Study Exposures, Outcomes:

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1 GSK Medicine: Coreg IR, Coreg CR, and InnoPran Study No.: WWE111944/WEUSRTP3149 Title: A nested case-control study of the association between Coreg IR and Coreg CR and hypersensitivity reactions: anaphylactic reaction/ angioedema Rationale: Review of post marketing safety data identified spontaneous adverse event reports describing serious hypersensitivity reactions after initiation of Coreg CR (carvedilol phosphate) by patients who were previously treated with Coreg IR (carvedilol). Objectives: The objectives of the study are as follows: 1. To provide crude estimates of the incidence rates of hypersensitivity reactions for Coreg IR, Coreg CR, long acting beta blockers (LA propranolol and S.A. metoprolol), other α1/β-adrenergic antagonists (excluding Coreg IR and Coreg CR, i.e., labetalol), short acting non-selective beta-blockers and short acting β1-selective agents, ACEi, ACEi plus Coreg IR, ACEi plus Coreg CR and ACEi plus (long acting beta blockers, labetolol, short acting non-selective beta-blockers or short acting β1-selective agents) 2. To assess whether Coreg CR is associated with a higher risk of hypersensitivity reactions (anaphylactic reaction/ angioedema) compared to Coreg IR. 3. To assess whether Coreg CR is associated with a higher risk of hypersensitivity reactions (anaphylactic reaction/ angioedema) compared to other long acting B-blockers. 4. To assess whether switching from Coreg IR to Coreg CR is associated with a higher risk of hypersensitivity reactions (anaphylactic reaction/ angioedema) compared to switching from Coreg IR to other long acting B- blockers. Indication: Congestive Heart Failure, Left ventricular dysfunction following myocardial infarction, and hypertension Study Investigators/Centers: GSK Research Methods: Data Source: The LabRx Database (referred to in publications as the i3 InVision Data Mart ), which is provided by Ingenix Pharmaceutical Services, Inc. It is a comprehensive, de-identified U.S. healthcare claims database that contains the aggregated health claims experience of the covered lives managed by United Healthcare. Overall, it is representative of the non-elderly, insurance-carrying population in the U.S., but it also contains information on several hundred thousand Managed Medicaid and Medicare Advantage members. It contains only those covered lives for which there exists a combined benefit structure including medical and prescription coverage. The database is geographically diverse, including data for members in all 50 states. It contains inpatient, outpatient and pharmacy claims, lab results and enrollment information on over 23.3 million lives from October 2004 through September In addition, the LabRx database includes and integrates the outpatient test result values for lab tests processed by the two largest national lab vendors. Study Design: case control analysis nested within a cohort of beta-blocker users. Study Population: Subjects who have at least one prescription claim for a beta-blocker in the LabRx database from Oct. 1 st 2004 to Sep. 30 th 2007 and at least one month of enrollment in the healthcare plan were eligible for the study. Selection of cases and controls Cases: Incident cases of hypersensitivity reactions with an ICD-9 diagnostic code of (other anaphylactic shock) or (angioneurotic edema). The date of the event was defined as the index date. Controls: For each subject defined as a case, three controls were matched to the case on age (+/- 5 years), gender, and year of first beta-blocker use. Controls were selected at random from the pool of eligible controls for each case. Controls were subjects with a treatment with beta-blocker who did not have a diagnosis of hypersensitivity reaction at any time during their follow-up in the database. Control patients were assigned the same index date as the case patients to which they are matched. Study Exposures, Outcomes: Exposure definition and Measures Subjects were classified according to their beta blocker and ACEi exposure. Subjects were considered exposed if their beta-blocker or ACEi prescription date was within 1 month prior to the index date. Drug exposure was inferred from prescription claims. The following 11 mutually exclusive drug exposure categories were created: 1. Coreg IR only 2. Coreg CR only 3. Long acting beta-blockers (LA propranolol and S.A. metoprolol) 4. other α1/βadrenergic antagonists (excluding Coreg IR and Coreg CR), i.e., labetalol 5. Short acting Non-selective beta-blockers

2 and short acting β1-selective agents 6. ACEi only 7. ACEi plus Coreg IR 8. ACEi plus Coreg CR 9.ACEi plus (long acting beta-blockers, labetolol, Short acting Non-selective beta-blockers or short acting β1-selective agents) 10. No beta-blocker or ACEi use 11. Other, i.e, does not fit in any of the above ten categories Non-selective beta-blockers: Carteolol, Levobunolol, Metipranolol, Nadolol, Penbutolol, Pindolol, Propranolol / LA propranolol, Sotalol, Timolol β1-selective agents: Acebutolol, Atenolol, Betaxolol, Bisoprolol, Metoprolol/ S.A.metoprolol Beta Blockers (α1/β-adrenergic antagonists): Carvedilol / IR and CR, Labetalol ACEi: Captopril, Benazepril, Enalapril, Lisinopril, Fosinopril, Ramipril, Perindopril, Quinapril, Moexipril, Trandolapril Outcome definitions and Measures Following are the ICD-9-CM codes for the outcomes (events) of interest: Other anaphylactic shock Angioneurotic edema The 2 ICD-9 codes were combined for the purposes of this analysis. Data Analysis Methods: Descriptive statistics, including age, gender, person-years of follow-up time, co-morbidities and concomitant medications, for the hypersensitivity reaction cases of interest and matched controls as well as the B- blocker users cohort from which they were sampled were calculated. The total follow-up time was calculated for cases by adding the length of time between subject s first beta-blocker prescription date and the hypersensitivity reaction diagnosis date (index date). The follow-up time for controls was defined as the time between the subject s first B- blocker prescription date and the index date of the case to which it was matched. For the cohort of beta-blocker users, unadjusted incidence rates of the hypersensitivity reactions of interest was calculated from the number of patients who developed a hypersensitivity reaction divided by the total person-years of follow-up. Follow-up began on the date of the first prescription of a beta-blocker in subjects who had at least six months of follow-up in the database prior to the first recorded dispensing of beta-blocker. Follow-up shifted between the eleven exposure classes defined above, on the basis of whether each day of follow-up fell within the period defined by the days supply associated with each dispensing of the drug category of interest. In addition, we allowed a 7-day extension past the end of each dispensing (calculated as days supply + 7 ) to account for minor gaps in refilling patterns. Patients were followed from their first beta-blocker prescription date until the first occurrence of any of the following: hypersensitivity reaction diagnosis; death; disenrollment from the health plan; or end of study period (Sep. 30 th, 2007). Other risk factors for hypersensitivity reaction adjusted for in this analysis include: age; gender; history of drug/food/or other allergies; respiratory disorders/asthma; cardiac disease; drugs with recognized risk of serious hypersensitivity such as NSAID, salicylates, antibiotics including penicillin and sulfonamides; inhaled beta-agonists (surrogate for bronchospastic disease); angiotensin receptor blockers (ARB) use. All analyses were conducted using SAS version 9 (SAS institute, Inc., Cary, N.C.). The following analyses were conducted to address each of the objectives: 1. To assess whether Coreg CR is associated with a higher risk of hypersensitivity reactions compared to Coreg IR. The reference group was Coreg IR. Odds ratios with 95% confidence intervals comparing Coreg CR to Coreg IR were generated using conditional logistic regression. In addition to the matching variables, the analyses were adjusted for other hypersensitivity reaction risk factors listed above. 2. To assess whether Coreg CR is associated with a higher risk of hypersensitivity reactions compared to other long acting B-blockers. The reference category was a combined cohort of LA propranolol and S.A. metoprolol. Odds ratios comparing Coreg CR to other long acting B-blockers (LA propranolol and S.A. metoprolol) were generated using conditional logistic regression. In addition to the matching variables, the analyses were adjusted for other hypersensitivity reaction risk factors listed above. 3. To assess whether switching from Coreg IR to Coreg CR is associated with a higher risk of hypersensitivity reactions compared to switching from Coreg IR to other long acting B-blockers. The reference group was switchers from Coreg IR to other long acting B-agonists (LA propranolol and S.A. metoprolol). The following exposure categories were created based on prescription dates: a. switchers from Coreg IR to Coreg CR b. switchers from Coreg IR to other long acting beta-blockers (LA propranolol

3 and S.A. metoprolol) c. all other switchers between various beta-blockers d. non-switchers e. no beta-blocker use Switching was accessed based on dates of prescription claims in the one month prior to index date. This is best illustrated by an example. For a subject (case or control) with a prescription for Coreg CR within one month prior to the index date, we would look back in the month prior to the prescription date for the Coreg CR. If this subject had a script for Coreg IR, he would be considered a switcher from Coreg IR to Coreg CR. Limitations: There are several limitations to the present study. The size of the Coreg CR cohort is relatively small (8744 exposed subjects with 8 cases of hypersensitivity reactions exposed to Coreg CR and 10 controls). Since Coreg CR was launched in March of 2007, subjects exposed to Coreg CR have shorter follow-up compared to the other cohorts captured in this study. This reduces the precision of our estimates. Further, beta blocker and ACEi exposure was inferred from prescription claims in the 1 month prior to the index date. We did not analyze data on prescriptions prior to this 1-month period. Therefore, we do not know if the subject had a previous prescription of the product that carried over into this 1-month window. We also do not know how long subjects were exposed to their medication or if they have recently switched medications. Additionally, while the medication was dispensed, it is not possible to determine whether patients actually consumed the prescribed medication. In addition, ICD9 codes were used to identify subjects with hypersensitivity reactions. These codes were reviewed by a clinician. However, a validation with chart review to confirm the hypersensitivity diagnoses was not performed. A claims based adjudication of the diagnosis of hypersensitivity reactions was conducted.

4 Study Results: A total of 1.3 million beta-blocker users were identified (Table 1). The beta-blocker cohort had equal representation of males and females. The average follow-up was 1.4 years. Fifty-seven percent of the cohort were years of age. Eighty percent had cardiac disease and 16% had respiratory disorders during their follow-up. Among this cohort, 4,441 cases of hypersensitivity reactions were identified and matched to 13,323 controls (Table 1). The unadjusted incidence rate of hypersensitivity reactions among the beta-blocker cohort was 2.38 events per 1,000 person-years (95% CI= ) (Table 2). The incidence rate of hypersensitivity reactions was higher among females (2.72 per 1,000 person-years (95% CI= )) compared to males (2.05 per 1,000 person-years (95% CI= )). The incidence rate was similar for the various age groups. The incidence rate of hypersensitivity reactions however was different for the various exposure categories and ranged from 2.07 per 1,000 person-years (95% CI= ) for short acting selective/non-selective beta-blockers to 5.89 per 1,000 person-years (95% CI= ) for Coreg CR (Table 3). The rates of hypersensitivity reactions among the various exposure categories are NOT adjusted for the baseline differences in comorbid conditions and drug exposures known to be associated with increased risk of hypersensitivity reactions. Table 4 represents the likelihood of developing hypersensitivity reactions for the various exposure categories of interest compared to Coreg IR among the beta-blocker users cohort. Compared to Coreg IR, the unadjusted odds ratio for hypersensitivity reactions in Coreg CR users was 2.15 (95% CI = ), indicating a 2.15 fold increased likelihood of hypersensitivity reactions in Coreg CR users compared to Coreg IR. However, after adjustment for risk factors for hypersensitivity reactions, the odds of a hypersensitivity reaction was 0.92 (95% CI= ) indicating a similar likelihood of a hypersensitivity reaction in Coreg CR users compared to Coreg IR users. After adjustment for risk factors for hypersensitivity rxns, ACEi plus (long acting beta blockers, labetolol, Short acting Non-selective beta-blockers or short acting β1-selective agents) was associated with 46% increased likelihood of hypersensitivity reactions (OR=1.46; 95% CI= ) compared to Coreg IR. As expected, respiratory disorders including asthma, cardiac disease, history of drug/food or other allergies, NSAID use, antibiotics (penicillin and sulfonamides) and inhaled beta-agonists were all associated with a significantly increased likelihood of developing hypersensitivity reactions. Table 5 displays the likelihood of hypersensitivity reactions for the various exposure categories of interest compared to other long acting beta-blockers among the beta-blocker users cohort. Similar to the previous table, the unadjusted odds ratio for hypersensitivity reactions in Coreg CR users was 2.2 fold higher than that of other long acting beta-blockers (OR= 2.20; 95% CI = ). However, after adjustment for risk factors for hypersensitivity reactions, there was no difference in the likelihood of a hypersensitivity reactions in Coreg CR users compared to other long acting betablockers (OR =0.96; 95% CI= ). The use of ACEi (OR=1.36; 95% CI= ), ACEi plus Coreg IR (OR=1.5; 95% CI= ) and ACEi plus (long acting beta blockers, labetolol, Short acting Non-selective B-Blockers or short acting β1-selective agents) (OR=1.53; 95% CI= ) were associated with 36%, 50% and 53% increased likelihood of developing hypersensitivity reactions, respectively, compared to long acting beta-blocker. Table 6 displays the prevalence of risk factors for hypersensitivity reactions among the cases and controls for the various exposure categories within the beta-blocker cohort. Among the cases, Coreg CR exposed subjects had a high proportion of respiratory disorders/asthma (37.5%), cardiac disease (100%), history of drug/food or other allergies (50%), NSAID use (12.5%), penicillin use (12.5%), inhaled beta-agonist (12.5%) and ARB use (37.5%). Similarly among the controls, Coreg CR exposed subjects had the highest prevalence of respiratory disorders/asthma (30%), cardiac disease (100%) and NSAID (10%) and penicillin use (10%). In addition, comorbid conditions and exposure to drugs in the one year preceding exposure to the drug exposure categories of interest within the Beta-blockers cohort were assessed (Table A in the Appendix). It is apparent that Coreg CR exposed subjects are among the highest cohorts studied in terms of the proportion of subjects with cardiac disease, salicylate use and ARB use. Table 7 displays the number and % of switchers (from Coreg IR to Coreg CR, from Coreg IR to other long acting B- blockers, switchers between other various B-blockers) in LabRx database, among the cases and controls of hypersensitivity reactions. The majority of the cases of hypersensitivity reactions were non-switchers (76.78%) based on an evaluation of switching patterns in the one month prior to the index date. Only one case was a switcher from Coreg IR to Coreg CR. Therefore, it is not possible to address whether switching from Coreg IR to Coreg CR is associated with a higher risk of hypersensitivity reactions compared to switching from Coreg IR to other long acting B- blockers. Conclusion: The results of this study show that exposure to Coreg CR is not associated with an increased likelihood of hypersensitivity reactions (anaphylactic reaction/ angioedema) compared to Coreg IR or other long acting B-blockers.

5 Table 1. Descriptive Statistics of the Beta-Blocker Users Cohort, Hypersensitivity Reactions Cases and Controls in the LabRx database, Beta-blocker Users Cohort N= % Hypersensitivity Rxns Cases N= % Hypersensitivity Rxns Controls N= % Mean SD Mean SD Mean SD Age (years) Follow-up (years) Gender N % N % N % Male Female Age category < > Co-Morbidities* Respiratory disorders/ asthma Cardiac disease History of drug/food/or other allergies Concomitant Meds* Salicylates

6 NSAID Penicillin Sulfonamides Inhaled Beta agonists ARB use *For the beta-blocker users cohort, the prevalence of co-morbidities and concomitant medications are calculated if reported at any time during the follow-up. For the cases and controls, the prevalence of co-morbidities is calculated if reported within 3 month prior to the index date and concomitant medications within 1 month prior to the index date. Table 2. Unadjusted Incidence Rate of Hypersensitivity Rxns in the Beta-Blocker Users Cohort According to Gender and Age in the LabRx database, N Events* Person- Years IR** 95% CI Total Gender Male Female Age category < > * Defined as ICD-9 codes for Hypersensitivity Rxns (995.0 for anaphylactic reaction/ for angioneurotic edema) * *per 1,000 person-years Table 3. Unadjusted Incidence Rate of Hypersensitivity Rxns according to exposure category in the month prior to the index date: LabRx database, N Events* Person-Years IR** 95% CI Total 1,327,

7 Coreg IR 67, , Coreg CR 8, , Long acting beta blockers (LA propranolol and S.A. metoprolol) Other α1/β-adrenergic antagonists (excluding Coreg IR and Coreg CR), i.e., labetalol Short acting Non-selective B- Blockers and short acting β1- Selective agents 378, , , , , , ACEi 269, , ACEi plus Coreg IR 45, , ACEi plus Coreg CR 4, , ACEi plus (long acting beta blockers, labetolol, Short acting Non-selective B-Blockers or short acting β1-selective agents) 356, , Other 57, , No B-blocker or ACEi use 1,327, , * Defined as ICD-9 codes for Hypersensitivity Rxns (995.0 for anaphylactic reaction/ for angioneurotic edema) * *per 1,000 person-years Table 4. Odds of Hypersensitivity Reactions for the Various Exposure Categories of Interest compared to Coreg IR users among B-blocker users cohort in the month prior to the index date: LabRx database, Case Control Unadjusted OR [95% n=4441 n=13323 CI] Adjusted OR** [95% CI] (100%) Coreg IR 73 (100%) (1.64%) Coreg CR 8 (1.49%) 10 (Reference group) (Reference group) 2.15( 0.82, 5.66) 0.92( 0.22, 3.74) Long acting beta blockers (LA propranolol and S.A. metoprolol) (0.18%) 501 (11.28%) (0.08%) 1367 (10.26%) 0.97( 0.73, 1.30) 0.96( 0.67, 1.36)

8 Other α1/β-adrenergic 34 antagonists (excluding Coreg IR and Coreg CR), i.e., labetalol (0.77%) Short acting Non-selective B Blockers and short acting β1- Selective agents (23.51%) ACEi 296 (6.67%) ACEi plus Coreg IR 73 (1.64%) ACEi plus Coreg CR 5 ACEi plus (long acting beta blockers, labetolol, Short acting Non-selective B- Blockers or short acting β1- Selective agents) (0.11%) 719 (16.19%) Other 5 (0.11%) No B-blocker or ACEi use (0.71%) 3417 (25.65%) 645 (4.84%) 154 (1.16%) 7 (0.05%) 1377 (10.34%) 8 (0.06%) ( 0.57, 1.48) 0.86( 0.47, 1.56) 0.80( 0.61, 1.06) 0.81( 0.58, 1.14) 1.23( 0.91, 1.66) 1.30( 0.90, 1.89) 1.29( 0.88, 1.90) 1.43( 0.89, 2.29) 1.95( 0.60, 6.35) 2.02( 0.49, 8.26) 1.40( 1.06, 1.86) 1.46( 1.03, 2.07) 1.67( 0.53, 5.29) 2.46( 0.62, 9.76) 0.73( 0.55, 0.96) 0.80( 0.57, 1.13) (37.90%) (45.37%) Age 0.99( 0.98, 1.01) Respiratory disorders/ asthma 961 (21.64%) Cardiac disease 3320 History of drug/food/or other allergies (74.76%) 1562 (35.17 %) Salicylates 16 (0.36%) NSAID 342 (7.70%) Penicillin 151 (3.40%) Sulfonamides 3 (0.07%) Inhaled Beta agonists 159 (3.58%) 650 (4.88%) 6323 (47.46%) 127 (0.95%) 44 (0.33%) 704 (5.28%) 277 (2.08%) 22 (0.17%) 173 (1.30%) 3.88( 3.34, 4.49) 3.17( 2.87, 3.51) 49.46(39.53, 61.89) 1.03( 0.50, 2.15) 1.48( 1.25, 1.77) 1.34( 1.03, 1.75) 0.26( 0.07, 0.99) 1.36( 1.00, 1.83)

9 ARB use 458 (10.31%) 1217 (9.13%) 1.03( 0.88, 1.19) ** Adjusted for age, gender, index-year, history of drug/food/other allergies, respiratory disorders/ asthma, cardiac disease, aspirin, penicillin, sulfonamides, beta agonists and ARB use Table 5. Odds of Hypersensitivity Rxns for the Various Exposure Categories of Interest compared to Other Long Acting B-blockers in the month prior to the index date: LabRx database, Long acting Beta blockers (LA propranolol and S.A. metoprolol) Case Control Unadjusted OR [95% CI] n=4441 n=13323 (100%) (100%) (Reference group) (11.28%) (10.26%) Adjusted OR** [95% CI] 1.00 (Reference group) Coreg CR 8 (0.18%) Coreg IR (0.08%) ( 0.86, 5.64) 0.96( 0.24, 3.81) 1.03( 0.77, 1.37) 1.05( 0.73, 1.49) Other α1/β-adrenergic antagonists (excluding Coreg IR and Coreg CR), i.e., labetalol (1.64%) 34 (0.77%) (1.49%) 94 (0.71%) 0.94( 0.63, 1.41) 0.90( 0.54, 1.50) Short acting Non-selective B- Blockers and short acting β1- Selective agents 1044 (23.51%) 3417 (25.65%) 0.83( 0.73, 0.94) 0.85( 0.72, 1.00) ACEi 296 (6.67%) ACEi plus Coreg IR 73 (1.64%) ACEi plus Coreg CR (4.84%) 154 (1.16%) ( 1.06, 1.49) 1.36( 1.10, 1.70) 1.32( 0.98, 1.78) 1.50( 1.04, 2.16) 2.00( 0.63, 6.35) 2.11( 0.53, 8.36) ACEi plus (long acting beta blockers, labetolol, Short acting Non-selective B- Blockers or short acting β1- Selective agents) (0.11%) 719 (16.19%) (0.05%) 1377 (10.34%) 1.44( 1.25, 1.65) 1.53( 1.28, 1.83) Other 5 (0.11%) 8 (0.06%) 1.71( 0.56, 5.28) 2.57( 0.67, 9.87)

10 No B-blocker or ACEi use ( 0.66, 0.84) 0.84( 0.72, 0.98) (37.90%) (45.37%) Age 0.99( 0.97, 1.00) Respiratory disorders/ asthma 961 (21.64%) Cardiac disease 3320 History of drug/food/or other allergies (74.76%) 1562 (35.17 %) Salicylates 16 (0.36%) NSAID 342 (7.70%) Penicillin 151 (3.40%) Sulfonamides 3 (0.07%) Inhaled Beta agonists 159 (3.58%) ARB use 458 (10.31%) 650 (4.88%) 6323 (47.46%) 127 (0.95%) 44 (0.33%) 704 (5.28%) 277 (2.08%) 22 (0.17%) 173 (1.30%) 1217 (9.13%) 3.88( 3.34, 4.49) 3.17( 2.87, 3.51) 49.46(39.53, 61.89) 1.03( 0.50, 2.15) 1.48( 1.25, 1.77) 1.34( 1.03, 1.75) 0.26( 0.07, 0.99) 1.36( 1.00, 1.83) 1.03( 0.88, 1.19) ** Adjusted for age, gender, index-year, history of drug/food/other allergies, respiratory disorders/asthma, cardiac disease, aspirin, penicillin, sulfonamides, beta agonists and ARB use.

11 Table 6: Prevalence of risk factors for hypersensitivity reactions among cases and controls in various exposure categories within the beta-blocker cohort in the LabRX database, Respiratory disorders/ asthma Cardiac disease History of drug/food/or other allergies Salicylates NSAID Penicillin Sulfonamides Inhaled Beta agonists ARB use Cases Coreg IR 73 Coreg CR 8 Long acting beta blockers (LA propranolo l and S.A. metoprolol) Other α1/βadrenergic antagonists (excluding Coreg IR and Coreg CR), i.e., labetalol Short acting Nonselective B- Blockers and short acting β1- Selective agents ACEi 296 ACEi plus 73 Coreg IR ACEi plus Coreg CR 5 ACEi plus (long acting beta blockers, labetolol, Short acting Nonselective B- Blockers or short acting β1-selective 719 agents) 14 (19.2) 3 (37.5) 98 (19.6) 13 (38.2) 229 (21.9) 47 (15.9) 11 (15.1) 0 (0.0) 94 (13.1) 63 (86.3) 8 (100.0) 368 (73.5) 30 (88.2) 772 (73.9) 266 (89.9) 68 (93.2) 5 (100.0) 635 (88.3) 17 (23.3) 0 (0.0) 3 (4.1) 3 (4.1) 0 (0.0) 5 (6.8) 4 (50.0) 0 (0.0) 188 (37.5) 1 (0.2) 1 (12.5) 43 (8.6) 1 (12.5) 0 (0.0) 1 (12.5) 16 (3.2) 1 (0.2) 10 (2.0) 9 (26.5) 0 (0.0) 1 (2.9) 1 (2.9) 0 (0.0) 2 (5.9) 400 (38.3) 3 (0.3) 77 (26.0) 3 (1.0) 93 (8.9) 31 (10.5) 35 (3.4) 1 (0.1) 56 (5.4) 9 (3.0) 0 (0.0) 11 (3.7) 15 (20.5) 1 (1.4) 7 (9.6) 4 (5.5) 0 (0.0) 1 (1.4) 1 (20.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 195 (27.1) 4 (0.6) 75 (10.4) 25 (3.5) 0 (0.0) 25 (3.5) Other 5 0 (0.0) 4 (80.0) 1 (20.0) 0 (0.0) 1 0 (0.0) 0 (0.0) 0 (0.0) 4 22 (30.1) 3 (37.5) 90 (18.0) 8 (23.5) 159 (15.2) 13 (4.4) 7 (9.6) 0 (0.0) 36 (5.0)

12 Respiratory disorders/ asthma Cardiac disease History of drug/food/or other allergies Salicylates NSAID Penicillin Sulfonamides Inhaled Beta agonists ARB use No B- blocker or ACEi use (26.9) 1,101 (65.4) 655 (38.9) 4 (0.2) (20.0) (80.0) 87 (5.2) 57 (3.4) 1 (0.1) 48 (2.9) 116 (6.9) Contro ls n (%) Coreg IR 199 Coreg CR 10 Long acting beta blockers (LA propranolo l and S.A. metoprolol) Other α1/βadrenergic antagonists (excluding Coreg IR and Coreg CR), i.e., labetalol Short acting Nonselective B- Blockers and short acting β1- Selective agents ACEi 645 ACEi plus 154 Coreg IR ACEi plus Coreg CR 7 ACEi plus (long acting beta blockers, labetolol, Short acting Nonselective B- Blockers or short acting 1377 β1-selective 13 (6.5) 3 (30.0) 83 (6.1) 4 (4.3) 143 (4.2) 39 (6.0) 7 (4.5) 142 (71.4) 10 (100.0) 698 (51.1) 56 (59.6) 1,638 (47.9) 410 (63.6) 105 (68.2) 0 (0.0) 1 (0.5) 8 (4.0) 7 (3.5) 0 (0.0) 3 (1.5) 0 (0.0) 0 (0.0) 16 (1.2) 5 (0.4) 1 (10.0) 86 (6.3) 1 (10.0) 0 (0.0) 0 (0.0) 24 (1.8) 1 (0.1) 24 (1.8) 1 (1.1) 0 (0.0) 5 (5.3) 4 (4.3) 1 (1.1) 2 (2.1) 34 (1.0) 11 (0.3) 5 (0.8) 1 (0.2) 224 (6.6) 39 (6.0) 72 (2.1) 8 (0.2) 45 (1.3) 10 (1.6) 1 (0.2) 6 (0.9) 1 (0.6) 0 (0.0) 7 (4.5) 4 (2.6) 0 (0.0) 2 (1.3) 1 (14.3) 5 (71.4) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 51 (3.7) 820 (59.5) 13 (0.9) 7 (0.5) 80 (5.8) 34 (2.5) 3 (0.2) 27 (2.0) 74 (37.2) 2 (20.0) 275 (20.1) 18 (19.1) 399 (11.7) 27 (4.2) 5 (3.2) 0 (0.0) 59 (4.3)

13 Respiratory disorders/ asthma Cardiac disease History of drug/food/or other allergies Salicylates NSAID Penicillin Sulfonamides Inhaled Beta agonists ARB use agents) Other No B- blocker or ACEi use (0.0) 7 (87.5) 0 (0.0) 0 (0.0) 306 (5.1) 2,432 (40.2) 57 (0.9) 19 (0.3) 1 (12.5) 253 (4.2) 0 (0.0) 0 (0.0) 0 (0.0) 121 (2.0) 8 (0.1) 64 (1.1) 1 (12.5) 357 (5.9)

14 Table 7. Number and % of switchers* (from Coreg IR to Coreg CR, from Coreg IR to other long acting B-blockers, switchers between other various B-blockers) in LabRx database, among the cases and controls of hypersensitivity reactions. Switchers from Coreg IR to Coreg CR Switchers from Coreg IR to other long acting B-blockers (LA propranolol and S.A. metoprolol) All other switchers between various B-blockers Case Control n=4441 n=13323 (100%) (100%) 1 5 (0.02%) (0.04%) 0 (0.00%) 82 (1.85%) Non-switchers 3410 (76.78%) no B-blocker use 948 (21.35%) 2 (0.02%) 178 (1.34%) 9343 (70.13%) 3795 (28.48%) * SWITCHING PATTERNS WERE EVALUATED IN THE ONE MONTH PRIOR TO THE INDEX DATE

15 Appendix Table A. Number and % of subjects with various comorbidities and drug exposures in the one year preceding exposure to the drug exposure categories of interest within the Beta-blockers cohort: Coreg IR Coreg CR Long acting beta blockers (LA propranolol and S.A. metoprolol) Total N 67,631 Respiratory disorders/ asthma 14,615 (21.6) 8,743 1,580 (18.1) 378,585 78,434 (20.7) Cardiac disease 64,689 (95.6) 8,427 (96.4) 332,467 (87.8) History of drug/food/or other allergies Salicylates 3,541 (5.2) 1,736 (2.6) NSAID 100 (0.1) Penicillin 1,310 (1.9) Sulfonamides 94 (0.1) Inhaled Beta agonists 847 (1.3) 392 (4.5) 306 (3.5) 1 (0.0) 181 (2.1) 7 (0.1) 83 (0.9) 24,000 (6.3) 12,148 (3.2) 486 (0.1) 8,535 (2.3) 516 (0.1) 4,093 (1.1) ARB use 3,280 (4.8) 670 (7.7) 16,211 (4.3) Other α1/βadrenergic antagonists (excluding Coreg IR and Coreg CR), i.e., labetalol Short acting Nonselective B-Blockers and short acting β1- Selective agents 30,848 5,793 (18.8) 927, ,043 (18.3) 25,932 (84.1) 771,545 (83.2) 1,740 (5.6) 1,253 (4.1) 51,219 (5.5) 27,208 (2.9) 53 (0.2) 1,348 (0.1) 858 (2.8) 39 (0.1) 18,242 (2.0) 1,094 (0.1) 407 (1.3) 9,521 (1.0) 1,333 (4.3) 27,533 (3.0) ACEi ACEi plus Coreg IR ACEi plus Coreg CR 268,743 51,655 (19.2) 45,368 9,157 (20.2) 4, (16.5) 258,756 (96.3) 43,773 (96.5) 4,273 (97.6) 14,446 (5.4) 6,236 (2.3) 2,115 (4.7) 776 (1.7) 396 (0.1) 62 (0.1) 4,097 (1.5) 275 (0.1) 665 (1.5) 45 (0.1) 2,553 (0.9) 425 (0.9) 175 (4.0) 76 (1.7) 0 (0.0) 58 (1.3) 1 (0.0) 28 (0.6) 5,171 (1.9) 750 (1.7) 99 (2.3)

16 ACEi plus (long acting beta blockers, labetolol, Short acting Non-selective B-Blockers or short acting β1-selective agents) Total N 356,631 Respiratory disorders/ asthma 61,491 (17.2) Cardiac disease 334,583 (93.8) History of drug/food/or other allergies Salicylates 17,530 (4.9) 7,979 (2.2) NSAID 519 (0.1) Penicillin 5,151 (1.4) Sulfonamides 371 (0.1) Inhaled Beta agonists 3,081 (0.9) ARB use 6,428 (1.8) Other No B-blocker or ACEi use 57,197 1,043,528 12,139 (21.2) 207,599 (19.9) 52,434 (91.7) 894,410 (85.7) 3,554 (6.2) 1,677 (2.9) 62,582 (6.0) 33,637 (3.2) 91 (0.2) 1,593 (0.2) 1,211 (2.1) 23,408 (2.2) 84 (0.1) 1,366 (0.1) 584 (1.0) 11,846 (1.1) 2,651 (4.6) 36,162 (3.5)