Cerivastatin and Reports of Fatal Rhabdomyolysis

Staffa, Judy A.; Chang, Jennie; Green, Lanh

doi:10.1056/nejm200202143460721

Cited by 577 publications

(313 citation statements)

References 2 publications

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“…10 The FDA performed a detailed review of all reports of fatal rhabdomyolysis in their Adverse Event Reporting System and obtained the number of prescriptions dispensed since marketing of each statin began in the U.S. Fatal rhabdomyolysis was extremely rare (less than 1 death/million prescriptions).…”

Section: Incidence Of Adverse Eventsmentioning

confidence: 99%

“…are not recommended". 10 Nevertheless, review of these data strongly sug-gests that there were no clinically important differences in the rate of fatal complications among the five statins now available in the U.S. (atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin). Clinicians should consider the rates of severe myopathy as equivalent among all of these approved statins.…”

Section: Incidence Of Adverse Eventsmentioning

confidence: 99%

“…The FDA reports that the rate of fatal rhabdomyolysis is 16 to 80 times more frequent for cerivastatin as compared to any other statin. 10 …”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

ACC/AHA/NHLBI Clinical Advisory on the Use and Safety of Statins

Pasternak¹,

Smith²,

Merz³

et al. 2002

Circulation

650

233

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Section: Incidence Of Adverse Eventsmentioning

confidence: 99%

Section: Incidence Of Adverse Eventsmentioning

confidence: 99%

See 1 more Smart Citation

ACC/AHA/NHLBI Clinical Advisory on the Use and Safety of Statins

Pasternak¹,

Smith²,

Merz³

et al. 2002

Circulation

650

233

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“…Assim, nos EUA foi descrito um número muito baixo de complicações graves, como a rabdomiólise, uma síndrome caracterizada por necrose muscular, elevação de creatinofosfoquinase (CPK) acima de 10 vezes o limite superior da normalidade (LSN), acompanhada de dores musculares, mioglobinúria e determinando, em geral, risco de vida devido à insuficiência renal. De fato, a incidência de rabdomiólise fatal nos EUA foi descrita como sendo de 0,15 casos por milhão de prescrições de estatinas 6 . Quando os sintomas musculares não se acompanham de elevação significativa das enzimas musculares, caracterizamos a mialgia, que parece incidir em 6 a 14% dos eventos adversos associados com a prescrição das estatinas 7 .…”

Section: Statins Pharmacokinetics Drug Interactionsunclassified

Farmacocinética das estatinas

Fonseca¹

2005

Arq. Bras. Cardiol.

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Os inibidores da HMG-CoA redutase (vastatinas ou estatinas) constituem uma notável classe de medicamentos redutores de colesterol e têm sido associados com uma expressiva diminuição da morbidade e mortalidade cardiovascular para pacientes em prevenção primária ou secundária da doença coronariana 1 (Figura 1).Entretanto, a questão que permaneceu após todos estes estudos é a de que apesar dos benefícios, um considerável resíduo de morbidade e mortalidade ainda foi observado, sugerindo que uma redução adicional do colesterol pudesse estar associada com vantagens adicionais. Após a publi-A necessidade de metas mais agressivas de redução do LDL-C determina a utilização de estatinas de primeira geração em doses mais altas ou o uso de fármacos mais recentes e mais efetivos. Neste contexto, torna-se essencial o conhecimento das propriedades farmacocinéticas e farma- As estatinas são agentes hipolipemiantes que exercem os seus efeitos através da inibição da HMG-CoA redutase, enzima fundamental na síntese do colesterol, levando a uma redução do colesterol tecidual e um conseqüente aumento na expressão dos receptores de LDL. Existem consideráveis diferenças entre as estatinas, no que tange às propriedades farmacocinéticas, bem como ao coeficiente de hidrofilicidade, via hepática de metabolização (especialmente, do citocromo P450 e isoenzimas), meia-vida plasmática e eficácia na redução lipídica. As estatinas também podem diferir na capacidade de interação com outras drogas que utilizam a mesma via de metabolização. Recentemente, muitos efeitos pleiotrópicos têm sido relatados com estas drogas, bem como propriedades antiinflamatórias, melhora na função endotelial e benefícios na hemostasia. A figura 2 mostra a relação log linear entre o risco de doença arterial coronariana e o valor do LDL-C 2 . Redução de eventos coronarianos com estatinas PALAVRAS-CHAVE

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“…Its dual mechanism of elimination mediated by CYP2C8 and CYP3A4 was originally thought to impart a safety benefit relative to other statins that were exclusively metabolized via the CYP3A4 pathway. However, despite the dual metabolizing pathways, cerivastatin caused rhabdomyolysis more frequently than other statins, especially when cerivastatin was given together with other drugs such as gemfibrozil (Farmer 2001;Staffa et al 2002). In vitro experiment with human liver microsome demonstrated that gemfibrozil inhibited CYP2C8 activity leading to a decreased level of M-23 in the cerivastatin-metabolizing pathway, which at least partially explains the interaction between gemfibrozil and cerivastatin (Wang et al 2002).…”

Section: Introductionmentioning

confidence: 99%

A frameshift variant of CYP2C8 was identified in a patient who suffered from rhabdomyolysis after administration of cerivastatin

et al. 2004

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A hypercholesterolemic patient medicated with cerivastatin for 22 days resulted in acute rhabdomyolysis. CYP2C8 and CYP3A4 are the major enzymes responsible for the metabolism of cerivastatin, and a transporter, OATP2, contributes to uptake of cerivastatin to the liver. In this study, the patient's DNA was sequenced in order to identify a variant that would lead to the adverse effect of cerivastatin. Three nucleotide variants, 475delA, G874C, and T1551C, were found in the exons of CYP2C8. The patient was homozygous for 475delA variant that leads to frameshift and premature termination. Accordingly, the patient is most likely lacking the enzyme activity. The patient's children were both heterozygous for the mutation. The patient had three nucleotide variants in exon 4 (A388G) and exon 5 (C571T and C597T) of OATP2 that were all heterozygous. No nucleotide variation in the exons of CYP3A4 was identified. To our knowledge, this is the first report showing that the adverse effect of cerivastatin might be caused by the genetic variant of CYP2C8.

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Cerivastatin and Reports of Fatal Rhabdomyolysis

Cited by 577 publications

References 2 publications

ACC/AHA/NHLBI Clinical Advisory on the Use and Safety of Statins

ACC/AHA/NHLBI Clinical Advisory on the Use and Safety of Statins

Farmacocinética das estatinas

A frameshift variant of CYP2C8 was identified in a patient who suffered from rhabdomyolysis after administration of cerivastatin

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