Drug Interactions between dexamethasone / ketorolac / moxifloxacin and toremifene

GENERALLY AVOID: Coadministration with potent inducers of CYP450 3A4 may significantly decrease the plasma concentrations of toremifene. According to the product labeling, toremifene is primarily metabolized by CYP450 3A4 to N-demethyltoremifene, an antiestrogenic metabolite with weak in vivo antitumor potency but whose serum concentrations are 2 to 4 times higher than those of toremifene at steady state. When a single 120 mg oral dose of toremifene was administered to 9 healthy volunteers following treatment with the potent CYP450 3A4 inducer rifampin at a dosage of 600 mg once daily for 5 days, toremifene peak plasma concentration (Cmax), systemic exposure (AUC) and elimination half-life decreased by 55%, 87% and 44%, respectively, compared to pretreatment with placebo. In addition, rifampin decreased the AUC of N-demethyltoremifene by 80% and increased its Cmax by 48%, suggesting enhanced presystemic metabolism of toremifene in the intestine. Loss of therapeutic efficacy of toremifene may occur.

MANAGEMENT: Concomitant use of toremifene with potent CYP450 3A4 inducers should generally be avoided. Alternative therapeutic agents with less enzyme induction potential should be considered whenever possible during treatment with toremifene. If coadministration is required, a doubling of the toremifene dosage may be necessary depending on patient tolerability. Close monitoring for toxicities (e.g., QT prolongation, hepatotoxicity, hypercalcemia and tumor flare) is recommended if the dosage of toremifene is increased. The dosage should be reduced to the indicated dosage following discontinuation of the potent CYP450 3A4 inducer.

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: Toremifene has the potential to prolong the QT interval of the electrocardiogram 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. The effect on the QT interval is dose- and concentration-dependent. In a placebo-controlled, parallel-design clinical trial, the mean QTc interval prolongation was 21 to 26 ms with 80 mg toremifene, and the 20 mg dose also affected the QTc interval. Abnormal new U waves were observed in 4.3% of subjects with the 80 mg dose. There are no data available for the therapeutic 60 mg dose. 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, women and elderly patients may be more susceptible to the QT prolonging effects of drugs.

MANAGEMENT: Coadministration of toremifene with other drugs that can prolong the QT interval should generally be avoided. If treatment with other QT-prolonging drugs is required, interruption of toremifene therapy should be considered. Caution and clinical monitoring are recommended if concomitant use is unavoidable. In patients at increased risk, electrocardiograms (ECGs) are recommended at baseline and as clinically indicated. 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.