Drug Interactions between dexamethasone / ketorolac / moxifloxacin and lapatinib

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 inducers of CYP450 3A4 may significantly decrease the plasma concentrations of lapatinib, which is primarily metabolized by the isoenzyme. In 24 healthy subjects, administration of a single 250 mg oral dose of lapatinib following treatment with the potent CYP450 3A4 inducer carbamazepine (100 mg twice daily for 3 days, then 200 mg twice daily for 17 days) decreased mean lapatinib peak plasma concentration (Cmax) and systemic exposure (AUC) by 59% and 72%, respectively, compared to administration of lapatinib alone. Reduced efficacy of lapatinib may occur.

MANAGEMENT: Concomitant use of lapatinib with potent CYP450 3A4 inducers should generally be avoided. If coadministration is required, a gradual dosage increase of lapatinib should be considered. The prescribing information recommends titrating the lapatinib dosage gradually from 1250 mg/day up to 4500 mg/day or from 1500 mg/day up to 5500 mg/day depending on the indication and patient tolerability. Based on pharmacokinetic studies, this dosage recommendation is predicted to adjust the lapatinib systemic exposure (AUC) to the range observed without inducers. However, clinical data are lacking. If the CYP450 3A4 inducer also carries a risk of prolonging the QT interval, then obtaining more frequent electrocardiograms (ECGs) to monitor the QT interval may be advisable. Patients should be counseled to seek immediate medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, syncope, palpitations, irregular heartbeat, and/or shortness of breath. The dosage of lapatinib should be reduced over approximately 2 weeks to the indicated dosage following discontinuation of the potent CYP450 3A4 inducer.

GENERALLY AVOID: Certain quinolones, including gatifloxacin and moxifloxacin, may cause dose-related prolongation of the QT interval in some patients. 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. During postmarketing surveillance, rare cases of torsade de pointes have been reported in patients taking gatifloxacin. These cases primarily involved patients with underlying medical conditions for which they were receiving concomitant medications known to prolong the QTc interval. Rare cases of tachycardia have been reported with moxifloxacin. 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). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Coadministration of gatifloxacin or moxifloxacin with other drugs that can prolong the QT interval should generally be avoided. Caution and clinical monitoring are recommended if concomitant use is required. Since the magnitude of QTc prolongation increases with increasing plasma concentrations of the quinolone, recommended dosages and intravenous infusion rates should not be exceeded. 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.

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.