Drug Interactions between dexamethasone / ketorolac / moxifloxacin and pralsetinib

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 moderate inducers of CYP450 3A4 may significantly decrease the plasma concentrations of pralsetinib, which is primarily metabolized by the isoenzyme. Concurrent use with the moderate CYP450 3A4 inducer efavirenz (600 mg once daily) is predicted to decrease the peak plasma concentration (Cmax) and systemic exposure (AUC) of pralsetinib by 18% and 45%, respectively. Reduced therapeutic efficacy may occur. In addition, when two or more medications with similar side effect profiles are given concurrently, the likelihood of experiencing these adverse reactions may be increased. For example, coadministration with other agents that can lead to elevations in liver transaminases may result in additive effects and an increased risk of hepatotoxicity.

MANAGEMENT: Concomitant use of pralsetinib with moderate CYP450 3A4 inducers should generally be avoided. If coadministration is considered clinically necessary, the current dose of pralsetinib should be increased starting on Day 7 of coadministration with the moderate CYP450 3A4 inducer. The manufacturer recommends increasing the dose of pralsetinib as follows: 600 mg once daily for patients receiving 400 mg once daily, 500 mg once daily for patients receiving 300 mg once daily, and 300 mg once daily for patients receiving 200 mg once daily. Once the moderate CYP450 3A4 inducer has been discontinued for at least 14 days, the pralsetinib dose taken prior to initiating the inducer may be resumed. Patients should be counseled to seek immediate medical attention if they experience symptoms that could indicate serious adverse effects including but not limited to hepatotoxicity. Consult the individual product labeling for further guidance; for example, in instances when the potency of the CYP450 3A4 inducer may be affected by dose or dosage form.

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.

MONITOR: Pralsetinib can cause prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. In clinical trials, QT prolongation occurred in 5.1% of 528 patients with non-small cell lung cancer (NSCLC) or other solid tumors. Two patients (0.4%) experienced grade 3 QT prolongation, which resolved in each case. There was no life-threatening or fatal QT prolongation. The QT interval prolongation potential of pralsetinib was assessed in 34 patients with rearranged during transfection (RET) altered solid tumors administered 400 mg once daily, and no mean increase in the corrected QT interval (QTc) greater than 20 ms was detected. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypocalcemia). Moreover, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Some authorities recommend caution if pralsetinib is coadministered with other agents known to prolong the QT interval. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope.