Drug Interactions between dexamethasone / moxifloxacin and saquinavir

MONITOR CLOSELY: Concomitant administration of corticosteroids may potentiate the risk of tendinitis and tendon rupture associated with fluoroquinolone treatment. The mechanism is unknown. Tendinitis and tendon rupture have most frequently involved the Achilles tendon, although cases involving the rotator cuff (the shoulder), the hand, the biceps, and the thumb have also been reported. Some have required surgical repair or resulted in prolonged disability. Tendon rupture can occur during or up to several months after completion of fluoroquinolone therapy.

MANAGEMENT: Caution is recommended if fluoroquinolones are prescribed in combination with corticosteroids, particularly in patients with other concomitant risk factors (e.g., age over 60 years; recipient of kidney, heart, and/or lung transplant). Patients should be advised to stop taking the fluoroquinolone, avoid exercise and use of the affected area, and promptly contact their physician if they experience pain, swelling, or inflammation of a tendon. In general, fluoroquinolones should only be used to treat conditions that are proven or strongly suspected to be caused by bacteria and only if the benefits outweigh the risks.

CONTRAINDICATED: Saquinavir in combination with ritonavir may cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. In a study of 59 healthy volunteers aged 18 to 55 years who were administered saquinavir/ritonavir at a therapeutic dosage of 1000 mg/100 mg twice daily and a supratherapeutic dosage of 1500 mg/100 mg twice daily, the maximum mean QT prolongation (QTcS; study-specific QT interval correction) on treatment day 3 was 18.9 msec for the lower dosage and 30.2 msec for the supratherapeutic dosage, compared to 12.2 msec for the active control (moxifloxacin 400 mg). The majority of subjects (89% and 80% in the therapeutic and supratherapeutic groups, respectively) had a QTcS less than 450 msec, and none had a QTc interval exceeding the potentially clinically relevant threshold of 500 msec. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Coadministration of ritonavir-boosted saquinavir with other drugs that can prolong the QT interval is considered contraindicated.

GENERALLY AVOID: Coadministration with protease inhibitors may increase the plasma concentration and pharmacologic effects of dexamethasone. The proposed mechanism is protease inhibitor-mediated inhibition of CYP450 3A4, the isoenzyme involved in the metabolic clearance of dexamethasone. Ritonavir has been reported to increase dexamethasone systemic exposure (AUC) by more than threefold. In one case report, an HIV patient who had been receiving long-term dexamethasone therapy for thrombotic thrombocytopenia purpura developed spinal epidural lipomatosis four months following the initiation of ritonavir. Although the patient was already cushingoid as a result of chronic dexamethasone administration, he did not have symptoms of myelopathy until after ritonavir was added. The effect of dexamethasone on the clearance of protease inhibitors has not been established. Theoretically, plasma levels of protease inhibitors may decrease due to dexamethasone induction of their metabolism by CYP450 3A4. This may lead to a loss of therapeutic effect and development of resistance to protease inhibitor-containing antiretroviral regimens; however, data are not available. These interactions may also be seen with cobicistat, a potent CYP450 3A4 inhibitor that solely acts as a pharmacokinetic booster in antiretroviral treatment regimen; however, data are not available.

MONITOR: Corticosteroids such as dexamethasone may cause hypokalemia and potentiate the risk of QT and/or PR interval prolongation associated with the use of certain protease inhibitors such as atazanavir, lopinavir-ritonavir, and saquinavir-ritonavir. The risk of torsade de pointes arrhythmia, bradycardia, and heart block may be increased.

MANAGEMENT: Caution is advised if dexamethasone must be used concomitantly with protease inhibitors or cobicistat. Some authorities advise against concomitant use unless the potential benefit outweighs the risk. Adrenal function should be monitored regularly during chronic use of these agents, and dexamethasone dosage adjusted as necessary. Patients should be monitored for symptoms of hypercorticism (e.g., acne, easy bruising, moon face, edema, hirsutism, buffalo hump, skin striae, glucose intolerance, and irregular menstruations), immunosuppression, and osteoporosis. In addition, it may be appropriate to monitor patients for potentially reduced antiretroviral response following initiation or any dosage increase of dexamethasone. Serum potassium and ECG monitoring should also be considered during coadministration of dexamethasone with certain protease inhibitors in accordance with the product labeling.