CESAMET TM (Nabilone) Innovations in Omnineuromodulation TM for Chemotherapy-Induced Nausea and Vomiting Cesamet TM is a trademark of Valeant Pharmaceuticals

CESAMETTM

(Nabilone)

Innovations in OmnineuromodulationTM for Chemotherapy-Induced Nausea and Vomiting

CESAMETTM

(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.

CesametTM is a trademark of Valeant Pharmaceuticals International. ©2006 Valeant Pharmaceuticals International. All Rights Reserved.

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Table of Contents

• CESAMET Product Profile • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • Slides 4-6Indications and Usage Dosage and Administration

• CESAMET Pharmacology • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • Slides 7-10Nabilone Clinical PharmacologyPharmacokinetic Overview of Available CannabinoidsPharmacology Conclusions

• CINV Overview • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • Slides 11-16Epidemiology and Risk FactorsClinical PresentationEmetogenic Potential for ChemotherapyPathophysiology

• CESAMET’s Mechanism of Action • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • Slides 17-24Distinct Therapeutic MechanismUbiquitous CB1OmnineuromodulationMechanism of Action Conclusions

• CESAMET Clinical Efficacy • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • Slides 25-34Pivotal Efficacy TrialsClinical Trial DesignComposite Efficacy EvaluationPlacebo-Controlled, Fixed-Dose TrialsActive-Controlled, Fixed-Dose TrialsActive-Controlled, Flexible-Dose TrialsEfficacy Conclusions

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Table of Contents

• CESAMET Safety and Tolerability • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • Slides 35-47

Important Safety InformationOther Nontherapeutic EffectsMost Common Adverse Events Adverse Events vs. Dose in CESAMET Clinical TrialsComparative Incidence of Adverse Events in CESAMET Clinical Trials Drug Interactions Published Drug InteractionsPregnancy Category CPediatric and Geriatric UseSafety and Tolerability Conclusions

• Role of CESAMET in Therapy • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • Slides 48-51

Role of CESAMET in CINV Therapy and Expected OutcomesPrinciples of Emesis ControlAlternate Pharmacological Treatments

• CESAMET Product Value and Overview • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • Slides 52-54

Product ValueProduct Overview

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Cesamet (Nabilone) Product Profile

• Synthetic cannabinoid for oral administration1

• Different mechanism of action (MOA) from conventional antiemetics2,3

Acts as OmnineuromodulatorTM4-9

• Efficacious for chemotherapy-induced nausea and vomiting (CINV)1

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

Synthetic Analog of ∆9-THCSynthetic Analog of ∆9-THC

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.

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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.

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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.


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Dosage and Administration1

• Convenient B.I.D. dosingUsual 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


CESAMET Pharmacology CESAMET Pharmacology

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Nabilone Clinical Pharmacology1

• PharmacodynamicsLong 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


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Overview of Available Cannabinoids1,2

1. CESAMETTM (nabilone) Package Insert. Valeant Pharmaceuticals North America. 2. MARINOL® (dronabinol) Package Insert. Solvay Pharmaceuticals, Inc.

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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.

CINV OverviewCINV Overview

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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.

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

http://www.cancer.org/

http://www.meds.com/pdq/supportive_pro.html

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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.

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Emetogenic Potential of Chemotherapy1,2

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?.


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• 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

CINV Pathophysiology

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.

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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.

CESAMETMechanism of Action: Omnineuromodulation

CESAMETMechanism of Action: Omnineuromodulation

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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.


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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.

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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

1. Neurotransmitter (NT) released from vesicles within the presynaptic neuron activates the postsynaptic neuron

2. Activation of the postsynaptic neuron leads to the biosynthesis and nonvesicular release of an endocannabinoid

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

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4433

•The Nucleus of the Solitary Tract (NTS) receives information about:

Blood-borne emetics via the brainstem (BS) CTZAbdominal irritants via vagal afferents

•NTS neurons, in turn, project to a BS central pattern generator, which coordinates emesis behavior

•Higher cortical and limbic 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

Dorsal Vagal Complex—NTSDorsal Vagal Complex—NTS

Brainstem Emetic

Circuitry

Brainstem Emetic

Circuitry

Cortex Limbic System

Cortex Limbic System

•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

•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

•Cannabinoids also increase motivation to eat through interaction with the dopamine and opioid systems in the Reward Path1,3

Hypothalamus Feeding Circuitry

Hypothalamus Feeding Circuitry

Nucleus Accumbens Reward Path

Nucleus Accumbens Reward Path

Ventral Tegmental Area (VTA)

Ventral Tegmental Area (VTA)

Leptin HormoneLeptin Hormone

1. Cota et al, 20032. Harrold and Williams, 20033. Fride et al, 2005

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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.


CESAMET Clinical EfficacyCINV Reduction and Appetite Improvement

CESAMET Clinical EfficacyCINV Reduction and Appetite Improvement

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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.

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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)

1. CESAMETTM (nabilone) Package Insert. Valeant Pharmaceuticals North America. 2. Data on File: Protocol 7, 9, 20, 28. Valeant Pharmaceuticals North America.

1-5 daysChemotherapy 1

1-5 daysChemotherapy 2

2-6 weeks OptionalOpen-label

CESAMET CESAMET

Control Drug Control Drug

*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.

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Composite Efficacy Evaluation1

2.2

1.11.3

4.5

0.6

10.8

0

2

4

6

8

10

VomitFrequency

NauseaSeverity

Food Intake

CESAMET

Placebo

Placebo-Controlled, Fixed-Dose Trials

N=129*P ≤0.01 †P ≤0.001

*

† †1.0

5.3

1.31.8

0.9

9.6

0

2

4

6

8

10

VomitFrequency

NauseaSeverity

Food Intake

CESAMET

Prochlorperazine

Active-Controlled, Fixed-Dose Trials

N=75‡P ≤0.007§P ≤0.012

‡

‡ §

Values plotted are based on the means of the average daily scores by the patient’s observations.


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Placebo-Controlled, Fixed-Dose Trials1

Primary Endpoint: Patient-Rated Efficacy Criteria

1. Data on File: Protocol 28. Valeant Pharmaceuticals North America.

Both Cycles Combined

Frequency of Vomits Severity of Nausea Food Intake

Average Day 1 Average Day 1 Average Day 1

CESAMETInvestigator 01 8.55 8.55 2.29 2.27 0.55 0.55Investigator 02 4.16 5.58 1.19 1.45 0.84 0.75Investigator 03 10.27 15.20 1.73 2.00 1.20 1.20Investigator 04 2.33 2.33 1.75 1.75 1.00 1.00Investigator 05 2.97 2.97 1.03 1.03 1.28 1.28Investigator 06 4.53 4.53 1.25 1.25 1.33 1.33Composite 4.51 5.09 1.31 1.39 1.10 1.09

PlaceboInvestigator 01 13.73 13.73 2.89 2.91 0.38 0.36Investigator 02 13.05 15.03 2.08 2.39 0.63 0.61Investigator 03 34.60 36.80 2.67 2.80 0.40 3.40Investigator 04 14.83 14.83 2.75 2.75 0.63 0.63Investigator 05 7.47 7.47 2.25 2.25 0.50 0.50Investigator 06 6.87 6.86 2.06 2.06 0.92 0.92Composite 10.81 11.43 2.25 2.34 0.64 0.64

Number of vomitsNausea severity: 0=none, 1=mild, 2=moderate, 3=severeFood intake: 0=none, 1=less than usual, 2=usual amount or average, 3=more than usual

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Primary Endpoint: Investigator-Related Efficacy and Adverse Events

Placebo-Controlled, Fixed-Dose Trials1

• 77% of evaluable patients preferred nabilone treatment

• 12% preferred placebo treatment

• 12% indicated no preference


Efficacy: 1=very good, 2=good, 3=fair, 4=poor, 5=very poorSafety: Based on the frequency of adverse events

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Active-Controlled, Fixed-Dose Trials1



Both Cycles Combined

Frequency of Vomits Severity of Nausea Food Intake

Average Day 1 Average Day 1 Average Day 1CESAMET

Investigator 301 7.85 7.85 1.38 1.38 1.16 1.16Investigator 302 3.24 6.47 1.29 1.58 0.99 1.06Investigator 306 7.00 7.00 1.29 1.29 0.86 0.86

Composite 5.43 7.07 1.33 1.47 1.05 1.08Prochlorperazine

Investigator 301 7.96 7.96 1.72 1.72 1.00 1.00Investigator 302 9.08 12.59 1.78 1.94 0.80 0.86Investigator 306 20.33 20.33 1.71 1.71 0.71 0.71

Composite 9.64 11.42 1.75 2.83 0.88 0.91


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• 73.3% of evaluable patients preferred CESAMET treatment

• 20% preferred prochlorperazine treatment

• 6.7% indicated no preference

Primary Endpoint: Investigator-Rated Efficacy and Safety

Active-Controlled, Fixed-Dose Trials1


Efficacy: 1=very good, 2=good, 3=fair, 4=poor, 5=very poorSafety: Based on the frequency of adverse events

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Active-Controlled, Flexible-Dose Trial1




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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.


CESAMETSafety and Tolerability CESAMETSafety and Tolerability

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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 periodAdverse 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


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• 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


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• 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


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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 resistanceThis effect has not been observed in asthmatic patients

1. CESAMETTM (nabilone) Package Inser. Valeant Pharmaceuticals North America.

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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


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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


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Comparative Incidence of Adverse Events in CESAMET Clinical Trials1

Incidence of Adverse Events in Placebo-Controlled Studies


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Comparative Incidence of Adverse Events in CESAMET Clinical Trials1

Incidence of Adverse Events in Active-Controlled Studies


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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


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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 year-old 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

AlcoholIncrease in the positive subjective mood effects of smoked marijuana


47

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


48

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 oldGenerally 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


49

Safety and Tolerability Conclusions1

• Cesamet is safe for the treatment of CINV in cancer patients receiving a wide range of chemotherapy regimens, including low-dose 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-administeredCo-administration reduced nabilone-associated CNS effects1

1. CESAMETTM (nabilone) Package Inser. Valeant Pharmaceuticals North America.

Role of CESAMET in TherapyRole of CESAMET in Therapy

51

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


52

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.

http://www.cms.hhs.gov/

53

Alternate Pharmacological Treatments1

Therapy Mechanism of Action Use in CINV

D2 and 5-HT3 Antagonists

• Prochlorperazine, metoclopramide, droperidol, haloperidol

• Ondansetron, granisetron, dolasetron, palonsetron

• Competitive dopamine D2 receptor antagonists

• Serotonin 5-HT3 receptor antagonists

• Prochlorperazine is perhaps the most 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

CorticosteroidsDexamethasone, methylprednisolone

Thought to work by reducing arginine vasopressin levels or modulating prostaglandin release3

Prophylaxis and treatment for mild to moderate emetogenic CINV

Adjunct Antiemetic4

Aprepitant

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

CannabinoidDronabinol

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

BenzodiazepinesLorazepam, alprazolam

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.


CESAMET

Product Value and OverviewCESAMET

Product Value and Overview

55

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?.

56

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.

CESAMETTM

(Nabilone)CESAMETTM

(Nabilone)

Please see full Prescribing Information, including Indications and Usage, Contraindications, Warnings, Precautions, and Adverse Events

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

CesametTM is a registered trademark of Valeant Pharmaceuticals North America. ©2006 Valeant Pharmaceuticals. All Rights Reserved. 01/06

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CESAMET TM (Nabilone) Innovations in Omnineuromodulation TM for Chemotherapy-Induced Nausea and Vomiting Cesamet TM is a trademark of Valeant Pharmaceuticals