Drug Interactions between dexamethasone / ketorolac / moxifloxacin and nintedanib

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 of corticosteroids or nonsteroidal anti-inflammatory drugs (NSAIDs) may potentiate the risk of gastrointestinal (GI) perforation that can occasionally occur with the use of nintedanib. Overall, premarketing clinical data reveal no increased risk of GI perforation in nintedanib-treated patients. There were no reports of GI perforation in patients receiving nintedanib in the phase III clinical studies cited by the prescribing information for the treatment of systemic sclerosis-associated interstitial lung disease and chronic fibrosing interstitial lung diseases with a progressive phenotype. GI perforation occurred in 0.3% of patients (2 cases, both serious) receiving nintedanib compared to 0 cases in placebo-treated patients in the clinical studies for idiopathic pulmonary fibrosis. In the phase III LUME-Lung1 study comparing treatment with nintedanib plus docetaxel against placebo plus docetaxel in patients with locally advanced, metastatic, or recurrent non-small cell lung cancer after first-line chemotherapy, the frequency of GI perforation was comparable between the treatment arms. However, cases of GI perforation and ischemic colitis, including some with fatal outcome, have been reported in the postmarketing period. Although a definitive causal relationship to nintedanib has not been established, the association is possible based on nintedanib's mechanism of action. Additional risk factors for GI perforation include recent abdominal surgery or hollow organ perforation, a prior history of peptic ulceration, or diverticular disease.

MANAGEMENT: Caution is recommended when using nintedanib in combination with other drugs associated with an increased risk of GI perforation, such as corticosteroids and NSAIDs, and in patients with other risk factors such as recent abdominal surgery or hollow organ perforation, a prior history of peptic ulceration, or diverticular disease. Nintedanib should only be used if the anticipated benefit outweighs the potential risk. Some authorities recommend waiting at least 4 weeks after abdominal surgery before initiating nintedanib. Patients should be advised to contact their healthcare provider if they experience signs and symptoms of GI perforation such as severe abdominal pain, fever, chills, nausea, or vomiting. Therapy with nintedanib should be permanently discontinued in patients who develop GI perforation.

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: Coadministration of corticosteroids or nonsteroidal anti-inflammatory drugs (NSAIDs) may potentiate the risk of gastrointestinal (GI) perforation that can occasionally occur with the use of nintedanib. Overall, premarketing clinical data reveal no increased risk of GI perforation in nintedanib-treated patients. There were no reports of GI perforation in patients receiving nintedanib in the phase III clinical studies cited by the prescribing information for the treatment of systemic sclerosis-associated interstitial lung disease and chronic fibrosing interstitial lung diseases with a progressive phenotype. GI perforation occurred in 0.3% of patients (2 cases, both serious) receiving nintedanib compared to 0 cases in placebo-treated patients in the clinical studies for idiopathic pulmonary fibrosis. In the phase III LUME-Lung1 study comparing treatment with nintedanib plus docetaxel against placebo plus docetaxel in patients with locally advanced, metastatic, or recurrent non-small cell lung cancer after first-line chemotherapy, the frequency of GI perforation was comparable between the treatment arms. However, cases of GI perforation and ischemic colitis, including some with fatal outcome, have been reported in the postmarketing period. Although a definitive causal relationship to nintedanib has not been established, the association is possible based on nintedanib's mechanism of action. Additional risk factors for GI perforation include recent abdominal surgery or hollow organ perforation, a prior history of peptic ulceration, or diverticular disease.

MANAGEMENT: Caution is recommended when using nintedanib in combination with other drugs associated with an increased risk of GI perforation, such as corticosteroids and NSAIDs, and in patients with other risk factors such as recent abdominal surgery or hollow organ perforation, a prior history of peptic ulceration, or diverticular disease. Nintedanib should only be used if the anticipated benefit outweighs the potential risk. Some authorities recommend waiting at least 4 weeks after abdominal surgery before initiating nintedanib. Patients should be advised to contact their healthcare provider if they experience signs and symptoms of GI perforation such as severe abdominal pain, fever, chills, nausea, or vomiting. Therapy with nintedanib should be permanently discontinued in patients who develop GI perforation.