Drug Profile

Rosuvastatin (CRESTOR) became the sixth cholesterol-lowering statin drug on the U.S. market when it was approved by the Food and Drug Administration (FDA) in 2003. The other members of the statin family are atorvastatin (LIPITOR), fluvastatin (LESCOL, LESCOL XL), lovastatin (ALTOPREV), pitavastatin (LIVALO, ZYPITAMAG), pravastatin (PRAVACHOL) and simvastatin (ZOCOR). These drugs are only approved to be used along with a low-cholesterol diet and an exercise program to lower cholesterol.

Rosuvastatin is the most dangerous of the popular cholesterol-lowering statin drugs, according to a study published in the medical journal Circulation.[1]

One statin, cerivastatin (BAYCOL), was removed from the market in 2001 because of at least 31 reports of fatal rhabdomyolysis, an adverse reaction involving the destruction of muscle tissue that can lead to kidney failure. We began warning patients not to use this drug more than three years before it was removed from the market.

A number of factors went into our decision to list rosuvastatin as a Do Not Use drug:

1. Rosuvastatin joins fluvastatin as one of the statins that have not been determined by the FDA to confer a health benefit in terms of reducing the serious cardiovascular consequences of high cholesterol, such as a first or second heart attack or stroke. Lovastatin, pravastatin, atorvastatin and simvastatin have shown such benefits to patients, in addition to cholesterol-lowering properties, and this is reflected in the professional product labels and advertising for these drugs.
   
   The only reliable, valid indicator that consumers can use to assess whether a drug has a demonstrated health benefit is the information contained in the drug’s FDA-approved product labeling. Advertising claims for drugs cannot be made unless research showing that the drug will actually do what a manufacturer claims it will do has been submitted to, and approved by, the FDA.
2. Rosuvastatin causes abnormal elevations of protein and blood in the urine and signs of serious kidney toxicity. Numerous cases of renal failure have now been reported after the drug's approval. Other statins are not associated with this risk of direct kidney toxicity.
3. Rosuvastatin is the only statin that has shown life-threatening rhabdomyolysis in preapproval clinical trials, and at least 68 additional cases have occurred after its approval.

Rosuvastatin was approved for use in both the U.K. and Canada in February 2003, six months before the drug’s approval in the U.S. Through the end of October 2003, cases of kidney failure and rhabdomyolysis were reported in the U.K. In Canada there had been reports of kidney toxicity in five patients taking rosuvastatin through September 2003.

AstraZeneca originally filed its application with the FDA to market rosuvastatin in June 2001. The application was delayed when the company halted clinical trials worldwide after reports of kidney damage and muscle weakness (an early sign of rhabdomyolysis) in patients taking 80 milligrams (mg) of the drug per day. The FDA asked AstraZeneca for more data, and the company stopped development of the 80-mg dose because of safety problems. Rosuvastatin is sold in 5-, 10-, 20-, and 40-mg doses. Because of safety concerns, there are also special restrictions on the distribution of the 40-mg dose.

Adverse effects

Public Citizen's Health Research Group made a formal presentation before the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee on July 19, 2003, strongly opposing the approval of rosuvastatin because of its unique kidney toxicity. We were also seriously concerned about seven cases of rhabdomyolysis; these cases were common enough to have shown up in the preapproval clinical trials of rosuvastatin in which the 80-mg dose was used. Not one case of rhabdomyolysis occurred in any of the preapproval studies of the previously approved statins, including cerivastatin, which was removed from the market because of an association with rhabdomyolysis.

We testified before the advisory committee that a major factor that distinguishes rosuvastatin from the other five statins that remain on the market is the drug’s potential to cause kidney toxicity. In the FDA review documents posted on the agency’s website before the Endocrinologic and Metabolic Drugs Advisory Committee, the following was noted: "In contrast to currently approved statins, rosuvastatin was also associated with renal [kidney] findings not previously reported with other statins."[2] A supplemental analysis by researchers at Public Citizen revealed that the rate of reports of kidney failure or damage among patients taking rosuvastatin is 75 times higher than in all patients taking all other statin drugs.[3]

A number of patients taking primarily the 40- and 80-mg doses of rosuvastatin had more frequent persistent protein in the urine (proteinuria) and blood in the urine (hematuria). In some subjects, these conditions also were associated with another abnormal test result: an elevated serum creatinine level, which is an early sign of kidney toxicity. The FDA documents pointed out that there were two cases of kidney failure and one case of kidney insufficiency associated with the 80-mg dose of rosuvastatin. These patients also had both protein and blood in the urine.

Rosuvastatin’s professional labeling also carries warnings about elevated liver enzymes, an early sign of possible liver toxicity, and muscle pain and weakness that may be precursors to rhabdomyolysis. These warnings appear in the labeling for all statin drugs:

It is recommended that liver function tests be performed before and at 12 weeks following both the initiation of therapy and any elevation of dose, and periodically (e.g., semiannually) thereafter.

Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria (a protein from muscle) have been reported with use of rosuvastatin and other drugs in this class.

An FDA medical officer reviewing rosuvastatin had sobering comments on the cases of kidney problems with the drug: "These three cases of renal insufficiency of unknown etiology are of concern because they present with a clinical pattern, which is similar to the renal disease seen with rosuvastatin in these clinical trials. There is mild proteinuria associated with hematuria and the suggestion of tubular inflammation or necrosis [death of cells]. All cases occurred at the 80 mg dose which was also associated with the greatest number of patients with abnormal renal findings in these clinical trials. Proteinuria and hematuria could be potentially managed with regular urinalysis screening. However, if they are the signals for the potential progression to renal failure in a small number of patients, this may represent an unacceptable risk since currently approved statins do not have similar renal effects."[2]

AstraZeneca attempted to "spin" the drug’s potential for causing elevated protein levels in the urine by claiming that it was due to a previously unobserved effect of the statin family of drugs. However, the research submitted by AstraZeneca to the FDA did not show a similar degree of urine protein elevation with any of the other statins.

The professional product labeling goes on to instruct physicians to tell patients "to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever."

The risk of muscle damage leading to rhabdomyolysis during treatment with rosuvastatin may be further increased when it is used together with other cholesterol-lowering drugs and cyclosporine (NEORAL, SANDIMMUNE), a drug used after transplantation to prevent organ rejection. When rosuvastatin was given together with cyclosporine in heart transplant patients, the amount of rosuvastatin in the blood was significantly higher than it was in healthy volunteers. This increase is considered to be clinically significant. The risk of muscle problems possibly leading to rhabdomyolysis also is increased when niacin is used in combination with rosuvastatin to lower cholesterol.

The statin drugs seem to share psychiatric risks with other cholesterol-lowering drugs. Aggressive behavior; memory impairment; mood changes; and cognitive, sleep and perception disorders, such as nightmares, have been reported with the use of many drugs used to treat high cholesterol: the statins, fenofibrate (TRICOR), gemfibrozil (LOPID), ezetimibe (ZETIA) and clofibrate.[4],[5] Though researchers have not yet established a direct link between these reports and the use of the cholesterol-lowering drugs listed, patients should be alert to this possibility and report unexpected changes to their doctor. Statin-induced memory impairment could be mistaken for other conditions such as early Alzheimer’s disease. This could result in the unnecessary prescribing of a drug to treat Alzheimer’s disease.[6]

In addition to the adverse effects listed above, there is also an association between the long-term use of statins and an increased, although rare, risk of neuropathy (damage to the nervous system). This can take the form of decreased or increased sensation, abnormal sensation (pins and needles) or muscle weakness. In most cases, the symptoms improved upon stopping the drug.[7]

A single dose of rosuvastatin given to healthy volunteers who were taking the cholesterol-lowering drug gemfibrozil (LOPID) resulted in a significant increase in the amount of rosuvastatin in the body. The Warnings section of rosuvastatin’s labeling states, in bold, that "Combination therapy with rosuvastatin and gemfibrozil should generally be avoided."

When rosuvastatin was given to patients on stable warfarin (COUMADIN, JANTOVEN) treatment to prevent blood clots, there was a clinically significant rise in the International Normalized Ratio, the laboratory test used to monitor warfarin therapy that can increase the risk of bleeding.

Risk of increased blood sugar levels and diabetes

In January 2013, Health Canada (an agency similar to the FDA) issued a communication to the public concerning the use of statins and the risk of increased blood sugar levels in patients with a pre-existing risk of diabetes. Close monitoring for diabetes is recommended in these patients when they are using statins.[8]

In May 2017, Nutrition, Metabolism & Cardiovascular Diseases published a study showing that statin drugs are associated with an increased risk of new-onset diabetes.[9]

Studies say...

In 2010 there were 11 reports of tendinitis and 10 reports of tendon rupture associated with statin drug therapy that were reported to the Netherlands Pharmacovigilance Centre Lareb. Tendinitis occurs when the tendon — fibers that join the muscles to the bones — becomes inflamed. Tendon rupture occurs when the tendon is torn.[10]

The Canadian Adverse Reactions Newsletter published an article in its October 2011 issue concerning the use of statin drug therapy and the occurrence of interstitial lung disease (ILD), a group of lung disorders that affects breathing. The article stated that "As of Mar. 31, 2010, Health Canada received 8 adverse reaction (AR) reports of ILD, or pathologies associated with ILD." These cases were suspected to be associated with statin drug use.[11]

In June 2012, the Archives of Internal Medicine published an article concerning a meta-analysis of previously published studies on the use of statins in women. The meta-analysis revealed two major findings: First, the benefits of statins were significant for all outcomes in men, a result consistent with previously published results; second, although there was a statistically significant risk reduction in both men and women for coronary mortality, heart attack (fatal and nonfatal) and cardiac intervention, there was "no statistically significant risk reduction for women taking statins compared with women taking placebo for the reduction of all-cause mortality [death from any cause] and any type of stroke."[12]

In 2012, a study was conducted reviewing muscle and tendon adverse events associated with statin drug use reported to the FDA Adverse Event Reporting System. The data studied in these post-marketing case reports showed that adverse events reported varied for the different drugs in the statin drug class. The drugs reviewed in the study were atorvastatin, simvastatin, lovastatin, pravastatin, rosuvastatin and fluvastatin. The study data examined the potency of each drug relative to the risk of muscle-related adverse events. The results showed that rosuvastatin had the highest relative risk of adverse events, atorvastatin and simvastatin had an intermediate risk, pravastatin and lovastatin had the lowest risk, and fluvastatin was "an apparent exception." (For a detailed description of adverse events reported for each drug, see the referenced article.)[13]

In 2013, the Annals of Internal Medicine published an article on the co-administration of statins (atorvastatin, lovastatin and simvastatin) with macrolide antibiotics (clarithromycin, erythromycin and azithromycin) in patients older than 65 years. The data reviewed showed that patients using atorvastatin, lovastatin or simvastatin experienced statin drug toxicity with co-administration of clarithromycin or erythromycin.[14]

The British Medical Journal published an article in May 2013 that examined the risk of new-onset diabetes in patients treated with statin drugs. The study analyzed the risk of new-onset diabetes in patients treated with atorvastatin, simvastatin or rosuvastatin compared with patients treated with pravastatin. The results of the study data found that patients treated with atorvastatin, simvastatin or rosuvastatin had a higher risk of new-onset diabetes. The study also stated that patients treated with lovastatin and fluvastatin did not show this increased risk.[15]

An article published in 2015 in Diabetologia showed that patients using statins had a 46% increase in the risk of type 2 diabetes.[16]

In 2016, the American Journal of Cardiovascular Drugs published an article showing that statin drugs were associated with an increased risk of developing diabetes.[17]

In 2013, the American Journal of Cardiology published a review of 17 different randomized, controlled studies on the use of rosuvastatin and the increased risk of developing diabetes compared with the use of other statin drugs.[18] The review found that of the statins, rosuvastatin was associated with the highest risk of diabetes (25%) compared with a placebo.

In 2018, the Journal of the American Medical Association Internal Medicine (JAMA Internal Medicine) published an article showing that statins are associated with a rare but potentially disabling autoimmune muscle disorder known as idiopathic inflammatory myositis.[19]

With more than 200 million prescriptions each year in the U.S., statins are one of the most prescribed drug categories here and in much of the world (at least in so-called developed countries). Yet about two-thirds of statins are not prescribed for secondary prevention but for primary prevention — that is, to prevent people who have not previously had heart attacks, strokes or other cardiovascular disease from developing such diseases. Over the past decade, especially in the last several years, a number of published studies and reviews have documented the overprescribing of statins for primary prevention, especially for those whose combination of age, medical history, cholesterol levels and other cardiovascular risk factors place them at the lower end of the scale of risk for first-time cardiovascular events. This research has raised serious questions regarding the need for any pharmacological intervention in these lower-risk people. These statin users are subjected to the risks of these drugs without benefits.

Regulatory actions surrounding rosuvastatin

2005: The FDA issued a public health advisory warning and required that the product label for rosuvastatin be updated to highlight the findings from a study showing increased rosuvastatin concentrations in Asian patients. The label was updated to state that the 5-mg dose should be considered the starting dose for Asian patients and that any increase in dose should take into consideration the increased exposure in this population. The label also emphasizes the risk of muscle pain and weakness (myopathy), particularly at the 40-mg dose. The FDA also made statements about the muscle and kidney safety of rosuvastatin based on an extensive review of available information.

In March 2005, the FDA denied two citizen’s petitions that would have required the professional product labeling for the cholesterol-lowering statin drugs to recommend that the dietary supplement coenzyme Q10 be added to statins to reduce the risk of muscle damage, heart damage and congestive heart failure. They found that there was not significant evidence to suggest that coenzyme Q10 levels are responsible for the adverse effects associated with statin use or that supplementation with coenzyme Q10 has any effect on preventing or lessening any of the potential adverse effects of the statin drugs.[20]

A popular buzzword frequently used by the FDA is "risk management" — assessing public health risks, analyzing methods for reducing them and taking appropriate action. The FDA’s risk-management strategy for the safety problems associated with rosuvastatin can hardly be called appropriate. The 40-mg tablet was not to be stocked in retail pharmacies, and pharmacies would need to go through a wholesaler to obtain the 40-mg tablets. This means that it takes an extra day for the tablets arrive at the pharmacy. Somehow the FDA believes that "these steps will help to ensure that the 40-mg dose is available only to patients who truly need this dose." However, there is nothing to prevent a physician from writing a prescription for 20-mg tablets and instructing the patient to take two tablets of rosuvastatin daily.

The only "appropriate" and safe risk-management strategy for rosuvastatin would have been to not approve the drug in the first place.

2012: In February, the FDA issued information concerning safety changes for statins. These changes include the removal of routine monitoring of liver enzymes from the drug product information and the addition of information about potential, generally non-serious and reversible cognitive adverse effects, as well as reports of increased blood sugar and glycosylated hemoglobin (HbA1c) levels.

Safety changes also were added for lovastatin concerning contraindications and dose limitations when lovastatin is taken with certain medicines that can increase the risk of muscle injury.[21]

In March, the FDA issued an advisory concerning interactions between protease inhibitors and certain statin drugs. Human immunodeficiency virus or hepatitis C virus protease inhibitors, when used with statins, may raise the levels of statins in the blood and increase the risk of muscle injury (myopathy).[22]

2013: The FDA updated the drug product label for statins to include information on rare reports of an autoimmune myopathy associated with use of such drugs. Immune-mediated necrotizing myopathy presents with proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of treatment with statins.[23]

2023: The FDA updated the drug product label for rosuvastatin to include information on rare reports of new or worsening myasthenia gravis (a disease causing muscle weakness).[24],[25]

Summary

Rosuvastatin has no proven health benefit in people with elevated cholesterol levels. It has caused potentially serious kidney toxicity that is not seen with the other statins; it is the only statin that caused rhabdomyolysis, a life-threatening adverse drug reaction, in preapproval clinical trials. It is more likely than other statins to increase the risk of diabetes. In addition, there are already four statins on the market that are safer than rosuvastatin and have demonstrated a health benefit to patients. See simvastatin (ZOCOR), pravastatin (PRAVACHOL), lovastatin (MEVACOR) and atorvastatin (LIPITOR).