Study No: LOV OMA-104 Title : Rationale: Phase: Study Period: Study Design: Centres: Indication: Treatment: Objectives: Statistical Methods

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1 The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. Study No: LOV OMA-104 Title : A Pharmacokinetic Interaction Study Evaluating the Effect of Lovaza on Plasma Pharmacokinetics of Zocor in Healthy Adult Volunteers Under Fasting Conditions Rationale: Some prescribers may add omega-3-acid ethyl esters to existing simvastatin therapy. The objective of this trial was to investigate the effect of concomitant dosing with Lovaza (omega-3-acid ethyl esters) (prescription omega-3-acid ethyl esters, appearing hereafter as POM) and Zocor (simvastatin) on the pharmacokinetic profile of simvastatin and its active betahydroxy metabolite in healthy adult volunteers. Phase: Phase1 Study Period: Date of first enrollment 13 March 2005 (Date of last completed) 27 April 2005 Study Design: This was an open-label, randomized, repeat dose 2-way crossover drug interaction study that evaluated single-dose and steady-state simvastatin kinetics under fasting conditions. The study consisted of two 14-day dosing periods separated by a washout period of at least 14 days. Subjects were randomized to receive daily morning oral doses of either 4 g (4 capsules) of POM coadministered with 80 mg (1 tablet) simvastatin (the test treatment) or 80 mg (1 tablet) simvastatin alone (the reference treatment) during the one 14-day dosing period. During the other 14-day dosing period, subjects received the alternate treatment. Centres: MDS Pharma Services 4747 East Beautiful Lane Phoenix, Arizona Indication: Healthy adult volunteers to assess the impact on simvastatin Treatment: Treatment A consisted of an oral dose of 4 POM 1 g capsules and 1 simvastatin 80 mg tablet coadministered with 240 ml of water on Days Treatment B consisted of an oral dose of 1 simvastatin 80 mg tablet administered with 240 ml of water on Days Objectives: The objective of this study was to determine the impact of POM capsules (4 gram dose) on the steady-state plasma pharmacokinetics of simvastatin and its beta-hydroxy metabolite from simvastatin 80 mg tablets Statistical Methods: Samples from Subjects 1-24 were assayed if the subjects completed at least 1 period of the study. In addition, concentration data from dropouts due to AEs were recorded in the final report. Data from Subjects 1-24 were included in the statistical analysis if the subjects completed at least 1 period of the study. Pharmacokinetics: Relative Bioavailability Analysis Analyses of variance (ANOVA) were performed on the Day 1 ln-transformed AUC0-t, AUCinf, and Cmax, and the n-transformed AUCτ and Cmax. The ANOVA model included sequence, treatment, and period as fixed effects, and subject nested within sequence as a random effect. Ratios of least-squares means (LSM) were calculated using the exponentiation of the LSM from the analyses on the ln-transformed PK parameters. Ninety percent (90%) confidence intervals (CI) for the ratios were derived by exponentiation of the CI obtained for the difference between treatment LSM resulting from the analyses on the ln-transformed PK parameters. The ratios and CI were expressed as a percentage relative to the reference treatment (Treatment B; simvastatin administered alone). Steady-State Analysis A steady-state analysis was performed on the ln-transformed predose Cmin concentrations, at Days 12, 13, and 14, using Helmert s Con trasts. Steady state was concluded if Helmert s contrasts were not statistically significant on at least 3 Cmin values, at a level of 5%. 1

2 Time Dependence Pharmacokinetic Linearity The PK parameter AUCτ () was compared against AUCinf (Day 1) using an ANOVA on the ln-transformed values. The final ANOVA model included treatment, day, period, sequence, and treatment day as fixed effects and subject-nested-within sequence as a random effect. The ratio of means and 90% CI were presented by treatment and expressed as a percentage relative to AUCinf (Day 1). Continued Study Population: Eligible subjects were healthy male or female volunteers, aged 18 to 55 years and within 15% of ideal weight according to the 1983 Metropolitan Life Insurance Tables. Subjects were required to be nonsmokers for at least 3 months before study entry. Female subjects were required to be past menopause by more than 2 years, sexually abstinent, or using an acceptable method of birth control. Persons with a history of hypersensitivity or idiosyncratic reaction to HMG-CoA reductase inhibitors or lipid-regulating agents, or allergy or sensitivity to fish, were ineligible. Persons who had used drugs or substances known to be strong inhibitors or inducers of CYP enzymes within 10 days (inhibitors) or 28 days (inducers) of the first dose also were excluded. Medications (other than hormonal contraceptives and hormone replacement therapy), herbal products, and vitamins were not to be taken within 7 days of the first dose and during the course of the study. Consumption of substances containing xanthines or caffeine, alcohol, or grapefruit was disallowed 24 hours, 48 hours, or 10 days, respectively, before the first dose and during the course of the study. Before any study procedures, each subject provided written informed consent. Number of Subjects: Overall Planned N 24 Dosed N 24 Completed n (%) 23 (95.8) Total Number Subjects Withdrawn N (%) 1(4.1) Withdrawn due to Adverse Events n (%) 1(4.1) Withdrawn due to Lack of Efficacy n (%) 0 (0) Withdrawn for Other Reasons n (%) 0 (0) Demographics Overall N 24 Females: Males n:n 4:20 Mean Age in Years (sd) 30 (9) Mean Weight in Kg (sd) 67.7 (7.6) Mean Height in cm (sd) 171 (8) Hispanic n (%) 20 (83.3) Pharmacokinetic Results: The PK parameters, relative bioavailability, steady state, and time dependence PK linearity results are presented in the following tables. PK s for and Following Oral Doses Geometric Mean (CV%) 2

3 Day 1 AUC0-t (72.4) 81.7 (79.7) 43.2 (68.7) 38.6 (72.9) AUCinf (69.3) 84.6 (77.0) 53.0 (67.8) 43.9 (77.4) Cmax 17.3 (71.5) 14.7 (64.3) 4.37 (78.0) 4.02 (71.1) AUCτ (58.0) (54.3) 73.2 (55.9) 73.7 (56.3) Cmax 13.8 (50.2) 12.2 (49.7) 5.15 (64.7) 5.29 (60.5) PK s for and Following Oral Doses Arithmetic Mean (±SD) Day 1 tmax (h) 2.12 (2.64) 1.74 (1.48) 5.84 (2.29) 5.72 (2.87) t½ (h) 5.96 (1.38) 5.64 (1.92) 9.00 (3.53) 6.42 (3.03) CL/F (L/h) 880 (700) 1181 (887) NC NC Varea/F (L) 7901 (7292) 8978 (6222) NC NC tmax (h) 2.35 (2.63) 2.58 (1.87) 5.52 (2.32) 5.60 (1.99) Cavg,ss 5.21 (2.62) 4.86 (2.67) 3.46 (1.76) 3.50 (1.85) (ng/ml) Cmin (ng/ml) 1.95 (1.61) 1.98 (1.66) 1.83 (1.31) 1.79 (1.26) t½ (h) 7.39 (1.62) 9.92 (5.53) 9.49 (5.76) 9.44 (5.86) Flux1 (%) 292 (151) 271 (132) 146 (62.3) 160 (52.4) Flux2 (%) 1135 (1045) 1021 (946) 395 (362) 467 (459) CLss/F (L/h) 838 (477) 872 (402) NC NC R (Accumulation ) 1.05 (0.488) 1.23 (0.658) 1.46 (0.527) 1.66 (0.818) NC = Not Calculated Relative Bioavailability Assessment Ratio s of LSM and 90% CI 3

4 (Day 1) A: mg, Q24h versus B: A: mg, Q24h versus B: AUC0-t (ng h/ml) 124.9% ( %) 110.2% ( %) AUCinf (ng h/ml) 127.9% ( %) 118.9% ( %) Cmax (ng/ml) 114.1% ( %) 104.6% ( %) AUCτ (ng h/ml) 99.8% ( %) 97.5% ( %) Cmax (ng/ml) 110.1% ( %) 93.5% ( %) Time Dependence Pharmacokinetic Linearity Ratios of LSM (90% CI) for AUCτ/AUCinf Treatment A: 121.7% ( %) 88.3% ( %) B: 108.3% ( %) 145.2% ( %) Steady-State Assessment Cm in Geometric Means for each Treatment and Time Analyte Treatment Day Geometric Mean (CV%) (122.4) A: (121.5) (113.3) (166.5) B: (220.1) (140.8) (129.5) A: (107.1) (117.3) (144.0) B: (197.4) (166.8) Steady-State Results P-v alues for Helmert s Contra sts Analyte Helmert s Contrasts P-value Cmin Day 12 versus mean of (Cmin Day 13 and Cmin ) Cmin Day 13 versus Cmin Cmin Day 12 versus mean of (Cmin Day 13 and Cmin ) Cmin Day 13 versus Cmin Safety results: Adverse Events: Treatment A POM 4 g and Treatment B N No. subjects with AEs n (%) 9 (37.5) 8 (34.7) No. of AE Incidents Most frequently reported Adverse Events 4

5 Abdominal distension 2 (8.3) 0 (0) Abdominal pain lower 0 (0) 2 (8.7) Constipation 2 (8.3) 1 (4.4) Headache 2 (8.3) 1 (4.3) Epistaxis 2 (8.3) 0(0) Serious Adverse Events, n (%) [n considered by the investigator to be related, possibly related, or probably related to study medication]: There was one SAE reported during this study. Subject 4, a 29-year-old Hispanic female in Sequence AB, experienced the severe SAE of acute cholecystitis during the washout period 4 days after the last scheduled dose of Treatment A (POM 4 g and simvastatin 80 ) administration. The subject was hospitalized for the SAE, underwent a laparoscopic cholecystectomy, and recovered without sequelae. The Investigator considered the cholecystitis to be unlikely related to study drug and discontinued the subject from the study on Day 22 during the washout period prior to Period 2. Publications: McKenney,JM, Swearingen D, DiSpirito M, Doyle R, Pantaleon C, Kling D, Shalwitz A. Study of the Pharmacokinetic Interaction Between and Prescription Omeaga-3-Acid Ethyl Esters. J Clin Pharmacol 2006;46: Date Updated: 14 Oct