimens assist in the
selection of most appropriate treatment regimens1
• Breakthrough or refractory emesis is generally treated by adding
an agent from a different drug class
• Practice guidelines in cancer patients include:2
Goal is prevention of CINV
Treat throughout full period of risk; at least 4 days in patients receiving moderate-/high-risk
chemotherapy
Lowest efficacious dose before chemo- or radiation therapy
Choose antiemetic(s) based on emetic risk, patient factors, toxicity of antiemetic agents
Oral and IV agents are equally effective;
oral formulations are preferred first-line agents3
1. Centers for Medicare & Medicaid Services. http://www.cms.hhs.gov, accessed 6/05. 2. National Comprehensive Cancer Network. Antiemesis: Clinical practice guidelines in
oncology. 2005;1:page nos?. 3. Gralla RJ, et al. Recommendations for the use of antiemetics: evidence-based, clinical practice guidelines. Adopted by the American Society
of Clinical Oncology. J Clin Oncol. 1999;17(9):2971-2994.
52
Alternate Pharmacological Treatments1
Therapy
Mechanism of Action
• Prochlorperazine is perhaps the most
D2 and 5-HT3 Antagonists
• Prochlorperazine, metoclopramide,
• Competitive dopamine D2
• Ondansetron, granisetron,
• Serotonin 5-HT3 receptor
droperidol, haloperidol
dolasetron, palonsetron
Use in CINV
receptor antagonists
antagonists
frequently used antiemetic
• 5-HT3 antagonists have fewer adverse
effects, and are generally more
efficacious than D2 antagonists2
• No single antiemetic agent is completely
effective in all patients
Corticosteroids
Dexamethasone, methylprednisolone
Adjunct Antiemetic4
Aprepitant
Thought to work by reducing
arginine vasopressin levels or
modulating prostaglandin release3
Prophylaxis and treatment for mild to
moderate emetogenic CINV
Substance P/Neurokinin-1 (NK1)
receptor antagonist
• Aprepitant prevents and controls acute
and delayed CINV
• Aprepitant augments the antiemetic
activity of 5-HT3 antagonists and
dexamethasone
Cannabinoid
Dronabinol
Benzodiazepines
Lorazepam, alprazolam
Dronabinol’s action on cannabinoid
receptors in neural tissues is
thought to play a role5
Dronabinol is as or more effective than
prochlorperazine and metoclopramide
(both D2 antagonists)6
Believed to act on the GABA-A
receptor, activation of which
dampens higher neuronal activity
Valuable adjuncts in prevention and
treatment of anxiety and anticipatory CINV
1. National Cancer Institute. http://www.meds.com/pdq/supportive_pro.html, accessed 6/05. 2. Gralla RJ, et al. Recommendations for the use of antiemetics: evidence-based, clinical practice
guidelines. Adopted by the American Society of Clinical Oncology. J Clin Oncol. 1999;17(9):2971-2994. 3. Berger, AM, Clark-Snow RA. Adverse Effects of Treatment. Cancer: Principles and
Practice of Oncology, 6th ed. Lippincott, Williams and Wilkins;2001:2869-2880. 4. National Comprehensive Cancer Network. Antiemesis: Clinical practice guidelines in oncology. 2005;1:page nos?.
5. MARINOL® (dronabinol) Package Insert. Solvay Pharmaceuticals, Inc. 6. Kumar RN, Chambers WA, Pertwee RG. Pharmacological actions and therapeutic uses of cannabis and cannabinoids.
Anesthesia. 2001;56:1059-1068.
53
CESAMET
Product Value and Overview
Product Value
• CINV occurs in 70% to 80% of all patients receiving chemotherapy,1 and an
estimated 30% of patients receiving moderately or highly emetogenic
agents will continue to have acute nausea/vomiting despite antiemetic
treatment2
• CINV can significantly impact patients’ lives and their ability to combat
cancer, as it can result in:1
Metabolic imbalances; nutrient depletion; anorexia
Impaired function and negative impact on self-care;
decline of patient’s performance and mental status
Wound dehiscence
Esophageal tears
Non-compliance with or withdrawal from potentially
useful or curative anticancer treatment
• Cesamet provides an important alternative treatment, with an MOA
different from conventional antiemetics3,4
• Cesamet given orally and B.I.D., offers convenience
1. Berger, AM, Clark-Snow RA. Adverse Effects of Treatment. Cancer: Principles and Practice of Oncology, 6th ed. Lippincott, Williams and Wilkins;2001:2869-2880. 2.
Carlson R. Better anti-emetic regimens still needed. Oncology Times 2001; 23: 19-23. 3. Tramer MR, et al. Cannabinoids for control of chemotherapy induced nausea and
vomiting: quantitative systematic review. Br Med J. 2001;323:1-8. 4. National Comprehensive Cancer Network. Antiemesis: Clinical practice guidelines in oncology.
2005;1:page nos?.
55
Product Overview
• Synthetic cannabinoid for oral administration1
• MOA differs from conventional antiemetics2,3
Acts as Omnineuromodulator
4-9
• Efficacious for CINV1
Favorable safety profile1
Predictable pharmacokinetics1
Convenient and easy to use1
• Improved appetite in CINV patients in clinical trials1
• No drug interactions were found in clinical trials with cancer
patients on a variety of medications (e.g., antineoplastic,
antibiotic, analgestic or anti-inflammatory agents)1
1. CESAMETTM (nabilone) Package Insert. Valeant Pharmaceuticals North America. 2. Tramer MR, et al. Cannabinoids for control of chemotherapy induced nausea and
vomiting: quantitative systematic review. Br Med J. 2001;323:1-8. 3. National Comprehensive Cancer Network. Antiemesis: Clinical practice guidelines in oncology.
2005;1:page nos?. 4. Data on File, Valeant Pharmaceuticals North America (The science behind Omnineuromodulation presentation and the trademark work). 5. Howlett AC,
et al. Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharm. 2004;47(suppl 1):345-358. 6. Croxford JL. Therapeutic potential of cannabiniods in
CNS disease. CNS Drugs. 2003;17(3):179-202. 7. Joy JE, et al. Marijuana and Medicine: Assessing the science base. National Academy Press; 1999:156. 8. Howlett AC, et
al. International union of pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev. 2002;54(2):161-202. 9. Martin BR. Cellular effects of cannabiniods.
Pharmacol Rev. 1986;38(1): 45-47.
56
CESAMET
TM
(Nabilone)
Please see full Prescribing Information,
including Indications and Usage,
Contraindications, Warnings,
Precautions, and Adverse Events
CesametTM is a registered trademark of Valeant
Pharmaceuticals North America. ©2006 Valeant
Pharmaceuticals. All Rights Reserved. 01/06