Rosuvastatin (Crestor) for dyslipidaemia
Published in NPS RADAR
Date published: About this date
Rosuvastatin is listed on the Pharmaceutical Benefits Scheme (PBS) as a restricted benefit for patients who meet the criteria set out in the General Statement for Lipid Lowering Drugs described in the Schedule of Pharmaceutical Benefits.
Reason for PBS listing
The Pharmaceutical Benefits Advisory Committee (PBAC) recommended rosuvastatin for listing on a cost-minimisation basis compared with atorvastatin, with an equi-effective dose of rosuvastatin to atorvastatin of 1:3.1 This recommendation was based on clinical trials that compared low-density lipoprotein–cholesterol (LDL-C) lowering with rosuvastatin and atorvastatin. There are currently no head-to-head studies comparing clinical outcomes with rosuvastatin at equipotent doses of other statins.
Place in therapy
Rosuvastatin is an HMG-CoA reductase inhibitor (statin) that lowers LDL-C levels.2 Statins are first line for the treatment of hypercholesterolaemia.3,4 Aim for a target LDL-C level < 2.5 mmol/L (total cholesterol < 4 mmol/L).5,6 Any step towards the target is likely to be beneficial.
Lowering LDL-C level
Choose any of the available statins (atorvastatin, fluvastatin, pravastatin, rosuvastatin or simvastatin) when initiating treatment to reduce LDL-C level in patients already compliant with lifestyle changes (such as diet and exercise). There is no clinical outcome evidence to suggest that one statin is better than another. If maximum recommended doses do not achieve treatment goals, switch to a statin that is more potent at lowering LDL-C. Alternatively, combining a statin with another lipid-modifying (non-statin) drug can also help reduce LDL-C.3–5
If changing from other statins to rosuvastatin
Before switching treatment to rosuvastatin, check that the patient has been compliant with taking their statin treatment and with lifestyle changes (such as diet and exercise). Monitor the patient for adverse effects, which can occur when treatments change, especially if titrating rosuvastatin to a higher dose.
Rosuvastatin lowers LDL-C levels across its dose range
Rosuvastatin is more potent at lowering LDL-C on a milligram-for-milligram basis compared with other statins7–9; dose equivalencies are outlined in Table 1.
Table 1: LDL-C-lowering dose equivalence for approved statin doses
|Rosuvastatin||5 mg||10 mg||20 mg||40 mg|
|Atorvastatin||15 mg||30 mg||60 mg|
|Simvastatin||40 mg||80 mg|
Higher doses of rosuvastatin (20–40 mg) achieve reductions in LDL-C not possible with other statins at most doses approved for use in Australia.8,9 Increasing the dose of rosuvastatin from 20 mg to 40 mg provides marginal additional reduction in LDL-C level. Mean percentage change in LDL-C levels from baseline7–9 are shown in Figure 1.
Figure 1: Mean percentage change in LDL-C levels from baseline
Rosuvastatin’s adverse-effect profile is similar to that of other statins. However, its full adverse-effect profile will only be established after more widespread and long-term use in a broader patient population. As with any new drug, use rosuvastatin with caution until more experience accumulates.
Rosuvastatin’s adverse effects include myalgia, asthenia, mild gastrointestinal symptoms, dizziness and headache. Rarely, myopathy, rhabdomyolysis, pancreatitis, and hepatic and skin hypersensitivity reactions can occur.2 Recommended adverse event monitoring is outlined in Box 1.
Box 1: Recommended adverse event monitoring with statins2,3
Statins pose a risk of myopathy and rhabdomyolysis
Stop treatment with rosuvastatin if patients develop unexplained muscle aches, mild to severe pain, or stiffness or weakness, even when plasma creatine kinase levels are normal. Monitor creatine kinase at baseline and repeat during treatment if clinically indicated or with any increase in dose.
Monitor liver transaminases, particularly at higher doses
Elevations in liver transaminase levels (alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST]) with statins are dose dependent but uncommon and rarely develop into serious hepatic reactions (e.g. cholestatic jaundice).
Perform liver function tests before initiating rosuvastatin and periodically thereafter. Stop rosuvastatin if ALT and/or AST levels are persistently 3 or more times the upper limit of normal.
Report suspected adverse reactions to the Adverse Drug Reactions Advisory Committee (ADRAC) online or by using the 'Blue Card' distributed with Australian Prescriber. For information about reporting adverse reactions, see the Therapeutic Goods Administration website.
Familiar statin adverse effects
Pre-registration clinical trials focus on efficacy and so are limited in their ability to detect rare or long-term adverse effects. Postmarketing reports of adverse events can be critical in determining the safety of new drugs, as experience with cerivastatin has shown (withdrawn from worldwide markets August 2001 because of serious muscle-related adverse effects).10
Myopathy rates reported in rosuvastatin clinical trials were similar to those of other statins11,12 and initial postmarketing reports overseas have shown the incidence of rosuvastatin-associated rhabdomyolysis to be similar to other statins.12 However, there have been public statements and analyses questioning rosuvastatin’s toxicity 13,14. In response to this, the US Food and Drug Administration (FDA) conducted a review of muscle and renal adverse event reports for all statins.15 During the first 6 months of each drug’s availability in the US, a myopathy/rhabdomyolysis reporting rate (per 100 000 prescriptions) of 0.3 for rosuvastatin compared with 0.06 for atorvastatin was observed — rates that are a magnitude less than that reported for cerivastatin. The FDA proposed reasons for the observed difference, including the possibility of enhanced reporting of adverse events following the withdrawal of cerivastatin, and acknowledged the small number of cases (2 cases for rosuvastatin and one for atorvastatin). Therefore, the FDA concluded that there was no evidence that rosuvastatin posed any greater risk of muscle toxicity than with other statins.
The incidence of dipstick proteinuria for rosuvastatin doses < 20 mg was similar to that for other statins and placebo13,16,17 and the FDA concluded that there was no convincing evidence that rosuvastatin posed a risk of renal toxicity.15
Postmarketing adverse-event reports are limited by variable information quality and the tendency in clinical practice to under-report adverse events, particularly less serious ones; these reports do not reflect the true adverse event incidence rate. While it is too early to draw definitive conclusions about rosuvastatin’s overall safety profile relative to that of other statins, such conclusions must include all the evidence available from pre-registration clinical trials, ongoing clinical trials and postmarketing reports.
Rosuvastatin interacts with cyclosporin, gemfibrozil and warfarin
Rosuvastatin dose adjustment is required with concurrent cyclosporin (maximum rosuvastatin dose 5 mg daily) or gemfibrozil (maximum rosuvastatin dose 10 mg daily).2 Monitor for increased INR in patients taking warfarin. Refer to the approved product information for further drug interaction information.2 Unlike atorvastatin and simvastatin, rosuvastatin clearance is not dependent on cytochrome P450 3A4 enzyme metabolism.2,3,11,18 As such, there are no interactions between rosuvastatin and cytochrome P450 3A4 inhibitors such as erythromycin, fluconazole, itraconazole and ketoconazole.
Start with 5 mg and titrate if necessary to achieve treatment goals (dose range 5–20 mg once daily). Patients of Asian descent require lower doses. Measure the LDL-C level within 4 weeks of initiating rosuvastatin, or after dose titration. Rosuvastatin can be taken at any time of the day, with or without food.2,3,19
Consider specialist supervision when prescribing rosuvastatin above 20 mg daily
Higher doses (20–40 mg) may be required to reduce LDL-C levels. The 40 mg dose should only be considered for patients who are still at high cardiovascular risk after their response to 20 mg daily is assessed and in whom regular follow-up is planned.2,3,19 Do not exceed the 40 mg dose in any patient and do not use this dose in patients of Asian descent.2
Information for patients
Advise patients that:
- rosuvastatin must be taken every day, together with lifestyle changes such as diet and exercise
- adverse effects of the muscle or liver are rare but are more likely to occur if blood levels of rosuvastatin are increased (e.g. by interaction with drugs such as cyclosporin and gemfibrozil)
- persistent muscle aches, mild to severe pain, or stiffness or weakness must be reported promptly, especially after any change in treatment.
Suggest or provide the consumer medicine information (CMI) when prescribing or supplying rosuvastatin.
- Pharmaceutical Benefits Advisory Committee. July 2006 Positive recommendations. Canberra: Australian Government Department of Health and Ageing, 2006. http:/
/ www. health. gov. au/ internet/ wcms/ publishing. nsf/ Content/ pbacrec-pbacrec-jul06 (accessed 27 September 2006)
- AstraZeneca Pty Ltd. Crestor product information. 11 April 2006.
- Rossi S, ed. Australian Medicines Handbook. Adelaide: Australian Medicines Handbook Pty Ltd, 2006.
- Cardiovascular Writing Group. Therapeutic Guidelines: Cardiovascular Version 4. Melbourne: Therapeutic Guidelines Ltd, 2003.
- New Zealand Guidelines Group. New Zealand Cardiovascular Guidelines. Evidence-based Best Practice Guidelines. Handbook for Primary Care Practitioners. Wellington: New Zealand Guidelines Group, 2005. http:/
/ www. nzgg. org. nz/ guidelines/ 0101/ 050624_CVD_Resource_(Final)_v5_for_printing_2. pdf (accessed 24 August 2006).
- National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand. Position Statement on Lipid Management. Heart, Lung Circ 2005;14:275–91. http:/
/ www. heartfoundation. com. au/ downloads/ Lipids_HLCPosStatementFINAL_2005.
- Blasetto JW, Stein EA, Brown WV, et al. Efficacy of rosuvastatin compared with other statins at selected starting doses in hypercholesterolemic patients and in special population groups. Am J Cardiol 2003;91:3C–10C. [PubMed]
- Schneck DW, Knopp RH, Ballantyne CM, et al. Comparative effects of rosuvastatin and atorvastatin across their dose ranges in patients with hypercholesterolemia and without active arterial disease. Am J Cardiol 2003;91:33–41. [PubMed]
- Jones PH, Davidson MH, Stein EA, et al. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* trial). Am J Cardiol 2003;92:152–60. [PubMed]
- Grundy SM. The issue of statin safety: Where do we stand? Circulation 2005;111:3016–9. [PubMed]
- Anonymous. Rosuvastatin. Opt for statins with evidence of efficacy on clinical outcome. Prescrire Int 2004;13:132–4. [PubMed]
- Davidson MH. Rosuvastatin safety: Lessons from the FDA review and post–approval surveillance. Expert Opin Drug Saf 2004;3:547–57. [PubMed]
- Wolfe SM. Dangers of rosuvastatin identified before and after FDA approval. Lancet 2004;363:2189–90. [PubMed]
- Alsheikh-Ali AA, Ambrose MS, Kuvin JT, et al. The safety of rosuvastatin as used in common clinical practice: A postmarketing analysis. Circulation 2005;111:3051–7. [PubMed]
- Glason SK. Re: Docket No: 2004P–0113/CPI. Rockville: Department of Health and Human Services, Food and Drug Administration, 2005. http:/
/ www. fda. gov/ cder/ drug/ infopage/ rosuvastatin/ crestor_CP. pdf (accessed 04 August 2006).
- Shepherd J, Hunninghake DB, Stein EA, et al. Safety of rosuvastatin. Am J Cardiol 2004;94:882–8. [PubMed]
- Tiwari A. An overview of statin-associated proteinuria. Drug Discov Today 2006;11:458–64. [PubMed]
- Bottorff MB. Statin safety and drug interactions: clinical implications. Am J Cardiol 2006;97:S27–S31. [PubMed]
- National Institute for Health and Clinical Excellence. Statins for the prevention of cardiovascular events. Technology Appraisal 94. London: National Institute for Health and Clinical Excellence, 2006. http:/
/ www. nice. org. uk/ page. aspx?o=TA094guidance (accessed 26 July 2006).
Updated 1 December 2006: Replaces a prerelease version that was distributed with the December 2006 update of Medical Director software version 2.89
First released: 1 December 2006