Drug Interactions between avapritinib 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.

GENERALLY AVOID: Coadministration with potent or moderate inducers of CYP450 3A4 may significantly decrease the plasma concentrations of avapritinib, which has been shown in vitro to be primarily metabolized by CYP450 3A4 and, to a lesser extent, by CYP450 2C9. When a single 400 mg dose of avapritinib was administered with the potent CYP450 3A4 inducer rifampin at a dosage of 600 mg once daily, avapritinib peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 74% and 92%, respectively. Based on pharmacokinetic modeling, coadministration of avapritinib 300 mg once daily with the moderate CYP450 3A4 inducer efavirenz at a dosage of 600 mg once daily is predicted to decrease avapritinib Cmax by 55% and AUC by 62% at steady-state.

MANAGEMENT: Concomitant use of avapritinib with potent or moderate CYP450 3A4 inducers should generally be avoided.

MONITOR CLOSELY: Coadministration of avapritinib and drugs that interfere with platelet function or coagulation may potentiate the risk of bleeding complications. Serious and fatal hemorrhagic events have been reported during avapritinib therapy, including gastrointestinal, hepatic, tumor, ocular, and intracranial hemorrhages. In clinical studies, intracranial hemorrhage (e.g., subdural hematoma, cerebral hemorrhage, cerebral hematoma) occurred in 1% to 3% of patients, with onset ranging from 1.7 to 19.3 months after initiating avapritinib. Overall, 0.9% of patients receiving avapritinib required permanent discontinuation for an intracranial hemorrhage, and 1.2% required treatment interruption followed by dosage reduction. The mechanism for the bleeding events is not well understood, although treatment with avapritinib commonly causes thrombocytopenia.

MANAGEMENT: Concomitant use of avapritinib with other drugs that increase the risk of bleeding should be approached with caution. Close clinical and laboratory monitoring for bleeding complications is recommended during therapy. Patients should be advised to promptly report any signs and symptoms of bleeding to their physician. Patients should also seek immediate medical attention if they experience neurological signs and symptoms that may be associated with intracranial hemorrhage such as severe headache, vision problems, somnolence, or focal weakness. Brain imaging by magnetic resonance imaging (MRI) or computed tomography (CT) may be performed at the discretion of the physician based on severity and clinical presentation. For patients with observed intracranial hemorrhage during treatment with avapritinib, some authorities recommend that avapritinib be discontinued permanently regardless of Grade. Others suggest withholding avapritinib for Grade 1 or 2 reactions until resolution, then resuming at a reduced dosage. However, avapritinib should be permanently discontinued upon recurrence of Grade 1 or 2 reactions or first occurrence of Grade 3 or 4 reactions.

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.