Summary

Ketoconazole significantly increases ticagrelor blood levels by inhibiting CYP3A4 metabolism, leading to enhanced antiplatelet effects and increased bleeding risk. This combination requires careful monitoring and potential dose adjustments.

Introduction

Ticagrelor (brand name Brilinta) is a P2Y12 receptor antagonist used as an antiplatelet medication to prevent blood clots in patients with acute coronary syndrome or history of myocardial infarction. Ketoconazole is a potent antifungal medication belonging to the azole class, commonly used to treat serious fungal infections. Both medications are metabolized through the cytochrome P450 system, creating potential for significant drug interactions.

Mechanism of Interaction

The interaction occurs through ketoconazole's potent inhibition of the CYP3A4 enzyme system. Ticagrelor is primarily metabolized by CYP3A4, and ketoconazole can increase ticagrelor plasma concentrations by up to 7-fold. This inhibition also affects the formation of ticagrelor's active metabolite (AR-C124910XX), which contributes to its antiplatelet activity. The result is significantly enhanced and prolonged antiplatelet effects beyond the intended therapeutic range.

Risks and Symptoms

The primary clinical risk is a substantially increased bleeding tendency, including major bleeding events such as intracranial hemorrhage, gastrointestinal bleeding, and excessive surgical bleeding. Patients may experience prolonged bleeding times, easy bruising, and difficulty with hemostasis during procedures. The interaction can also lead to other ticagrelor-related adverse effects including dyspnea, bradycardia, and ventricular pauses due to elevated drug concentrations. This interaction is considered clinically significant and potentially dangerous.

Management and Precautions

Concurrent use of ticagrelor and ketoconazole should generally be avoided when possible. If co-administration is absolutely necessary, consider alternative antifungal agents with less CYP3A4 inhibition such as fluconazole (with appropriate monitoring) or echinocandins. If the combination cannot be avoided, close monitoring for bleeding signs and symptoms is essential, including regular complete blood counts and coagulation studies. Patients should be educated about bleeding precautions and advised to report any unusual bleeding or bruising immediately. Healthcare providers should consider temporary discontinuation of ticagrelor during ketoconazole treatment if clinically appropriate, with cardiology consultation recommended.

Ticagrelor interactions with food and lifestyle

Ticagrelor should be taken with or without food as food does not significantly affect absorption. However, patients should avoid grapefruit juice as it may increase ticagrelor levels in the blood through CYP3A4 inhibition, potentially increasing bleeding risk. Alcohol consumption should be limited as it may increase the risk of bleeding when combined with ticagrelor. Patients should also be cautious with activities that may increase bleeding risk, such as contact sports or activities with high injury potential, due to ticagrelor's antiplatelet effects.

Ketoconazole interactions with food and lifestyle

Ketoconazole requires an acidic environment for optimal absorption. Take ketoconazole with food or an acidic beverage to enhance absorption. Avoid taking ketoconazole with antacids, H2 blockers, or proton pump inhibitors as these medications reduce stomach acid and significantly decrease ketoconazole absorption. If antacids must be used, take them at least 2 hours after ketoconazole. Alcohol should be avoided during ketoconazole treatment as both ketoconazole and alcohol can cause liver toxicity, and concurrent use may increase the risk of hepatotoxicity. Grapefruit juice may increase ketoconazole blood levels and should be avoided to prevent increased risk of side effects.