Patients taking ciclosporin, fluconazole: 20 mg bid. Recommendations may vary among countries or individual products. Refer to specific product guidelines.
Pharmacogenomics:
Statin-associated musculoskeletal symptoms (SAMS) including myalgia, myopathy, or rhabdomyolysis may occur with fluvastatin use in relation to genes such as the
SLCO1B1 and
CYPC2C9 as variations in these genes may impair the systemic exposure to fluvastatin. Although available product information may not reference these genes, current international guidelines recommend that genetic testing may be considered to help identify those at significant risk, to reduce the risk of SAMS and to optimise fluvastatin therapy.
The
SLCO1B1 gene encodes the organic anion transporting polypeptide 1B1 (OATP1B1) an influx transporter which enables the hepatic uptake of all statins and other exogenous and endogenous compounds (e.g. bilirubin). The CYP2C9 enzyme is vital for the Phase-I metabolism of multiple medicines including fluvastatin. A reduced function of the transporter and the genetic polymorphisms of
CYP2C9 may cause an increased systemic exposure to statins, which is thought to be the contributor to SAMS. The data regarding the combination of
SLCO1B1 and
CYP2C9 genotypes are limited, and although the combinations of these genes are expected to cause an additive effect on fluvastatin pharmacokinetics, the combinatorial gene-based recommendations are rated as optional by the international guidelines.
Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline as of January 2022:
Dosage recommendations based on SLCO1B1 phenotype:
| Phenotype and Genotype |
Implications |
Recommendations |
SLCO1B1 decreased function
Patients carrying 1 normal or increased functional allele and 1 non-functional allele e.g. *1/*5, *1/*15
|
Typical myopathy risk with ≤40 mg doses; increased exposure in comparison to SLCO1B1 normal function.
|
Initiate treatment at standard doses and adjust doses according to disease-specific guidelines.
|
SLCO1B1 possible decreased function
Patients carrying 1 non-functional allele and 1 unknown/uncertain functional allele e.g. *5/*6, *15/*10, *5/*43
|
Typical myopathy risk with ≤40 mg doses; increased exposure in comparison to SLCO1B1 normal function.
|
Initiate treatment at standard doses and adjust doses according to disease-specific guidelines.
|
SLCO1B1 poor function
Patients carrying 2 non-functional alleles e.g. *5/*5, *5/*15, *15/*15
|
Typical myopathy risk with standard doses; increased exposure in comparison to SLCO1B1 normal and decreased function.
|
Initiate treatment at a dose of ≤40 mg and adjust doses according to disease-specific guidelines. If the patient is tolerating 40 mg doses but a higher potency is needed, an alternative statin or combination therapy may be considered; refer to specific country guidelines. Although there may be an increased risk of myopathy, doses >40 mg may be considered.
|
Dosage recommendations based on CYP2C9 phenotype:
| Phenotype and Genotype |
Implications |
Recommendations |
CYP2C9 intermediate metaboliser
Patients carrying 1 normal functional allele and 1 decreased or 1 non-functional allele or patients carrying 2 decreased functional alleles e.g. *1/*2, *1/*3, *2/*2
|
Increased risk of myopathy; increased fluvastatin exposure in comparison to CYP2C9 normal metabolisers.
|
Initiate treatment at a dose of ≤40 mg and adjust doses according to disease-specific guidelines. If doses >40 mg are needed for the desired efficacy, an alternative statin or combination therapy may be considered; refer to specific country guidelines.
|
CYP2C9 poor metaboliser
Patients carrying 1 non-functional allele and 1 decreased functional allele or patients carrying 2 non-functional alleles e.g. *2/*3, *3/*3
|
Increased risk of myopathy; increased fluvastatin exposure in comparison to CYP2C9 normal and intermediate metabolisers.
|
Initiate treatment at a dose of ≤20 mg and adjust doses according to disease-specific guidelines. If doses >20 mg are needed for the desired efficacy, an alternative statin or combination therapy may be considered; refer to specific country guidelines.
|
Combinatorial gene-based recommendations based on SLCO1B1 and CYP2C9 phenotype:
Phenotype combination
|
Recommendations
|
SLCO1B1 decreased/possible decreased function and CYP2C9 intermediate metaboliser
|
Initiate treatment at a dose of ≤20 mg and adjust doses according to disease-specific guidelines. If doses >20 mg are needed for the desired efficacy, an alternative statin or combination therapy may be considered; refer to specific country guidelines.
|
SLCO1B1 decreased/possible decreased function and CYP2C9 poor metaboliser
|
An alternative agent is recommended depending on the desired potency; refer to specific country guidelines.
|
SLCO1B1 poor function and CYP2C9 intermediate metaboliser
|
An alternative agent is recommended depending on the desired potency; refer to specific country guidelines.
|
SLCO1B1 poor function and CYP2C9 poor metaboliser
|
An alternative agent is recommended depending on the desired potency; refer to specific country guidelines.
|
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