Drug Interactions between dexamethasone / ketorolac / moxifloxacin and tipranavir

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.

MONITOR: The combined use of corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the potential for serious gastrointestinal (GI) toxicity, including inflammation, bleeding, ulceration, and perforation. In a large, case-control study of elderly patients, those who used corticosteroids and NSAIDs concurrently had an estimated relative risk (RR) for peptic ulcer disease and GI hemorrhage of 14.6 compared to those who used neither. Corticosteroid use was associated with a doubling of the risk (estimated RR = 2.0), but the risk was confined to those who also used NSAIDs. It is possible that both categories of agents are ulcerogenic and have additive effects on the GI mucosa during coadministration. Some investigators have also suggested that the primary effect of corticosteroids in this interaction is to delay healing of erosions caused by NSAIDs rather than cause de novo ulcerations.

MANAGEMENT: Caution is advised if corticosteroids and NSAIDs are used together, especially in patients with a prior history of peptic ulcer disease or GI bleeding and in elderly and debilitated patients. During concomitant therapy, patients should be advised to take the medications with food and to immediately report signs and symptoms of GI ulceration and bleeding such as severe abdominal pain, dizziness, lightheadedness, and the appearance of black, tarry stools. The selective use of prophylactic anti-ulcer therapy (e.g., antacids, H2-antagonists) may be considered.

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.

MONITOR: Coadministration with nonsteroidal anti-inflammatory drugs (NSAIDs) may potentiate the risk of central nervous system toxicity sometimes associated with fluoroquinolone use. The interaction has been reported most often with enoxacin. It may occur with other fluoroquinolones as well, but is poorly documented. The exact mechanism of interaction is unknown. Some investigators suggest that the piperazine ring of fluoroquinolones may inhibit the binding of gamma-aminobutyric acid (GABA) to brain receptors and that NSAIDs may synergistically add to this effect. Patients with a history of seizures may be at greater risk.

MANAGEMENT: Clinical monitoring for signs of CNS stimulation such as tremors, involuntary muscle movements, hallucinations, or seizures is recommended if fluoroquinolone antibiotics are prescribed in combination with NSAIDs.