Drug Interactions between dexamethasone / ketorolac / moxifloxacin and methotrexate

MONITOR CLOSELY: Coadministration with nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the plasma concentrations and toxicities of methotrexate. The proposed mechanism is NSAID inhibition of the renal elimination of methotrexate and its metabolite, 7-hydroxymethotrexate, although data from pharmacokinetic studies are inconsistent and conflicting. Displacement of methotrexate binding to serum albumin by certain NSAIDs may also play a secondary role. Unexpectedly severe and sometimes fatal bone marrow suppression, aplastic anemia, gastrointestinal toxicity, and nephrotoxicity have been reported during concomitant administration of methotrexate with NSAIDs. The risk is greatest in patients receiving high dosages of methotrexate and those with renal impairment. In clinical studies, methotrexate at dosages of 7.5 to 15 mg/week has been used without apparent problems in patients with rheumatoid arthritis who also received constant dosage regimens of NSAIDs. However, there have been occasional reports of stomatitis, pneumonitis, bone marrow toxicity, and fatality in patients receiving low-dose weekly methotrexate with daily NSAIDs.

MANAGEMENT: NSAIDs should generally not be administered prior to or concomitantly with high dosages of methotrexate, such as those used to treat osteosarcoma. Caution should be exercised when NSAIDs are administered concomitantly with lower dosages of methotrexate. Close monitoring for signs and symptoms of bone marrow suppression, nephrotoxicity, and hepatotoxicity is recommended during treatment. Patients should be advised to contact their physician if they develop stomatitis, nausea, vomiting, diarrhea, rash, anorexia, jaundice, dark urine, dry cough, shortness of breath, and/or signs and symptoms of myelosuppression such as pallor, dizziness, fatigue, lethargy, fainting, easy bruising or bleeding, fever, chills, sore throat, body aches, and other influenza-like symptoms. Patients should also be counseled to avoid any other over-the-counter NSAID products.

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: Although they are often used together in clinical practice, limited data suggest that corticosteroids may increase the risk of methotrexate toxicity. Individual cases of severe and fatal bone marrow suppression and fatal systemic moniliasis have been reported. Data have been conflicting. A pediatric study found no increased methotrexate toxicity; however, hepatic enzyme elevations were noted. The mechanism is unknown.

MANAGEMENT: Close monitoring for signs and symptoms of bone marrow suppression and nephrotoxicity is advisable during concomitant administration. Patients should be advised to report possible symptoms of toxicity including nausea, vomiting, diarrhea, stomatitis, sore throat, chills, fever, rash, unusual bruising or bleeding, jaundice, dark urine, swelling of the extremities, or shortness of breath to their physician.

MONITOR: Coadministration with ciprofloxacin or other quinolones may increase the plasma concentrations of methotrexate. The exact mechanism of interaction is unknown but may involve competitive inhibition of the renal tubular secretion of methotrexate. In a case report of two pediatric patients treated with high-dose methotrexate, coadministration of ciprofloxacin was associated with delayed elimination of methotrexate resulting in severe toxicity. Both patients tolerated the methotrexate regimen and had normal drug clearance in the absence of ciprofloxacin. Limited data also suggest that chemotherapy with antineoplastic agents may reduce the plasma concentrations of orally administered quinolones. The proposed mechanism is decreased quinolone absorption secondary to alteration of intestinal mucosa by cancer chemotherapy. In six patients with newly diagnosed hematologic malignancy, treatment with various antineoplastic agents (cyclophosphamide, cytarabine, daunorubicin, doxorubicin, mitoxantrone, prednisolone, vincristine) decreased the mean peak serum concentration (Cmax) and area under the concentration-time curve (AUC 0 to 4 hours) of ciprofloxacin by approximately 46% each. Data are not available for other quinolone antibiotics, but the possibility of a similar interaction should be considered.

MANAGEMENT: Caution is advised if quinolones must be used with methotrexate. The authors of the case report recommend that ciprofloxacin and related antibiotics not be coadministered with high-dose methotrexate. During concomitant use, patients should be monitored for altered pharmacologic effects of both drugs and the dosage(s) adjusted accordingly if necessary.

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.

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.