A nurse is caring for a client who is taking atorvastatin and has a new prescription for gemfibrozil

After coronary bypass five years ago this patient was treated with atorvastatin 40 mg daily and gemfibrozil 600 mg twice daily for combined hyperlipidaemia. He also took extended-release diltiazem for hypertension and aspirin 100 mg daily. He complained of minor, tolerable muscle aches but his creatine kinase levels were normal.

In March, cerivastatin 0.3 mg daily was substituted for atorvastatin. Three weeks later, the patient noticed flu-like symptoms with aching of the neck, shoulders and limbs. He persisted with his therapy in spite of severe muscle aching and stiffness, weakness, lethargy and decreasing urinary output. When he presented in April he had signs of acute renal failure and his urine contained pigmented casts typical of myoglobinuria. His creatine kinase peaked at over 30 000 U/L with a high creatinine (0.75 mmol/L) and urea (49.7 mmol/L). His liver function was also affected (LDH 2727 U/L, ALT 1089 U/L, AST 1827 U/L). After haemodialysis for 15 days, his initially profound muscle weakness improved and his strength returned to normal over subsequent weeks, as did his renal function.

Case 2

A 63-year-old woman with combined hyperlipidaemia (total cholesterol 7.5 mmol/L, triglycerides 10.2 mmol/L) was prescribed cerivastatin 0.4 mg daily. Three years previously she had been treated with atorvastatin, but ceased this after six months because of severe muscle aches and pains. Gemfibrozil 600 mg daily was subsequently added to cerivastatin when her total cholesterol and triglycerides were 5.4 and 5.7 mmol/L respectively. Three weeks later, she developed stiffness and pain in the lower back, with severe impairment of mobility. She ceased medications and her symptoms had largely resolved on presentation two days later. Her plasma concentrations were: creatine kinase 14 500 U/L, LDH 647 U/L, AST 352 U/L, ALT 191 U/L. Glucose, creatinine and urea concentrations were normal. TSH was marginally elevated (4.7 mIU/L) and free T4 borderline (11 pmol/L). Two days later her creatine kinase was 45600 U/L. Her symptoms and creatine kinase concentrations were normal one week later.

Comment

Rhabdomyolysis has been a frequent adverse drug reaction with cerivastatin-gemfibrozil combination therapy. Fatalities have led to the withdrawal of cerivastatin from the market, other than in Japan where gemfibrozil is not available.

High plasma concentrations of `statins' predispose to rhabdomyolysis with either high doses or co-administration of cytochrome P450 inhibitors, including calcium channel blockers1 (see Case 1).

Conditions predisposing to myopathy include severe hypoxia, hyperthermia, hypotension, hypothyroidism (see Case 2), recent major surgery, severe acute infections, severe endocrine, metabolic and electrolyte disturbances, uncontrolled seizures and possibly underlying genetic myopathies.2 Patients experiencing myopathy with one statin are likely to experience it with another (see Cases 1 and 2).

Severe myopathy may occur without elevation of creatine kinase, and therapy should be withdrawn in patients, especially elderly women, complaining of muscle weakness.3 Patients should have normal thyroid function before starting treatment with lipid-lowering therapy. Adverse drug reactions should be reported to the Adverse Drug Reactions Advisory Committee to ensure adequate post-marketing surveillance.

[Posted 07/20/2021]

AUDIENCE: Patient, Health Professional, OBGYN, Cardiology, Endocrinology, Pharmacy

ISSUE: The FDA is requesting revisions to the information about use in pregnancy in the prescribing information of the entire class of statin medicines. These changes include removing the contraindication against using these medicines in all pregnant patients. A contraindication is FDA's strongest warning and is only added when a medicine should not be used because the risk clearly outweighs any possible benefit. Because the benefits of statins may include prevention of serious or potentially fatal events in a small group of very high-risk pregnant patients, contraindicating these drugs in all pregnant women is not appropriate.

FDA expects removing the contraindication will enable health care professionals and patients to make individual decisions about benefit and risk, especially for those at very high risk of heart attack or stroke. This includes patients with homozygous familial hypercholesterolemia and those who have previously had a heart attack or stroke.

BACKGROUND: Statins are a class of prescription medicines that have been used for decades to lower low-density lipoprotein (LDL-C or "bad") cholesterol in the blood. Medicines in the statin class include atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

RECOMMENDATIONS:

• Patients: Patients taking statins should notify their health care professionals if they become pregnant or suspect they are pregnant. Your health care professional will be able to advise whether you should stop taking the medicine during pregnancy and whether you may stop your statin temporarily while breastfeeding. Patients who are at high risk of heart attack or stroke who require statins after giving birth should not breastfeed and should use alternatives such as infant formula.
• Health Care Professionals: Health care professionals should discontinue statin therapy in most pregnant patients, or they can consider the ongoing therapeutic needs of the individual patient, particularly those at very high risk for cardiovascular events during pregnancy. Because of the chronic nature of cardiovascular disease, treatment of hyperlipidemia is not generally necessary during pregnancy. Discuss with patients whether they may discontinue statins temporarily while breastfeeding. Advise those who require a statin because of their cardiovascular risk that breastfeeding is not recommended because the medicine may pass into breast milk

The FDA hopes the revised language in the prescribing information will help reassure health care professionals that statins are safe to prescribe in patients who can become pregnant, and help them reassure patients with unintended statin exposure in early pregnancy or before pregnancy is recognized that the medicine is unlikely to harm the unborn baby.

For more information visit the FDA website at: http://www.fda.gov/Safety/MedWatch/SafetyInformation and http://www.fda.gov/Drugs/DrugSafety.

1. Huerta-Alardín AL, Varon J, Marik PE. Bench-to-bedside review: Rhabdomyolysis––an overview for clinicians. Crit Care. 2005 Apr;9(2):158–169. [PMC free article] [PubMed] [Google Scholar]

2. Cervellin G, Comelli I, Lippi G. Rhabdomyolysis: historical background, clinical, diagnostic and therapeutic features. Clin Chem Lab Med. 2010 Jun;48(6):749–756. [PubMed] [Google Scholar]

3. Bosch X, Poch E, Grau JM. Rhabdomyolysis and acute kidney injury. N Engl J Med. 2009 Jul 2;361(1):62–72. [PubMed] [Google Scholar]

4. Book of Numbers. 11:18–34. [Google Scholar]

5. Korkmaz I. Kukul Güven FM, Eren SH, Dogan Z. Quail consumption can be harmful. J Emerg Med. 2011 Nov;41(5):499–502. [PubMed] [Google Scholar]

6. Billis AG, Kastanakis S, Giamarellou H, Daikos GK. Acute renal failure after a meal of quail. Lancet. 1971 Sep 25;2(7726):702. [PubMed] [Google Scholar]

7. Lewis DC, Metallinos-Katzaras E, Grivetti LE. Coturnism: human poisoning by European migratory quail. J Cultur Geogr. 1987;7(2):51–65. [Google Scholar]

8. Rizzi D, Basile C, Di Maggio A, et al. Clinical spectrum of accidental hemlock poisoning: neurologic manifestations, rhabdomyolysis and acute tubular necrosis. Nephrol Dial Transplant. 1991;6(12):939–943. [PubMed] [Google Scholar]

9. Bagley WH, Yang H, Shah KH. Rhabdomyolysis. Intern Emerg Med. 2007 Oct;2(3):210–218. [PubMed] [Google Scholar]

10. Vanholder R, Sever MS, Erek E, Lameire N. Rhabdomyolysis. J Am Soc Nephrol. 2000 Aug;11(8):1553–1561. [PubMed] [Google Scholar]

11. Bywaters EG, Beall D. Crush injuries with impairment of renal function. Br Med J. 1941 Mar 22;1(4185):427–432. [PMC free article] [PubMed] [Google Scholar]

12. Pasternak RC, Smith SC, Jr, Bairey-Merz CN, et al. ACC/AHA/NHLBI Clinical Advisory on the Use and Safety of Statins. Stroke. 2002 Sep;33(9):2337–2341. [PubMed] [Google Scholar]

13. Kasaoka S, Todani M, Kaneko T, et al. Peak value of blood myoglobin predicts acute renal failure induced by rhabdomyolysis. J Crit Care. 2010 Dec;25(4):601–604. [PubMed] [Google Scholar]

14. Watanabe T. Rhabdomyolysis and acute renal failure in children. Pediatr Nephrol. 2001 Dec;16(12):1072–1075. [PubMed] [Google Scholar]

15. Watemberg N, Leshner RL, Armstrong BA, Lerman-Sagie T. Acute pediatric rhabdomyolysis. J Child Neurol. 2000 Apr;15(4):222–227. [PubMed] [Google Scholar]

16. Al-Ismaili Z, Piccioni M, Zappitelli M. Rhabdomyolysis: pathogenesis of renal injury and management. Pediatr Nephrol. 2011 Oct;26(10):1781–1788. [PubMed] [Google Scholar]

17. Khan FY. Rhabdomyolysis: a review of the literature. Neth J Med. 2009 Oct;67(9):272–283. [PubMed] [Google Scholar]

18. Melli G, Chaudhry V, Cornblath DR. Rhabdomyolysis: an evaluation of 475 hospitalized patients. Medicine (Baltimore) 2005 Nov;84(6):377–385. [PubMed] [Google Scholar]

19. Mannix R, Tan ML, Wright R, Baskin M. Acute pediatric rhabdomyolysis: causes and rates of renal failure. Pediatrics. 2006 Nov;118(5):2119–2125. [PubMed] [Google Scholar]

20. Jukema JW, Cannon CP, de Craen AJ, Westendorp RG, Trompet S. The controversies of statin therapy: weighing the evidence. J Am Coll Cardiol. 2012 Sep 4;60(10):875–881. [PubMed] [Google Scholar]

21. U.S. Food and Drug Administration. FDA announces safety changes in labeling for some cholesterol-lowering drugs. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm293623.htm. February 28, 2012. Updated March 2, 2012. Accessed November 21, 2014. [Google Scholar]

22. Chatzizisis YS, Koskinas KC, Misirli G, Vaklavas C, Hatzitolios A, Giannoglou GD. Risk factors and drug interactions predisposing to statin-induced myopathy: implications for risk assessment, prevention and treatment. Drug Saf. 2010 Mar 1;33(3):171–187. [PubMed] [Google Scholar]

23. Joy TR, Hegele RA. Narrative review: statin-related myopathy. Ann Intern Med. 2009 Jun 16;150(12):858–868. [PubMed] [Google Scholar]

24. Bays H. Statin safety: an overview and assessment of the data––2005. Am J Cardiol. 2006 Apr 17;97((8A)):6C–26C. [PubMed] [Google Scholar]

25. Antons KA, Williams CD, Baker SK, Phillips PS. Clinical perspectives of statin-induced rhabdomyolysis. Am J Med. 2006 May;119(5):400–409. [PubMed] [Google Scholar]

26. Fernandez G, Spatz ES, Jablecki C, Phillips PS. Stain myopathy: a common dilemma not reflected in the clinical trials. Cleve Clin J Med. 2011 Jun;78(6):393–403. [PubMed] [Google Scholar]

27. Guyton JR. Benefit versus risk in statin treatment. Am J Cardiol. 2006 Apr 17;97((8A)):95C–97C. [PubMed] [Google Scholar]

28. Thompson PD, Clarkson P, Karas RH. Statin-associated myopathy. JAMA. 2003 Apr 2;289(13):1681–1690. [PubMed] [Google Scholar]

29. Davidson MH, Clark JA, Glass LM, Kanumalla A. Statin safety: an appraisal from the adverse event reporting system. Am J Cardiol. 2006 Apr 17;97((8A)):32C–43C. [PubMed] [Google Scholar]

30. Staffa JA, Chang J, Green L. Cerivastatin and reports of fatal rhabdomyolysis. N Engl J Med. 2002 Feb 14;346(7):539–540. [PubMed] [Google Scholar]

31. Kashani A, Phillips CO, Foody JM, et al. Risks associated with statin therapy: a systematic overview of randomized clinical trials. Circulation. 2006 Dec 19;114(25):2788–2797. [PubMed] [Google Scholar]

32. Allison RC, Bedsole DL. The other medical causes of rhabdomyolysis. Am J Med Sci. 2003 Aug;326(2):79–88. [PubMed] [Google Scholar]

33. Tomaszewski M, Stępień KM, Tomaszewska J, Czuczwar SJ. Statin-induced myopathies. Pharmacol Rep. 2011;63(4):859–866. [PubMed] [Google Scholar]

34. Rowan CG, Brunelli SM, Munson J, et al. Clinical importance of the drug interaction between statins and CYP3A4 inhibitors: a retrospective cohort study in the Health Improvement Network. Pharmacoepidemiol Drug Saf. 2012 May;21(5):494–506. [PMC free article] [PubMed] [Google Scholar]

35. Jacobson TA. Comparative pharmacokinetic interaction profiles of pravastatin, simvastatin, and atorvastatin when coadministered with cytochrome P450 inhibitors. Am J Cardiol. 2004 Nov 1;94(9):1140–1146. [PubMed] [Google Scholar]

36. Law M, Rudnicka AR. Statin safety: a systematic review. Am J Cardiol. 2006 Apr 17;97((8A)):52C–60C. [PubMed] [Google Scholar]

37. Goh IX, How CH, Tavintharan S. Cytochrome P450 drug interactions with statin therapy. Singapore Med J. 2013 Mar;54(3):131–135. [PubMed] [Google Scholar]

38. Jones PH, Davidson MH. Reporting rate of rhabdomyolysis with fenofibrate + statin versus gemfibrozil + any statin. Am J Cardiol. 2005 Jan 1;95(1):120–122. [PubMed] [Google Scholar]

39. Pan WJ, Gustavson LE, Achari R, et al. Lack of clinically significant pharmacokinetic interaction between fenofibrate and pravastatin in healthy volunteers. J Clin Pharmacol. 2000 Mar;40(3):316–323. [PubMed] [Google Scholar]

40. Davidson MH. Combination therapy for dyslipidemia: safety and regulatory considerations. Am J Cardiol. 2002 Nov 20;90((10B)):50K–60K. [PubMed] [Google Scholar]

41. Landau ME, Kenney K, Deuster P, Campbell W. Exertional rhabdomyolysis: a clinical review with a focus on genetic influences. J Clin Neuromuscul Dis. 2012 Mar;13(3):122–136. [PubMed] [Google Scholar]

42. Schwaber MJ, Liss HP, Steiner I, Brezis M. Hazard of sauna use after strenuous exercise. Ann Intern Med. 1994 Mar 1;120(5):441–442. [PubMed] [Google Scholar]

43. Alpers JP, Jones LK., Jr Natural history of exertional rhabdomyolysis: a population-based analysis. Muscle Nerve. 2010 Oct;42(4):487–491. [PubMed] [Google Scholar]

44. Warren JD, Blumbergs PC, Thompson PD. Rhabdomyolysis: a review. Muscle Nerve. 2002 Mar;25(3):332–347. [PubMed] [Google Scholar]

45. Loke J, MacLennan DH. Malignant hyperthermia and central core disease: disorders of Ca2+ release channels. Am J Med. 1998 May;104(5):470–486. [PubMed] [Google Scholar]

46. Bagnulo H, Rodríguez F. Rhabdomyolysis during a case of streptococcal toxic shock syndrome [in Spanish] Enferm Infecc Microbiol Clin. 2001 Feb;19(2):82–83. [PubMed] [Google Scholar]

47. Erdogan H, Yilmaz A, Kal O, Erdogan A, Arslan H. Rhabdomyolysis-induced acute renal failure associated with legionnaires' disease. Scand J Urol Nephrol. 2006;40(4):345–346. [PubMed] [Google Scholar]

48. Swaringen JC, Seiler JG, 3rd, Bruce RW., Jr Influenza A induced rhabdomyolysis resulting in extensive compartment syndrome. Clin Orthop Relat Res. 2000 Jun;(375):243–249. [PubMed] [Google Scholar]

49. Paletta CE, Lynch R, Knutsen AP. Rhabdomyolysis and lower extremity compartment syndrome due to influenza B virus. Ann Plast Surg. 1993 Mar;30(3):272–273. [PubMed] [Google Scholar]

50. Peraldi MN, Maslo C, Akposso K, Mougenot B, Rondeau E, Sraer JD. Acute renal failure in the course of HIV infection: a single-institution retrospective study of ninety-two patients and sixty renal biopsies. Nephrol Dial Transplant. 1999 Jun;14(6):1578–1585. [PubMed] [Google Scholar]

51. Wang YM, Zhang Y, Ye ZB. Rhabdomyolysis following recent severe coxsackie virus infection in patient with chronic renal failure: one case report and a review of the literature. Renal Fail. 2006;28(1):89–93. [PubMed] [Google Scholar]

52. Osamah H, Finkelstein R, Brook JG. Rhabdomyolysis complicating acute Epstein-Barr virus infection. Infection. 1995 Mar-Apr;23(2):119–120. [PubMed] [Google Scholar]

53. Wong WM. Wai-Hung Shek T, Chan KH, Chau E, Lai KC. Rhabdomyolysis triggered by cytomegalovirus infection in a heart transplant patient on concomitant cyclosporine and atorvastatin therapy. J Gastroenterol Hepatol. 2004 Aug;19(8):952–953. [PubMed] [Google Scholar]

54. Shanmugam S, Seetharaman M. Viral rhabdomyolysis. South Med J. 2008 Dec;101(12):1271–1272. [PubMed] [Google Scholar]

55. Will MJ, Hecker RB, Wathen PI. Primary varicella-zoster-induced rhabdomyolysis. South Med J. 1996 Sep;89(9):915–920. [PubMed] [Google Scholar]

56. Gupta M, Ghaffari M, Freire AX. Rhabdomyolysis in a patient with West Nile encephalitis and flaccid paralysis. Tenn Med. 2008 Apr;101(4):45–47. Erratum in: Tenn Med. 2008 Jun;101(6):61. [PubMed] [Google Scholar]

57. Gabow PA, Kaehny WD, Kelleher SP. The spectrum of rhabdomyolysis. Medicine (Baltimore) 1982 May;61(3):141–152. [PubMed] [Google Scholar]

58. Better OS, Abassi ZA. Early fluid resuscitation in patients with rhabdomyolysis. Nat Rev Nephrol. 2011 May 17;7(7):416–422. [PubMed] [Google Scholar]

59. Elsayed EF, Reilly RF. Rhabdomyolysis: a review, with emphasis on the pediatric population. Pediatr Nephrol. 2010 Jan;25(1):7–18. [PubMed] [Google Scholar]

60. Cereda M, Horak J, Neligan PJ. Renal diseases. In: Fleisher LA, editor. Anesthesia and Uncommon Diseases. 5th ed. Philadelphia, PA: Saunders Elsevier;; 2006. pp. 229–260. [Google Scholar]

61. Muenster T, Mueller C, Forst J, Huber H, Schmitt HJ. Anaesthetic management in patients with Duchenne muscular dystrophy undergoing orthopaedic surgery: a review of 232 cases. Eur J Anaesthesiol. 2012 Oct;29(10):489–494. [PubMed] [Google Scholar]

62. Segura LG, Lorenz JD, Weingarten TN, et al. Anesthesia and Duchenne or Becker muscular dystrophy: review of 117 anesthetic exposures. Paediatr Anaesth. 2013 Sep;23(9):855–864. [PubMed] [Google Scholar]

63. Coco TJ, Klasner AE. Drug-induced rhabdomyolysis. Curr Opin Pediatr. 2004 Apr;16(2):206–210. [PubMed] [Google Scholar]

64. Weiner AL, Vieira L, McKay CA, Bayer MJ. Ketamine abusers presenting to the emergency department: a case series. J Emerg Med. 2000 May;18(4):447–451. [PubMed] [Google Scholar]

65. Gurnaney H, Brown A, Litman RS. Malignant hyperthermia and muscular dystrophies. Anesth Analg. 2009 Oct;109(4):1043–1048. [PubMed] [Google Scholar]

66. Friedman S, Baker T, Gatti M, Simon G, Paskin S. Probable succinylcholine-induced rhabdomyolysis in a male athlete. Anesth Analg. 1995 Aug;81(2):422–423. [PubMed] [Google Scholar]

67. Ryan JF, Kagen LJ, Hyman AI. Myoglobinemia after a single dose of succinylcholine. N Engl J Med. 1971 Oct 7;285(15):824–827. [PubMed] [Google Scholar]

68. Wong JM. Propofol infusion syndrome. Am J Ther. 2010 Sep-Oct;17(5):487–491. [PubMed] [Google Scholar]

69. Stelow EB, Johari VP, Smith SA, Crosson JT, Apple FS. Propofol-associated rhabdomyolysis with cardiac involvement in adults: chemical and anatomic findings. Clin Chem. 2000 Apr;46(4):577–581. [PubMed] [Google Scholar]

70. Mehta N, DeMunter C, Habibi P, Nadel S, Britto J. Short-term propofol infusions in children. Lancet. 1999 Sep 4;354(9181):866–867. [PubMed] [Google Scholar]

71. Burrow BK, Johnson ME, Packer DL. Metabolic acidosis associated with propofol in the absence of other causative factors. Anesthesiology. 2004 Jul;101(1):239–241. [PubMed] [Google Scholar]

72. Roberts RJ, Barletta JF, Fong JJ, et al. Incidence of propofol-related infusion syndrome in critically ill adults: a prospective, multicenter study. Crit Care. 2009;13(5):R169. [PMC free article] [PubMed] [Google Scholar]