1 Spontaneous Adverse Event Reporting Information Introduction This document provides information regarding spontaneous adverse event reports received concerning patients taking rosuvastatin, which relates to muscle, liver and kidney. Spontaneous Adverse Event (AE) Reporting constitutes an important component of the ongoing post marketing surveillance programme for rosuvastatin as for all marketed products. As part of this process, spontaneous reports of all adverse events, irrespective of causality assessment by the reporter, are collected and monitored closely by AstraZeneca. In addition, the AEs are reported to worldwide regulatory health authorities according to local regulatory requirements. While spontaneous adverse event reporting can be helpful in identifying a potential safety signal about rare and previously unknown adverse events, there are several limitations to the information provided. Such reports may fail to take into account important information about the patient, such as underlying medical conditions and other drugs the patient may be taking which may be associated with the present adverse event. Adverse events initially suspected of being drug-related are frequently shown, after additional information is obtained, to be unrelated to drug therapy. However, additional information in some cases is not available or is delayed causing at times an inaccurate or incomplete interpretation of the adverse event. The level of reporting is affected by a number of external factors. For example, increased adverse event reporting often occurs during the first 2-3 years that a new drug is marketed. Because spontaneous reports depend on voluntary reporting by health care professionals and patients, there is under-reporting of adverse events. This is especially true once a drug has been on the market for a period of years and there is increased familiarity with a product s safety profile. Thus, comparisons between levels of spontaneous reports for a newer drug versus an older drug may be difficult to interpret. Small changes in the level of reporting of an adverse event, which has an extremely low underlying reporting rate, can be misinterpreted and the change exaggerated causing unnecessary concern. To control for the disproportionate effects of external factors on reporting rates, proportional reporting ratios can be used which take into account
the background level of adverse event reporting occurring with a medicine. In summary, spontaneous reporting provides additional information to that provided from a clinical development programme about the benefit/risk profile of a drug in clinical practice. Owing to the limitations discussed above, spontaneous adverse event reporting rates are not regarded as a definitive mechanism for understanding the true incidence of an adverse event, but may signal the need to conduct further controlled investigation either through prospectively designed clinical trials or welldesigned pharmacoepidemiology studies. Muscle Effects The spontaneous reporting frequency of serious muscle adverse events, including myopathy and rhabdomyolysis, in patients taking rosuvastatin is very rare (less than 1 in 1,) which is consistent with that reported with other marketed statins. Due to the increased awareness among prescribers of the rare but potentially life-threatening occurrence of rhabdomyolysis in patients receiving statin therapy, information relating to spontaneous reports of myopathy and rhabdomyolysis in patients taking rosuvastatin has received particular scrutiny. Data related to spontaneous reports of myopathy and rhabdomyolysis from the AstraZeneca worldwide database are presented below. AstraZeneca has monitored the cumulative weekly reporting rate of spontaneous reports of myopathy and rhabdomyolysis for rosuvastatin by patient exposure since launch (Figures 1 and 2).
Figure 1: Cumulative post-marketing reporting rate of myopathy for rosuvastatin 1.9.8 Patients = new and switched prescriptions Reporting rate <1:1, = very rare (CIOMS).7.6.5.4.3.2.1 4-Jun-23 18-Jun-23 2-Jul-23 16-Jul-23 3-Jul-23 13-Aug-23 27-Aug-23 1-Sep-23 24-Sep-23 8-Oct-23 22-Oct-23 5-Nov-23 19-Nov-23 3-Dec-23 17-Dec-23 31-Dec-23 14-Jan-24 28-Jan-24 11-Feb-24 25-Feb-24 1-Mar-24 24-Mar-24 7-Apr-24 21-Apr-24 5-May-24 19-May-24 2-Jun-24 16-Jun-24 3-Jun-24 14-Jul-24 28-Jul-24 11-Aug-24 25-Aug-24 8-Sep-24 22-Sep-24 6-Oct-24 2-Oct-24 3-Nov-24 17-Nov-24 1-Dec-24 15-Dec-24 29-Dec-25 Reporting Rate Week Starting Reporting Rate Per 1, Patients
Figure 2: Cumulative post-marketing reporting rate of rhabdomyolysis for rosuvastatin 1.9.8.7 Patients = new and switched prescriptions Reporting rate <1:1, = very rare (CIOMS).6.5.4.3.2.1 4-Jun-23 18-Jun-23 2-Jul-23 16-Jul-23 3-Jul-23 13-Aug-23 27-Aug-23 1-Sep-23 24-Sep-23 8-Oct-23 22-Oct-23 5-Nov-23 19-Nov-23 3-Dec-23 17-Dec-23 31-Dec-23 14-Jan-24 28-Jan-24 11-Feb-24 25-Feb-24 1-Mar-24 24-Mar-24 7-Apr-24 21-Apr-24 5-May-24 19-May-24 2-Jun-24 16-Jun-24 3-Jun-24 14-Jul-24 28-Jul-24 11-Aug-24 25-Aug-24 8-Sep-24 22-Sep-24 6-Oct-24 2-Oct-24 3-Nov-24 17-Nov-24 1-Dec-24 15-Dec-24 29-Dec-25 Week Starting Reporting Rate-ALL ''Reporting Rate -ACC/AHA criteria" Reporting Rate per 1, Patients
Multiple definitions of rhabdomyolysis exist in published literature. For consistency, AstraZeneca evaluates cases by both the reported term (that is, according to whether the case was reported as rhabdomyolysis, independent of supportive data) and also by the American College of Cardiology/American Heart Association (ACC/AHA) consensus criteria 1. In figure 2, rhabdomyolysis rates are presented both ways, in terms of total reports containing the reported term and also according to whether the reports met the ACC/AHA diagnostic criteria for rhabdomyolysis. The reporting rates for both myopathy and rhabdomyolysis with rosuvastatin are very rare (less than 1 in 1,) regardless, of which approach is used. In addition to the weekly reporting rate, a comparison of post-marketing data for rosuvastatin, other statins and ezetimibe has also been performed (Figures 3 and 4). As shown in figure 3, the worldwide semiannual reporting rate for rosuvastatin is in line with the US reporting rates for other statins taking the limitations of comparative spontaneous reporting rates into consideration, particularly a higher reporting rate of adverse events for a new drug during the first 2 years of launch (Weber effect) 2. As clearly depicted, the reporting rate of rhabdomyolysis for cerivastatin was much higher compared with currently marketed statins.
Figure 3: Reporting rates of rhabdomyolysis with lipid-modifying therapy Reporting Rate Per 1,, US Prescriptions ** Semiannual Reporting Rates for All Reports of Rhabdomyolysis 12 1 8 6 4 2 3/99-8/99 9/99-2/ 3/- 8/ US Cases* 9/- 2/1 3/1-8/1 9/1-2/2 3/2-8/2 Cerivastatin Fluvastatin Atorvastatin Lovastatin Pravastatin Simvastatin Ezetimibe Rosuvastatin 9/2-2/3 3/3-8/3 Worldwide Cases 6/3-11/3 Rosuvastatin 12/3-5/4 6/4-11/4 12 1 8 6 4 2 Reporting Rate Per 1,, Rosuvastatin Prescriptions Worldwide *All spontaneous reports including expedited, periodic and direct reports. **US reporting rate for all statins and ezetimibe based on FDA Adverse Events Reporting System made available through Freedom of Information Act divided by US prescribing data supplied by IMS through August 23. Cerivastatin reports received after September 1, 21, are excluded. Global reporting rate for rosuvastatin based on spontaneous report counts of rhabdomyolysis within AstraZeneca global drug safety database divided by estimated worldwide prescriptions to end November 24. Total prescriptions based on IMS data from US, Canada, UK, France, Italy and The Netherlands; rest of world prescriptions based on actual sales calculations. Update: 8 December 24
Figure 4: Reporting rates of fatal rhabdomyolysis with lipid-modifying therapy Semiannual Reporting Rates for All Reports of Fatal Rhabdomyolysis Reporting Rate Per 1,, US Prescriptions ** 25 2 15 1 5 3/99-8/99 9/99-2/ 3/- 8/ US Cases* 9/- 2/1 3/1-8/1 9/1-2/2 3/2-8/2 Cerivastatin Fluvastatin Atorvastatin Lovastatin Pravastatin Simvastatin Ezetimibe Rosuvastatin 9/2-2/3 3/3-8/3 Worldwide Cases 6/3-11/3 Rosuvastatin 12/3-5/4 6/4-11/4 25 2 15 1 5 Reporting Rate Per 1,, Rosuvastatin Prescriptions Worldwide *All spontaneous reports including expedited, periodic and direct reports. **US reporting rate for all statins and ezetimibe based on FDA Adverse Events Reporting System made available through Freedom of Information Act divided by US prescribing data supplied by IMS through August 23. Cerivastatin reports received after September 1, 21, are excluded. Approximately 1% of cases of rhabdomyolysis for all statins are fatal. Global reporting rate for rosuvastatin based on spontaneous report counts of rhabdomyolysis within AstraZeneca global drug safety database divided by estimated worldwide prescriptions to end November 24. Total prescriptions based on IMS data from US, Canada, UK, France, Italy and The Netherlands; rest of world prescriptions based on actual sales calculations. Update: 8 December 24
Within figure 3, the global semi-annual reporting rates of rhabdomyolysis in rosuvastatin-treated patients were calculated by dividing the worldwide spontaneous reports of rhabdomyolysis (received by the internal global safety database for AstraZeneca) by the worldwide prescriptions for rosuvastatin during a series of 6-month periods. These rates represent the most recent and comprehensive information for rosuvastatin to date. US spontaneous reports of rhabdomyolysis for comparator statins and ezetimibe were obtained from the Federal Drug Administration (FDA) Adverse Event Reporting System (AERS), available to the public through the Freedom of Information Act (FOIA). The US semiannual reporting rates of rhabdomyolysis for these drugs from 1999 to 23 were then calculated by dividing the report counts by the numbers of US prescriptions. The US data on the electronic AERS database represent the time frame up to and including fourth quarter of 23 and therefore contain only very few reports of rhabdomyolysis for rosuvastatin, which was only launched in US in September 23. All reporting rates of rhabdomyolysis are expressed as reports of rhabdomyolysis per million prescriptions. Figure 4 shows a similar comparison based on reports of fatal rhabdomyolysis. For the currently marketed statins the case fatality rate is approximately 1%.
It is well recognised that spontaneous adverse event (AE) reporting is affected by a number of external factors. Notably, increased AE reporting often occurs during the first 2-3 years that a new drug is marketed, a phenomenon previously described by Weber et al. In the case of rosuvastatin, increased reporting is likely to have been compounded by media activity, as it is the first statin launched since the withdrawal of cerivastatin. To control for external factors that may affect spontaneous adverse event reporting rates, reporting ratios may be evaluated. These take into account the background level of adverse event reports for a product. This evaluation involves calculating the overall proportion of an adverse event out of the total number of events reported for that product. If the proportion is substantially higher than the proportion for the same event for other products this may form the basis for identifying a potential safety signal. The cumulative reporting proportion for a specific AE is the proportion of the total AE reports for a product, which is attributable to that specific AE. When comparing adverse event reporting rates between newer and established products, the cumulative reporting proportion is therefore a useful measure to control for the impact of the Weber effect, as it corrects for the expected higher overall rate of adverse event reporting observed with the newly introduced product. Figure 5 shows reports of rhabdomyolysis as a proportion of all adverse event reports for rosuvastatin and for other statins. The proportion of rhabdomyolysis reports for rosuvastatin is in line with the proportion calculated for the other marketed statins. Data for rosuvastatin are taken from the FDA AERS Freedom of Information report issued on 5 October 24. This report provides the proportion of all reports of rhabdomyolysis for rosuvastatin received by the FDA from April 22 to October 24, including both spontaneous and clinical trial reports, initial and follow-up reports (and therefore some duplicate reports) from the US as well as some worldwide reports.
Figure 5: Reports of rhabdomyolysis as a proportion of total adverse event reports based on FDA AERS data 12 11.6% 11.8% Reports of rhabdomyolysis as a % of all AE reports other statins 11 1 9 8 7 6 5 4 3 2 1 3.7% 6.2% 6.% 3.8% Reports of rhabdomyolysis as a % of all AE reports - rosuvastatin atorvastatin pravastatin lovastatin simvastatin fluvastatin rosuvastatin Proportion of all reports of rhabdomyolysis for other currently marketed statins from November 1997 to 3 September 23, based on analysis of the electronic FDA Adverse Events Reporting System (AERS) database by Galt Associates with elimination of duplicate reports Proportion of all reports of rhabdomyolysis (initial and duplicate follow-up reports) (from 24 April 22 to 5 October 24) from FDA AERS Freedom of Information (FOI) Report issued on 4 October 24
Data for other statins is based on an analysis conducted by Galt Associates of the FDA AERS database using proprietary software to remove duplicate reports and includes reports of rhabdomyolysis for currently marketed statins (other than rosuvastatin) from November 1997 to September 23. Liver Effects The frequency of serious hepatic adverse events, such as hepatitis, in patients taking rosuvastatin is very rare (less than 1 in 1,), which is consistent with that seen with other marketed statins. AstraZeneca has very rarely received reports of hepatic adverse events, including fatal hepatic events, hepatitis, jaundice and/or abnormal liver function in patients taking rosuvastatin. Figure 6 shows the cumulative reporting proportion for hepatitis (including the reported terms of hepatitis, acute hepatitis and toxic hepatitis). The proportion of hepatic adverse event reports for rosuvastatin is in line with the proportion calculated for the other marketed statins. As with reports of rhabdomyolysis, data for rosuvastatin is taken from the FDA AERS report issued on 5 October 24 and data for other statins is based on an analysis conducted by Galt Associates on data from the FDA AERS database.
Figure 6: Reports of hepatitis* as a proportion of total adverse event reports based on FDA AERS data Reports of hepatitis as a % of all AE reports other statins 8 7 6 5 4 3 2 1 1.7% 4.2% 1.5% 1.7% 3.2% 1.4% Reports of hepatitis as a % of all AE reports - rosuvastatin atorvastatin pravastatin lovastatin simvastatin fluvastatin rosuvastatin Proportion of all reports of hepatitis* for other currently marketed statins from November 1997 to 3 September 23, based on analysis of the electronic FDA Adverse Events Reporting System (AERS) database by Galt Associates with elimination of duplicate reports. Proportion of all reports of hepatitis* (initial and duplicate follow-up reports) (from 24 April 22 to 5 October 24) from FDA AERS Freedom of Information (FOI) Report issued on 4 October 24 *Hepatitis includes MedDRA preferred terms of hepatitis, hepatitis Acute & toxic hepatitis
Kidney Effects The evaluation of spontaneous adverse event reports for renal failure is fundamentally different to the evaluation of muscle and liver events for the following reasons: In contrast to muscle and liver events, renal events are not a recognised side effect of statins The background annual incidence of acute renal failure in the general population is not uncommon (approximately 1 case in 5) and even higher for the patient population on statin therapy (approximately 1 case in 1 ) 3-6 Renal failure has been monitored in both the rosuvastatin clinical development programme and in the post-marketing safety data. The spontaneous reporting frequency of renal failure, in patients taking rosuvastatin is very rare (less than 1 in 1,) which is consistent with that reported with other marketed statins. This section summarises the overall findings of the renal safety data for rosuvastatin: The weekly monitoring of the worldwide spontaneous reporting rate of renal failure for rosuvastatin shows that the rate has been stable and is below the background rate of acute renal failure in the general population. The comparative reporting rate analysis for renal failure shows that the reporting rate for rosuvastatin is in line with the reporting rate for lovastatin after its first year on the market, the first statin available in the US. A proportional reporting analysis of renal failure for rosuvastatin versus the other marketed statins, based on the concept of proportional reporting ratio, does not reveal a potential safety signal. A medical review of the spontaneous renal reports for rosuvastatin shows that the reports had alternative likely causes of renal failure or had insufficient information for analysis.there is no clear evidence provided by any of these reports that rosuvastatin causes renal failure. The clinical trial safety data on over 45, patients in the ongoing clinical studies have raised no safety concerns. Analysis of data on over 2 patients on rosuvastatin for at least 2 years showed that renal function remained stable. 7 In summary, AstraZeneca continues to monitor all renal events closely. The ongoing pharmacoepidemiology programme will deliver comparative renal safety data results from 25. Weekly monitoring of worldwide spontaneous reporting rate of renal failure for rosuvastatin The cumulative spontaneous reporting rate for renal failure has been stable. AstraZeneca has monitored the weekly cumulative reporting rate
of spontaneous reports of renal failure (includes MedDRA terms of renal failure acute, renal insufficiency, renal tubular necrosis, glomerulonephritis, and nephritis interstitial) for rosuvastatin since its first launch in Canada February 23. Despite the Weber effect, and a heightened awareness of potential side effects, the worldwide reporting rate of renal failure increased marginally within the first 6 months of launch and then stabilised (<.1% or very rare by CIOMS definition) as shown in Figure 7.
Figure 7: Cumulative post-marketing reporting rate of renal failure for rosuvastatin 1.9.8.7 Patients = new and switched prescriptions Reporting rate <1:1, = very rare (CIOMS).6.5.4.3.2.1 4-Jun-23 18-Jun-23 2-Jul-23 16-Jul-23 3-Jul-23 13-Aug-23 27-Aug-23 1-Sep-23 24-Sep-23 8-Oct-23 22-Oct-23 5-Nov-23 19-Nov-23 3-Dec-23 17-Dec-23 31-Dec-23 14-Jan-24 28-Jan-24 11-Feb-24 25-Feb-24 1-Mar-24 24-Mar-24 7-Apr-24 21-Apr-24 5-May-24 19-May-24 2-Jun-24 16-Jun-24 3-Jun-24 14-Jul-24 28-Jul-24 11-Aug-24 25-Aug-24 8-Sep-24 22-Sep-24 6-Oct-24 2-Oct-24 3-Nov-24 17-Nov-24 1-Dec-24 15-Dec-24 29-Dec-25 Week Starting Reporting Rate Reporting Rate Per 1, Patients
Background Incidence of acute renal failure in the community The annual incidence of acute renal failure in the community has been estimated at 1 case in 5, distributed over the entire adult population independent of age or renal disease risk factors, as reported in several large studies 3-6 The rate of acute renal failure in the population of patients taking statin therapy is estimated at 5 fold higher (1:1), as many of these patients have common risk factors for renal failure (higher age, hypertension, diabetes, atherosclerotic cardiovascular disease) compared to the entire adult population. Thus the spontaneous reporting rate of renal failure for rosuvastatin is much lower than the background incidence in the general population.
Figure 8: Semi-annual reporting rates of renal failure,# excluding rhabdomyolysis, with statins from launch Global spontaneous reporting rate for CRESTOR versus US spontaneous rates for other statins* Semi-annual Reporting Rate Per 1,, Prescriptions 1 Atorvastatin Fluvastatin 8 Lovastatin Pravastatin 6 Simvastatin 4 Rosuvastatin 2-2 All spontaneous reports including expedited, periodic and direct reports. *US reporting rate for statins based on FDA Adverse Events Reporting System made available through Freedom of Information Act divided by US prescribing data supplied by IMS through August 23. #Renal failure includes the MedDRA preferred terms of renal failure/renal insufficiency, renal failure acute and renal failure chronic. Update: 17 December 24 Background reporting rates of acute renal failure in the entire population are estimated to be 1 case per 5 Global 6-monthly reporting rate for rosuvastatin based on spontaneous report counts of within AstraZeneca global drug safety database divided by estimated worldwide prescriptions to end November 24. Total prescriptions based on IMS data from US, Canada, UK, France, Italy and The Netherlands; rest of world prescriptions based on actual sales calculations.
Comparative reporting rate analysis of renal failure with the other statins Figure 8 shows the cumulative semi-annual reporting rate of renal failure for all statins from their first year of launch and shows that the global rate for rosuvastatin is in line with the rate for lovastatin that occurred shortly after launch. Lovastatin was the first statin available and was subject to heightened awareness of potential side effects. Subsequent to this initial period, the rate of reporting of renal failure in patients taking lovastatin remained low. Rosuvastatin is the first statin launched since the withdrawal of cerivastatin and is also subject to heightened awareness of potential side effects. The renal failure reports include MedDRA preferred terms of acute renal failure, renal failure, renal insufficiency and/or chronic renal failure. As the FDA has only released the electronic AERS database through fourth quarter of 23, the database contained very few reports of renal failure for rosuvastatin, which was launched in US in September 23. Thus, the global reporting rate of renal failure for rosuvastatin is presented here. The semi-annual reporting rate for rosuvastatin is calculated by dividing the worldwide spontaneous reports of acute renal failure (received by the internal global safety database for AstraZeneca) by the worldwide prescriptions for rosuvastatin during that 6 month period. These rates represent the most recent and comprehensive information to date. US spontaneous reports of acute renal failure for comparator statins and ezetimibe were obtained from the US Food and Drug Administration (FDA) Adverse Event Reporting System (AERS), available to the public through the Freedom of Information Act (FOIA). The US semi-annual reporting rates of renal failure for other statins from their launches to quarter 4 of 23 were then calculated by dividing the report counts by the numbers of US prescriptions. All reporting rates of renal failure are expressed as reports of renal failure per million prescriptions. Cumulative Reporting Proportion As previously discussed, increased AE reporting often occurs during the first 2-3 years that a new drug is marketed. In the case of rosuvastatin, the level of reporting of renal adverse events is likely to have been increased still further by the level of publicity that has been generated related to the renal tolerability of rosuvastatin. The cumulative reporting proportion is therefore a useful measure to control somewhat for the various external factors affecting reporting rates across marketed products from the same database. As shown in figures 9 and 1, the proportion of renal failure to all AEs for rosuvastatin is similar to that for the other currently marketed statins, suggesting that there is no potential safety signal of renal failure for rosuvastatin versus that of the other statins. Figures 9 and 1 show the cumulative reporting proportion for renal failure (with and without rhabdomyolysis association). As with reports of rhabdomyolysis, data for
rosuvastatin is taken from the FDA AERS report issued on 5 October 24 and data for other statins is based on an analysis conducted by Galt Associates on the other statins based on the electronic FDA AERS database.
Figure 9: Reports of renal failure* as a proportion of total adverse event reports based on FDA AERS data Reports of renal failure as a % of all AE reports other statins 8 7 6 5 4 3 2 1 2.2% 3.% 5.7% 4.% 4.% 3.5% Reports of renal failure as a % of all AE reports - rosuvastatin atorvastatin pravastatin lovastatin simvastatin fluvastatin rosuvastatin Proportion of all reports of renal failure* for other currently marketed statins from November 1997 to 3 September 23, based on analysis of the electronic FDA Adverse Events Reporting System (AERS) database by Galt Associates with elimination of duplicate reports. Proportion of all reports of renal failure* (initial and duplicate follow-up reports) (from 24 April 22 to 5 October 24) from FDA AERS Freedom of Information (FOI) Report issued on 4 October 24 *Renal failure includes MedDRA preferred terms of renal failure, acute renal failure and renal insufficiency with and without rhabdomyolysis
Figure 1: Reports of renal failure independent of rhabdomyolysis as a proportion of the total adverse event reports based on FDA AERS data Reports of renal failure as a % of all AE reports other statins 8 7 6 5 4 3 2 1 1.4% 1.% 2.% 1.2% 1.8% 1.7% Reports of renal failure as a % of all AE reports - rosuvastatin atorvastatin pravastatin lovastatin simvastatin fluvastatin rosuvastatin Proportion of all reports of renal failure* for other currently marketed statins from November 1997 to 3 September 23, based on analysis of the electronic FDA Adverse Events Reporting System (AERS) database by Galt Associates with elimination of duplicate reports. Proportion of all reports of renal failure* (from 24 April 22 to 4 October 24) from manual counting and elimination of duplicate reports based on FDA AERS text file AE listing. *Renal failure includes MedDRA preferred terms of renal failure acute, renal failure acute or chronic, renal failure aggravated, renal failure chronic, renal failure chronic aggravated, renal failure NOS, renal insufficiency with the drug as a primary and secondary suspect
Medical review of the spontaneous reports of renal failure for rosuvastatin Most of the spontaneous adverse event reports of renal failure and renal insufficiency were either assigned alternative causality by the reporting physician or contain information associating the event with alternative, plausible causes of the event e.g. trauma, surgery or other diseases. With respect to this detailed medical review, AstraZeneca continues to monitor all key adverse events weekly, including but not limited to renal events, and has detected no pattern of reports suggesting that rosuvastatin causes renal failure. Summary AstraZeneca continues to monitor post-marketing adverse event reports rigorously and dedicates intensive efforts to follow up reports and evaluate individual cases. The post-marketing safety profile of rosuvastatin is consistent with that seen in the clinical trial programme and similar to that of other currently marketed statins. It is important to note the following limitations with comparative spontaneous reporting rates: Spontaneous reports (including the FDA AERS reports) are voluntary reports from health care professionals and/or patients. They are often incomplete and cannot be fully investigated, and do not imply a causal relationship. Prescription data are also crude estimates of patient exposure because of uncertainty of patient compliance. Spontaneous reporting rates are expected to be lower than the actual incidence of adverse events due to under-reporting. Spontaneous reporting rates are susceptible to reporting bias including an increase in reporting due to the Weber effect, increased publicity and enhanced awareness of the potential sideeffects. The spontaneous reporting rates of rhabdomyolysis for rosuvastatin, other statins and ezetimibe do not represent head-tohead comparative studies and must be interpreted with caution References 1. Pasternak RCD, Smith SC Jr, Bairey-Merz CN, et al. ACC/AHA/NHLBI advisory on the use and safety of statins. J Am Coll Cardiol. 22;4:568-573.
2. Weber JCP. Epidemiology of adverse reactions to nonsteroidal antiinflammatory drugs. In: Rainsford KD, Velo GP, eds. Advances in Inflammation Research. Vol. 6. New York, NY: Raven Press;1984:1-7. 3. Madrid Acute Renal Failure Study Group. Epidemiology of acute renal failure: a prospective, multicenter, community-based study. Kidney Int 1996; 5(3):811-8. 4. Freest TG et al. Incidence of severe acute renal failure in adults: results of a community based study. BMJ 36: 481-483, 1993. 5. Robertson S et al. High incidence of renal failure requiring shortterm dialysis: a prospective observational study. QJM 95: 585-59, 22. 6. Metcalfe W et al. Acute renal failure requiring renal replacement therapy: incidence and outcome. QJM 95: 579-583, 22. 7. Vidt DG et al. Rosuvastatin-Induced Arrest in Progression of Renal Disease. Cardiology 24;12:52-6 1 Pasternak RCD, Smith SC Jr, Bairey-Merz CN, et al. ACC/AHA/NHLBI advisory on the use and safety of statins. J Am Coll Cardiol. 22;4:568-573. 2 Weber JCP. Epidemiology of adverse reactions to nonsteroidal antiinflammatory drugs. In: Rainsford KD, Velo GP, eds. Advances in Inflammation Research. Vol. 6. New York, NY: Raven Press;1984:1-7.