Drug Interactions between calaspargase pegol and dexamethasone / ketorolac / moxifloxacin

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.

ADJUST DOSING INTERVAL: The administration of asparaginase with or immediately preceding prednisone may increase the risk of hyperglycaemia. Although they are often combined in clinical practice, asparaginase and corticosteroids may increase the risk of hyperglycemia in some patients, especially in children 10 years of age or older.

MONITOR: Concomitant use of asparaginase and corticosteroids may increase the risk of thrombosis or hemorrhage. The proposed mechanism may be related to asparaginase-induced fluctuation of coagulation proteins. In addition, the potential hypercoagulability induced by asparaginase may increase the risk of glucocorticoid-induced osteonecrosis in children older than 10 years of age, particularly females. Increased incidence of thromboembolism has been reported with concomitant use of asparaginase and prednisone or dexamethasone as compared to asparaginase alone. Other corticosteroids may interact.

MANAGEMENT: If combination therapy is necessary, the Australian product labeling for asparaginase (Leunase(R)) recommends that asparaginase be administered after prednisone. Close monitoring for clinical and laboratory evidence of hyperglycemia and/or altered coagulation is also recommended at baseline and periodically throughout concurrent treatment with corticosteroids and asparaginase-derived products. Patients should be advised to promptly report any signs and symptoms of hyperglycemia, bleeding, blood clots or bone pain.

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: Asparaginase therapy may lead to imbalances in coagulation factors predisposing the patient to bleeding or thrombosis. Theoretically, concurrent use of anticoagulants and asparaginase may increase the risk of bleeding. Hemorrhages grade 3 and above and CNS hemorrhages have been observed with asparaginase treatment. However, serious thromboembolic events have also been reported with the use of asparaginase. Some investigators have suggested that anticoagulants could be used prophylactically with asparaginase for the prevention of thromboembolic events.

MANAGEMENT: Coagulation parameters should be monitored at baseline and periodically during concomitant treatment with asparaginase and anticoagulants such as heparin, dipyridamole, aspirin and nonsteroidal anti-inflammatory drugs. Patients should be advised to promptly report any signs and symptoms of bleeding.

MONITOR: Concomitant use of asparaginase with other hepatotoxic agents may potentiate the risk of liver injury. Asparaginase-associated hepatotoxicity has been reported more commonly in adults than in children and has been strongly associated with obesity. Hepatomegaly, acute severe hepatotoxicity, and fatal liver failure have been reported with asparaginase treatment in adults. Also, asparaginase may increase the toxicity of drugs bound to plasma proteins or metabolized by the liver.

MANAGEMENT: The risk of additive hepatotoxicity should be considered when asparaginase is used with other hepatotoxic agents (e.g., alcohol, androgens, antituberculosis agents, azole antifungal agents, ACE inhibitors, macrolide antibiotics, nonsteroidal anti-inflammatory agents, nucleoside reverse transcriptase inhibitors, sulfonamides, thiazolidinediones, and statins). Liver function tests should be monitored at regular intervals during asparaginase treatment with or without other hepatotoxic drugs. Patients should be advised to seek medical attention if they experience potential symptoms of hepatotoxicity such as right upper quadrant pain, increasing abdominal size, fever, rash, itching, anorexia, nausea, vomiting, fatigue, malaise, dark urine, pale stools, and jaundice.