Drug Interactions between dexamethasone / ketorolac / moxifloxacin and diroximel fumarate

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: The use of monomethyl fumarate (MMF) or its prodrugs, dimethyl fumarate and diroximel fumarate, with other immunosuppressive or myelosuppressive agents may increase the risk of infections. Treatment with MMF or its prodrugs can cause lymphopenia as well as serious and potentially life-threatening opportunistic infections (e.g., progressive multifocal leukoencephalopathy (PML), herpes zoster, herpes simplex, West Nile virus, cytomegalovirus, Candida, Aspergillus, Nocardia, Listeria monocytogenes, Mycobacterium tuberculosis), and the risk may be theoretically potentiated in the presence of other agents that also suppress the immune system or bone marrow function. In multiple sclerosis studies, the concomitant treatment of relapses with a short course of intravenous corticosteroids was not associated with a clinically relevant increase of infection.

MANAGEMENT: The safety and efficacy of monomethyl fumarate (MMF), dimethyl fumarate, or diroximel fumarate in combination with other immunosuppressive or myelosuppressive agents have not been evaluated. Until further information is available, concomitant use should be avoided if possible. Short courses of intravenous corticosteroids may be used in combination with MMF or its prodrugs for the treatment of multiple sclerosis relapses. When switching patients from one immunosuppressive or myelosuppressive agent to another, the half-life and mode of action of each therapy should be considered to avoid unintended additive effects on the immune system while simultaneously reducing the risk of reactivation of multiple sclerosis.

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.

MONITOR: The use of fumaric acid esters in combination with medications that can cause nephrotoxicity (e.g., aminoglycosides, diuretics, nonsteroidal anti-inflammatory drugs, cyclosporine, lithium, methotrexate) may increase the potential for adverse renal reactions. In clinical trials in patients with multiple sclerosis treated with dimethyl fumarate, a fumaric acid ester that is converted to the active metabolite monomethyl fumarate, adverse events of proteinuria were reported at slightly higher frequencies than in patients receiving placebo. The clinical significance of these observations is unknown. Cases of Fanconi syndrome have been reported for a medicinal product containing dimethyl fumarate in combination with other fumaric acid esters. Renal toxicity, including tubular changes and/or interstitial fibrosis, has been observed in animal studies with dimethyl fumarate and diroximel fumarate.

MANAGEMENT: The use of fumaric acid esters in patients who receive concomitant treatment with potentially nephrotoxic agents, particularly for longer durations, has not been evaluated and should be approached with caution. Assessment of renal function (e.g., serum creatinine, blood urea nitrogen, urinalysis) is recommended prior to initiating treatment with fumaric acid esters and as clinically indicated during treatment.

MONITOR: The use of fumaric acid esters in combination with medications that can cause nephrotoxicity (e.g., aminoglycosides, diuretics, nonsteroidal anti-inflammatory drugs, cyclosporine, lithium, methotrexate) may increase the potential for adverse renal reactions. In clinical trials in patients with multiple sclerosis treated with dimethyl fumarate, a fumaric acid ester that is converted to the active metabolite monomethyl fumarate, adverse events of proteinuria were reported at slightly higher frequencies than in patients receiving placebo. The clinical significance of these observations is unknown. Cases of Fanconi syndrome have been reported for a medicinal product containing dimethyl fumarate in combination with other fumaric acid esters. Renal toxicity, including tubular changes and/or interstitial fibrosis, has been observed in animal studies with dimethyl fumarate and diroximel fumarate.

MANAGEMENT: The use of fumaric acid esters in patients who receive concomitant treatment with potentially nephrotoxic agents, particularly for longer durations, has not been evaluated and should be approached with caution. Assessment of renal function (e.g., serum creatinine, blood urea nitrogen, urinalysis) is recommended prior to initiating treatment with fumaric acid esters and as clinically indicated during treatment.