Drug Interactions between dexamethasone / ketorolac / moxifloxacin and mycophenolate mofetil

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 CLOSELY: Antibiotics which affect beta-glucuronidase producing bacteria in the intestine (e.g., aminoglycosides, cephalosporins, fluoroquinolones, and penicillins) may reduce systemic exposure to mycophenolic acid (MPA) products. The exact mechanism is not known; but is thought to be due to interference with enterohepatic recirculation of the active drug, MPA, via alterations in the gastrointestinal flora that are responsible for regenerating MPA from its glucuronide metabolite. One study reviewed 64 kidney transplant patients taking mycophenolate mofetil (MMF) who received either oral ciprofloxacin (500 mg twice daily for 7 days) or amoxicillin plus clavulanic acid (375 mg three times daily for at least 14 days). This study demonstrated approximately 50% reductions in the median trough MPA concentrations from baseline (MMF alone) in 3 days following the start of oral ciprofloxacin or amoxicillin plus clavulanic acid. The reductions in trough MPA concentrations tended to diminish within 14 days of antimicrobial therapy and cease within 3 days of the discontinuation of antibiotics. It is important to note that the trough level may not accurately reflect changes in the overall MPA exposure as the systemic exposure (AUC) was not evaluated in this study. In a study of 11 healthy volunteers who received a single-dose of MMF 1 gram on day 4 of a 5-day course of dual antibiotic therapy with both norfloxacin and metronidazole, the average AUC of MPA was reduced by 33% compared to the administration of MMF alone. However, when MMF was administered with norfloxacin alone or metronidazole alone (as opposed to the combination of MMF with norfloxacin and metronidazole), the reduction in AUC was not statistically significant. In a study of 12 healthy male volunteers, a single dose of MMF 1.5 grams was administered on day 8 of a 10-day course of trimethoprim 160 mg/sulfamethoxazole 800 mg twice daily and no effect on the bioavailability of MPA was observed.

MANAGEMENT: Close clinical and laboratory monitoring for evidence of diminished immunosuppressive effects of mycophenolic acid products is recommended during concomitant therapy and shortly after antibiotic treatment is completed. Advise patients to report any symptoms of transplant rejection such as a decrease in organ function (e.g., reduced urine output for kidney transplant patients, shortness of breath and/or swelling in heart transplant patients, jaundice in liver transplant patients), and/or flu-like symptoms.

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.