Accutane (Isotretinoin) and Clopidogrel Interaction: What Patients and Prescribers Need to Know

Does the Accutane Label Cover Clopidogrel?

The label's Drug Interactions section names vitamin A supplements, tetracyclines, micro-dosed progesterone, norethindrone and ethinyl estradiol, St. John's wort, phenytoin and systemic corticosteroids [1]. Clopidogrel does not appear in that list.

How Clopidogrel Is Activated

Clopidogrel is a thienopyridine prodrug. CYP2C19 catalyzes its bioactivation, and CYP2C19 genotype changes how much active metabolite is formed [2]. The CPIC guideline states that CYP2C19 intermediate and poor metabolizers taking clopidogrel have reduced platelet inhibition and a higher risk of major adverse cardiovascular and cerebrovascular events [2].

The size of that effect has been measured. In healthy volunteers (162 people), carriers of at least one reduced-function CYP2C19 allele had a 32.4% relative reduction in exposure to clopidogrel's active metabolite, and their absolute reduction in maximal platelet aggregation was 9 percentage points smaller than in noncarriers. In a separate cohort of 1,477 patients with acute coronary syndrome treated with clopidogrel, carriers had a 53% relative increase in the composite of cardiovascular death, heart attack or stroke (12.1% vs 8.0%) and a stent thrombosis rate of 2.6% vs 0.8% [3].

What the Accutane Label Covers

Oral isotretinoin is approved only for severe recalcitrant nodular acne, with nodules 5 mm or larger, that has not responded to conventional therapy including systemic antibiotics. It is dispensed only through the iPLEDGE REMS in supplies of no more than 30 days, with no refills [1]. On metabolism, the label states that in vitro studies indicate the primary P450 isoforms involved in isotretinoin metabolism are CYP2C8, 2C9, 3A4 and 2B6. It also reports that isotretinoin did not alter phenytoin pharmacokinetics in a study of seven healthy volunteers, consistent with the in vitro finding that neither isotretinoin nor its metabolites induce or inhibit CYP2C9 [1].

Platelet-Related Findings on the Isotretinoin Side

The Accutane label's adverse reaction list includes bruising, thrombocytopenia and elevated platelet counts [1]. In a cohort of 13,772 isotretinoin users, new abnormalities in white cell count, hemoglobin or platelet count were uncommon. The authors concluded that routine monitoring of those values may be of little utility without clinical suspicion of an abnormality [4].