1. CESAMET TM (Nabilone) Innovations in Omnineuromodulation TM for Chemotherapy-Induced Nausea and Vomiting Cesamet TM is a trademark of Valeant Pharmaceuticals International. ©2006 Valeant Pharmaceuticals International. All Rights Reserved. Cesamet TM is a trademark of Valeant Pharmaceuticals International. ©2006 Valeant Pharmaceuticals International. All Rights Reserved.

2. 2 Table of Contents CESAMET Product Profile Slides 4-6 Indications and Usage Dosage and Administration CESAMET Pharmacology Slides 7-10 Nabilone Clinical Pharmacology Pharmacokinetic Overview of Available Cannabinoids Pharmacology Conclusions CINV Overview Slides 11-16 Epidemiology and Risk Factors Clinical Presentation Emetogenic Potential for Chemotherapy Pathophysiology CESAMET’s Mechanism of Action Slides 17-24 Distinct Therapeutic Mechanism Ubiquitous CB1 Omnineuromodulation Mechanism of Action Conclusions CESAMET Clinical Efficacy Slides 25-34 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

3. 3 Table of Contents CESAMET Safety and Tolerability 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 Role of CESAMET in Therapy Slides 48-51 Role of CESAMET in CINV Therapy and Expected Outcomes Principles of Emesis Control Alternate Pharmacological Treatments CESAMET Product Value and Overview Slides 52-54 Product Value Product Overview

4. 4 Cesamet (Nabilone) Product Profile Synthetic cannabinoid for oral administration 1 Different mechanism of action (MOA) from conventional antiemetics 2,3 Acts as Omnineuromodulator TM 4 - 9 Efficacious for chemotherapy-induced nausea and vomiting (CINV) 1 Favorable safety profile 1 Predictable pharmacokinetics 1 Convenient and easy to use 1 Improved appetite in CINV patients in clinical trials 1 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 -THC 1. CESAMET TM (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.

5. 5 Indications and Usage 1 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. CESAMET TM (nabilone) Package Insert. Valeant Pharmaceuticals North America.

6. 6 Safety Statement 1 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. CESAMET TM (nabilone) Package Insert. Valeant Pharmaceuticals North America.

7. 7 Dosage and Administration 1 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. CESAMET TM (nabilone) Package Insert. Valeant Pharmaceuticals North America.

8. CESAMET Pharmacology

9. 9 Nabilone Clinical Pharmacology 1 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. CESAMET TM (nabilone) Package Insert. Valeant Pharmaceuticals North America.

10. 10 Overview of Available Cannabinoids 1,2 1. CESAMET TM (nabilone) Package Insert. Valeant Pharmaceuticals North America. 2. MARINOL ® (dronabinol) Package Insert. Solvay Pharmaceuticals, Inc.

11. 11 CESAMET Pharmacology Conclusions CESAMET, an oral medication, possesses a long duration of action, which allows for easy B.I.D. dosing 1,2 Nabilone has predictable pharmacokinetics, 1 which may allow for a more predictable patient response to treatment 1. CESAMET TM (nabilone) Package Insert. Valeant Pharmaceuticals North America. 2. MARINOL ® (dronabinol) Package Insert. Solvay Pharmaceuticals, Inc.

12. CINV Overview

13. 13 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.http://www.cancer.org, http://www.meds.com/pdq/supportive_pro.html, CINV Epidemiology and Risk Factors CINV occurs in 70% to 80% of all patients receiving chemotherapy 1 Approximately 1.37 million new cancer cases were reported in 2004 2 An estimated 30% of patients receiving moderately or highly emetogenic agents will continue to have acute nausea/vomiting, even following antiemetic prophylaxis 3 Primary Risk Factor 4,5 Emetogenicity of the chemotherapeutic regimen Additional Risk Factors 5 Female gender Younger age (age <50 years) Susceptibility to motion sickness History of alcoholism

14. 14 CINV Clinical Presentation 1 Emetic SyndromesCharacterization 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.

15. 15 Emetogenic Potential of Chemotherapy 1,2 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?.http://www.meds.com/pdq/supportive_pro.html,

16. 16 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.

17. 17 CINV Pathophysiology Neurotransmitters and receptors involved: Serotonin (5-HT) and dopamine (DA) acting on 5-HT 3 and D 2 receptors are involved in signaling peripheral stimuli to the brainstem emetic circuitry, which may lead to emesis 1,2 5-HT and 5-HT 3 receptors play a major role in acute phase CINV 1 Substance P, a neuropeptide found in the GI tract and the CTZ, and its Neurokinin-1 (NK 1 ) receptors are thought to be important in acute and delayed CINV 1 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.

18. CESAMET Mechanism of Action: Omnineuromodulation

19. 19 Distinct Therapeutic Mechanism Cesamet has an MOA different from conventional antiemetics (e.g., 5-HT 3 or D 2 receptor antagonists) 1-3 The antiemetic effect of nabilone is thought to be due to interaction with cannabinoid CB1 receptors found in neural tissues 4 Cesamet acts as an OMNINEUROMODULATOR 5-10 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 CINV 3 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. http://www.meds.com/pdq/supportive_pro.html

20. 20 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 receptors 1 Endocannabinoids also activate CB2 receptors, mainly located on immune cells in the periphery 2 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.

21. 21 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

22. 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 5 5 1 1 2 2 4 4 3 3

23. 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 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-HT 3 and D 2 receptors are implicated Dorsal Vagal Complex—NTS Brainstem Emetic Circuitry Cortex Limbic System

24. 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 hormone 1-2 Cannabinoids also increase motivation to eat through interaction with the dopamine and opioid systems in the Reward Path 1,3 Hypothalamus Feeding Circuitry Nucleus Accumbens Reward Path Ventral Tegmental Area (VTA) Leptin Hormone 1. Cota et al, 2003 2. Harrold and Williams, 2003 3. Fride et al, 2005

25. 25 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 antiemetics 1-3 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.http://www.meds.com/pdq/supportive_pro.html

26. CESAMET Clinical Efficacy CINV Reduction and Appetite Improvement

27. 27 CESAMET Pivotal Efficacy Trials 1 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 efficacy 2 1. CESAMET TM (nabilone) Package Insert. Valeant Pharmaceuticals North America. 2. Data on File: Protocol 20 and 28. Valeant Pharmaceuticals North America.

28. 28 Double-blind, Crossover Clinical Trial Design 1,2 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. CESAMET TM (nabilone) Package Insert. Valeant Pharmaceuticals North America. 2. Data on File: Protocol 7, 9, 20, 28. Valeant Pharmaceuticals North America. 1-5 days Chemotherapy 1 1-5 days Chemotherapy 2 2-6 weeksOptional Open-label CESAMET 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.

29. 29 Composite Efficacy Evaluation 1 2.2 1.1 1.3 4.5 0.6 10.8 0 2 4 6 8 10 Vomit Frequency Nausea Severity Food Intake CESAMET Placebo Placebo-Controlled, Fixed-Dose Trials N=129 * P ≤0.01 † P ≤0.001 * † † 1.0 5.3 1.3 1.8 0.9 9.6 0 2 4 6 8 10 Vomit Frequency Nausea Severity 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. 1. CESAMET TM (nabilone) Package Insert. Valeant Pharmaceuticals North America.

30. 30 Placebo-Controlled, Fixed-Dose Trials 1 Primary Endpoint: Patient-Rated Efficacy Criteria 1. Data on File: Protocol 28. Valeant Pharmaceuticals North America. 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

31. 31 Primary Endpoint: Investigator-Related Efficacy and Adverse Events Placebo-Controlled, Fixed-Dose Trials 1 77% of evaluable patients preferred nabilone treatment 12% preferred placebo treatment 12% indicated no preference 1. Data on File: Protocol 28. Valeant Pharmaceuticals North America. Efficacy: 1=very good, 2=good, 3=fair, 4=poor, 5=very poor Safety: Based on the frequency of adverse events

32. 32 Active-Controlled, Fixed-Dose Trials 1 1. Data on File: Protocol 20. Valeant Pharmaceuticals North America. Primary Endpoint: Patient-Rated Efficacy Criteria 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

33. 33 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 Trials 1 1. Data on File: Protocol 20. Valeant Pharmaceuticals North America. Efficacy: 1=very good, 2=good, 3=fair, 4=poor, 5=very poor Safety: Based on the frequency of adverse events

34. 34 Active-Controlled, Flexible-Dose Trial 1 Primary Endpoint: Patient-Rated Efficacy Criteria 1. Data on File: Protocol 9. Valeant Pharmaceuticals North America. 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

35. 35 Efficacy Conclusions Cesamet is effective in controlling CINV, and was shown to increase food intake by cancer patients in clinical trials 1-4 Cesamet is superior to prochlorperazine in controlling CINV 1,3,4 Majority of patients prefer Cesamet over placebo 2 and prochlorperazine 3 Cesamet is effective in patients receiving cisplatin, 1-4 which has severe emetogenic potential 5 1. CESAMET TM (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.http://www.meds.com/pdq/supportive_pro.html,

36. CESAMET Safety and Tolerability

37. 37 Important Safety Information 1 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. CESAMET TM (nabilone) Package Insert. Valeant Pharmaceuticals North America.

38. 38 Important Safety Information 1 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. CESAMET TM (nabilone) Package Insert. Valeant Pharmaceuticals North America.

39. 39 Important Safety Information 1 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. CESAMET TM (nabilone) Package Insert. Valeant Pharmaceuticals North America.

40. 40 Other Nontherapeutic Effects 1 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. CESAMET TM (nabilone) Package Inser. Valeant Pharmaceuticals North America.

41. 41 Most Common Adverse Events 1 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. CESAMET TM (nabilone) Package Insert. Valeant Pharmaceuticals North America.

42. 42 Adverse Events vs. Dose in CESAMET Clinical Trials 1 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 1. CESAMET TM (nabilone) Package Insert. Valeant Pharmaceuticals North America.

43. 43 Comparative Incidence of Adverse Events in CESAMET Clinical Trials 1 Incidence of Adverse Events in Placebo-Controlled Studies 1. CESAMET TM (nabilone) Package Insert. Valeant Pharmaceuticals North America.

44. 44 Comparative Incidence of Adverse Events in CESAMET Clinical Trials 1 Incidence of Adverse Events in Active-Controlled Studies 1. CESAMET TM (nabilone) Package Insert. Valeant Pharmaceuticals North America.

45. 45 Drug Interactions 1 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. CESAMET TM (nabilone) Package Insert. Valeant Pharmaceuticals North America.

46. 46 Published Drug Interactions 1 Concomitant DrugClinical Effect(s) Amphetamines, cocaine, other sympathomimetic agentsAdditive 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 OpioidsCross-tolerance and mutual potentiation NaltrexoneOral THC effects were enhanced by opioid receptor blockade Alcohol Increase in the positive subjective mood effects of smoked marijuana 1. CESAMET TM (nabilone) Package Insert. Valeant Pharmaceuticals North America.

47. 47 Pregnancy Category C 1 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. CESAMET TM (nabilone) Package Insert. Valeant Pharmaceuticals North America.

48. 48 Pediatric and Geriatric Use 1 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. CESAMET TM (nabilone) Package Insert. Valeant Pharmaceuticals North America.

49. 49 Safety and Tolerability Conclusions 1 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-administered Co-administration reduced nabilone-associated CNS effects 1 1. CESAMET TM (nabilone) Package Inser. Valeant Pharmaceuticals North America.

50. Role of CESAMET in Therapy

51. 51 Role of CESAMET in CINV Therapy and Expected Outcomes 1 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. CESAMET TM (nabilone) Package Insert. Valeant Pharmaceuticals North America.

52. 52 Principles of Emesis Control First-line antiemetic therapy is not always effective in preventing acute emesis 1 Knowledge of anticipated severity of emesis and use of algorithms that determine emetogenicity of chemotherapeutic regimens assist in the selection of most appropriate treatment regimens 1 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 agents 3 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. 53 Alternate Pharmacological Treatments 1 TherapyMechanism of ActionUse in CINV D 2 and 5-HT 3 Antagonists Prochlorperazine, metoclopramide, droperidol, haloperidol Ondansetron, granisetron, dolasetron, palonsetron Competitive dopamine D 2 receptor antagonists Serotonin 5-HT 3 receptor antagonists Prochlorperazine is perhaps the most frequently used antiemetic 5-HT 3 antagonists have fewer adverse effects, and are generally more efficacious than D 2 antagonists 2 No single antiemetic agent is completely effective in all patients Corticosteroids Dexamethasone, methylprednisolone Thought to work by reducing arginine vasopressin levels or modulating prostaglandin release 3 Prophylaxis and treatment for mild to moderate emetogenic CINV Adjunct Antiemetic 4 Aprepitant Substance P/Neurokinin-1 (NK 1 ) receptor antagonist Aprepitant prevents and controls acute and delayed CINV Aprepitant augments the antiemetic activity of 5-HT 3 antagonists and dexamethasone Cannabinoid Dronabinol Dronabinol’s action on cannabinoid receptors in neural tissues is thought to play a role 5 Dronabinol is as or more effective than prochlorperazine and metoclopramide (both D 2 antagonists) 6 Benzodiazepines Lorazepam, 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.http://www.meds.com/pdq/supportive_pro.html,

54. CESAMET Product Value and Overview

55. 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 treatment 2 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 antiemetics 3,4 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. 56 Product Overview Synthetic cannabinoid for oral administration 1 MOA differs from conventional antiemetics 2,3 Acts as Omnineuromodulator 4-9 Efficacious for CINV 1 Favorable safety profile 1 Predictable pharmacokinetics 1 Convenient and easy to use 1 Improved appetite in CINV patients in clinical trials 1 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. CESAMET TM (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.

57. CESAMET TM (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 Cesamet TM is a registered trademark of Valeant Pharmaceuticals North America. ©2006 Valeant Pharmaceuticals. All Rights Reserved. 01/06