Avodart and Simvastatin Interaction: What Patients and Clinicians Need to Know

Is there a known interaction between Avodart and simvastatin?

The Avodart label's drug interactions section covers potent CYP3A4 inhibitors such as ritonavir, the alpha-blockers tamsulosin and terazosin, verapamil and diltiazem, cholestyramine, digoxin and warfarin [1]. Simvastatin is not among them.

Not being on that list is not the same as being shown to be safe. The Avodart label reports no measurement of simvastatin concentrations in men taking dutasteride, so the size of any effect in either direction is not known.

Why these two drugs get linked

Dutasteride is extensively metabolized by CYP3A4 and CYP3A5 [1]. Simvastatin is metabolized by CYP3A4 [2]. Sharing an enzyme alone does not show that one drug changes the other's levels, and being broken down by an enzyme is not the same as blocking it.

The Avodart label describes dutasteride as a competitive, specific inhibitor of 5-alpha-reductase types 1 and 2 that does not bind the androgen receptor. It does not describe the drug as a CYP3A4 inhibitor [1]. The interaction the label does address runs the other way: the effect of potent CYP3A4 inhibitors on dutasteride has not been studied, and the label advises caution when Avodart is prescribed with potent, chronic CYP3A4 inhibitors such as ritonavir [1].

What the Avodart label covers

Verapamil and diltiazem decrease dutasteride clearance and raise exposure to dutasteride; the label does not consider that change clinically significant and recommends no dose adjustment [1].

A single 5 mg dutasteride dose followed an hour later by 12 g of cholestyramine did not change dutasteride bioavailability [1]. Dutasteride 0.5 mg daily for 3 weeks did not alter the steady-state pharmacokinetics of digoxin or warfarin and did not change warfarin's effect on prothrombin time. Dutasteride also did not change the steady-state pharmacokinetics of tamsulosin or terazosin [1].

What raises simvastatin levels

Simvastatin is a prodrug, hydrolyzed after administration to simvastatin acid, the form that inhibits HMG-CoA reductase. It is metabolized by CYP3A4 [2], and its uptake into the liver depends on the transporter OATP1B1, encoded by SLCO1B1 [3].

A review of lipid-lowering drug interactions reports that simvastatin, lovastatin and atorvastatin are metabolized by CYP3A4, that strong CYP3A4 inhibitors such as itraconazole and ritonavir greatly raise their plasma concentrations and the risk of myotoxicity, and that weak or moderately potent inhibitors such as verapamil and diltiazem can be used cautiously with small doses of CYP3A4-dependent statins [2].

Grapefruit juice has been tested directly against simvastatin. In a randomized crossover study of 10 healthy volunteers, 200 mL of double-strength grapefruit juice three times daily for 2 days raised simvastatin AUC 16-fold and its peak concentration about 9-fold, and raised simvastatin acid AUC and peak concentration about 7-fold, after a single 60 mg simvastatin dose [4].

Dose and genetics matter on their own. A genomewide study compared 85 people who developed definite or incipient myopathy on simvastatin 80 mg daily with 90 controls; each copy of the SLCO1B1 rs4149056 C allele raised the odds of myopathy 4.5-fold (95% CI 2.6 to 7.7), and the reported frequency of that allele was 15% [3].

Statin choice changes the picture. Pravastatin, rosuvastatin and pitavastatin are excreted mainly unchanged, and their plasma concentrations are not significantly increased by pure CYP3A4 inhibitors [2].

If you take both

Simvastatin's main hazard is muscle injury. Lipid-lowering drugs can cause myopathy and even rhabdomyolysis, and the risk is increased by certain drug interactions [2]; myopathy is more common at higher statin doses and with certain other medications [3].

Dutasteride's timing is the unusual part. Its terminal half-life at steady state is about 5 weeks, and serum levels stay above 0.1 ng/mL for up to 4 to 6 months after the last dose [1]. The Avodart label says men being treated with Avodart should not donate blood until at least 6 months after their last dose, to avoid giving dutasteride to a pregnant transfusion recipient [1].

Avodart itself is approved for symptomatic benign prostatic hyperplasia in men with an enlarged prostate; hair-loss use is off-label [1].