The FDA recommends against 80mg daily simvastatin dosage. In patients with the C allele at SLCO1B1 rs4149056, there are modest increases in myopathy risk even at lower simvastatin doses (40mg daily); if optimal efficacy is not achieved with a lower dose, alternate agents should be considered.
Guidelines regarding the use of pharmacogenomic tests in dosing for simvastatin have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC).
Excerpt from the simvastatin dosing guidelines:
For simvastatin, the evidence linking myopathy to rs4149056 in SLCO1B1 is of high quality, and this association has been reproduced in randomized trials and clinical practice-based cohorts. Conversely, the association of rs4149056 with myopathy has been less compelling for other statins. We therefore focus this guideline on simvastatin. Our recommended approach (Table 2 and Figure 1) begins with product-label changes recently implemented by the FDA. (The agency's recommendations are further summarized in Supplementary Table S1 online.) Decision-support tools are already being used to direct providers away from initiating the 80-mg simvastatin dose. At many of our institutions, SLCO1B1 genotype is further used to underscore this warning (i.e., myopathy risk for 80 mg of simvastatin) for subjects with a C allele at rs4149056 (see details in Supplementary Material).
The table below summarizes the therapeutic CPIC guidelines for simvastatin based on SLCO1B1 genotypes. These guidelines have been limited to the SLCO1B1*5 allele (rs4149056). At lower simvastatin doses (e.g., 40 mg daily), it is our position that this information should be used to warn providers about modest increases in myopathy risk for subjects with a C allele at rs4149056 (Figure 1). Under these circumstances, we also highlight the potential utility of routine creatine kinase (CK) surveillance (Table 2). If subjects with a C allele at rs4149056 do not achieve optimal low-density lipoprotein cholesterol-lowering efficacy with a lower dose of simvastatin, we recommend that the prescribing physician consider an alternative statin based on (i) potency differences, (ii) kinetic differences, (iii) comedications, (iv) hepatic function, (v) renal function, and (vi) relevant comorbidities.
Dosing recommendations for simvastatin, when rs4149056 genotype (or phenotype) is available (Table 2):
At the time of the development of this recommendation, there are no data available on the possible role of SLCO1B1 in simvastatin-induced myopathies in pediatric patient populations; however, there is no reason to suspect that SLCO1B1 variant alleles would affect simvastatin hepatic uptake differently in children compared to adults. Please see below for full details of these guidelines, with supporting evidence and disclaimers.
|Genotype at rs4149056||Anticipated phenotype||Implications for simvastatin||Therapeutic recommendations||Classification of recommendations|
|TT||Normal activity||Normal myopathy risk||FDA recommends against 80 mg (unless already tolerated 12 months). Prescribe desired starting dose and adjust doses of simvastatin based on disease-specific guidelines.||Strong|
|TC||Intermediate activity||Intermediate myopathy risk||FDA recommends against 80 mg. Consider a lower dose; if suboptimal efficacy, consider an alternative statin.||Strong|
|CC||Low activity||High myopathy risk||FDA recommends against 80 mg. Prescribe a lower dose or consider an alternative statin; consider routine creatine kinase (CK) surveillance.||Strong|
Figure 1: PREDICT (Pharmacogenomics Resource for Enhanced Decisions in Clinical Care and Treatment) decision support algorithm for simvastatin. CK, creatine kinase.