Drug Interactions between dexamethasone / ketorolac / moxifloxacin and pemetrexed

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.

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.

ADJUST DOSING INTERVAL: Coadministration with nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the plasma concentrations of pemetrexed. The mechanism has not been described but may be related to NSAID inhibition of renal prostaglandins. Use of NSAIDs has been associated with nephropathy manifested as elevations in serum creatinine and BUN, tubular necrosis, glomerulitis, renal papillary necrosis, acute interstitial nephritis, nephrotic syndrome, and renal failure. Since pemetrexed is primarily eliminated unchanged by renal excretion, coadministration with NSAIDs may result in delayed and/or decreased clearance. Daily ibuprofen dosage of 400 mg four times a day has been shown to reduce pemetrexed clearance by about 20% in patients with normal renal function, whereas aspirin at 325 mg every 6 hours did not. The effect of higher dosages of ibuprofen or aspirin is unknown.

MANAGEMENT: Ibuprofen at 400 mg and aspirin at 325 mg four times a day, or less, may be used with pemetrexed in patients with normal renal function. However, caution is advised in patients with mild to moderate renal insufficiency (creatinine clearance (CrCl) 45 to 79 mL/min). These patients should avoid taking NSAIDs with short elimination half-lives (e.g., diclofenac, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamate, mefenamic acid, sulindac, tolmetin, low dosages of salicylates) 2 days before to 2 days after pemetrexed administration. If concomitant administration is necessary, patients should be monitored closely for toxicity, especially myelosuppression, nephrotoxicity, and gastrointestinal toxicity. In the absence of data regarding use with NSAIDs with longer half-lives (e.g., meloxicam, nabumetone, piroxicam), withholding NSAID dosing for at least 5 days before to 2 days after pemetrexed administration is recommended. In patients with CrCl below 45 mL/min, concomitant administration is not recommended.

MONITOR: Coadministration with drugs that are eliminated by active tubular secretion may delay and/or decrease the clearance of pemetrexed. The mechanism is competitive inhibition of the renal excretion of pemetrexed, which is primarily eliminated unchanged via glomerular filtration and active tubular secretion. Drugs (and/or their metabolites) that are thought to undergo active tubular secretion include acyclovir, allopurinol, aminosalicylic acid, cidofovir, cimetidine, creatine, dyphylline, famciclovir, famotidine, flecainide, ganciclovir, levetiracetam, metformin, methotrexate, midodrine, mycophenolic acid, oseltamivir, pralatrexate, probenecid, procainamide, quinidine, ranitidine, tenofovir, triamterene, trimethoprim, valacyclovir, valganciclovir, zalcitabine, zidovudine, and many of the beta-lactam and quinolone antibiotics.

MANAGEMENT: Patients receiving pemetrexed in combination with other drugs that undergo active tubular secretion should be monitored for excessive pharmacologic effects of one or both drugs, and the dosages of the drugs adjusted if necessary. The potential for increased toxicity of pemetrexed such as bone marrow suppression should be considered. Renal function should be closely monitored during therapy. Pemetrexed should not be administered to patients whose creatinine clearance is below 45 mL/min.