Summary

Ritonavir significantly increases fluticasone levels by inhibiting CYP3A4 metabolism, potentially leading to systemic corticosteroid effects including adrenal suppression and Cushing's syndrome. This interaction is considered clinically significant and requires careful monitoring or alternative therapy consideration.

Introduction

Fluticasone is a synthetic corticosteroid primarily used as an inhaled medication for asthma and allergic rhinitis, available in nasal sprays and inhalers. It works by reducing inflammation in the airways and nasal passages. Ritonavir is an HIV protease inhibitor used in combination antiretroviral therapy for HIV treatment, often prescribed as a pharmacokinetic booster due to its potent inhibition of cytochrome P450 enzymes, particularly CYP3A4.

Mechanism of Interaction

The interaction occurs through ritonavir's potent inhibition of the CYP3A4 enzyme system, which is the primary metabolic pathway for fluticasone. When ritonavir blocks CYP3A4, fluticasone clearance is dramatically reduced, leading to significantly increased systemic exposure to the corticosteroid. This can result in plasma fluticasone concentrations that are hundreds of times higher than normal, converting what should be a locally-acting medication into one with significant systemic effects.

Risks and Symptoms

The primary risks include development of iatrogenic Cushing's syndrome, characterized by weight gain, moon face, buffalo hump, and metabolic disturbances. Adrenal suppression is a serious concern, potentially leading to adrenal insufficiency if fluticasone is discontinued abruptly. Other risks include hyperglycemia, hypertension, osteoporosis, increased infection susceptibility, and growth suppression in pediatric patients. Case reports have documented severe systemic corticosteroid toxicity requiring hospitalization.

Management and Precautions

Avoid concurrent use when possible by considering alternative corticosteroids with less CYP3A4 dependence, such as beclomethasone or budesonide. If fluticasone must be continued, use the lowest effective dose and monitor closely for signs of corticosteroid excess. Regular monitoring should include blood glucose, blood pressure, bone density, and adrenal function tests. Patients should be educated about symptoms of Cushing's syndrome and adrenal insufficiency. Consider gradual tapering if discontinuing fluticasone after prolonged concurrent use with ritonavir.

Ritonavir interactions with food and lifestyle

Ritonavir should be taken with food to improve absorption and reduce gastrointestinal side effects. Taking ritonavir on an empty stomach may result in decreased drug levels and reduced effectiveness. Alcohol consumption should be avoided or limited while taking ritonavir, as both can cause liver toxicity and the combination may increase the risk of hepatic adverse effects. Patients should also avoid grapefruit juice, as it may affect the metabolism of ritonavir through CYP3A4 inhibition, potentially leading to increased drug levels and toxicity. St. John's wort should be strictly avoided as it significantly reduces ritonavir levels by inducing CYP3A4, which can lead to treatment failure and development of drug resistance.