Drug Interactions between dexamethasone / ketorolac / moxifloxacin and tamoxifen

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: 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 inducers of CYP450 3A4 may decrease the plasma concentrations of tamoxifen and its major metabolite, N-desmethyltamoxifen. According to the product labeling, tamoxifen is primarily metabolized by CYP450 3A4 to N-desmethyltamoxifen, an antiestrogenic metabolite with similar biological activity to tamoxifen but an elimination half-life that is estimated to be approximately 10 to 14 days versus 5 to 7 days for tamoxifen. N-desmethyltamoxifen itself is further metabolized by CYP450 2D6 to endoxifen, a major metabolite that is thought to be primarily responsible for tamoxifen's therapeutic effect. When a single 80 mg oral dose of tamoxifen was administered to 10 healthy volunteers following pretreatment with the potent CYP450 3A4 inducer rifampin at a dosage of 600 mg once daily for 5 days, tamoxifen peak plasma concentration (Cmax), systemic exposure (AUC) and elimination half-life decreased by 55%, 86% and 44%, respectively, compared to pretreatment with placebo. In addition, rifampin decreased the AUC and half-life of N-desmethyltamoxifen by 62% and 36%, respectively, and increased the Cmax by approximately 50% compared to placebo. These changes indicate that rifampin enhanced the metabolism of tamoxifen during both the presystemic and elimination phases. In another study, patients with glioma who received high-dose tamoxifen with phenytoin (n=15) demonstrated a 60% lower mean plasma tamoxifen concentration than patients not on concomitant phenytoin (n=10), although the difference did not reach statistical significance due to high interpatient variability and low patient numbers. The interaction has also been described in case reports of two tamoxifen-treated patients who had significantly reduced and subtherapeutic endoxifen levels during or after coadministration with a potent CYP450 inducer. One of them was receiving phenytoin and the other, rifampin. Induction of endoxifen clearance via P-glycoprotein-mediated efflux and/or uridine diphosphate glucuronosyltransferase (UGT)-mediated metabolism may be involved. Aminoglutethimide has also been reported to significantly reduce the serum concentrations of tamoxifen and most of its major metabolites, including N-desmethyltamoxifen and endoxifen, in association with a greater than 3-fold increase in the clearance of tamoxifen. Coadministration of another CYP450 3A4 inducer, bexarotene, resulted in a 35% decrease in plasma concentrations of tamoxifen. The extent to which other CYP450 3A4 inducers may affect tamoxifen and its active metabolites is unknown.

MANAGEMENT: Caution is advised when tamoxifen is prescribed with CYP450 3A4 inducers. Therapeutic drug monitoring of tamoxifen and endoxifen should be considered to optimize therapy.

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.