Interactions between Lonafarnib and Tamoxifen

Generally avoid

Lonafarnib can cause prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in a greater increase of the QT interval. This may increase the risk of adverse reactions associated with QT interval prolongation, including torsade de pointes, other serious arrhythmias, and sudden death. The impact of lonafarnib on the QTC interval was studied in a randomized, double-blind, placebo- and positive-controlled (moxifloxacin 400 mg single dose), multiple-dose, QTc study in 64 healthy subjects. Subjects received 200 mg lonafarnib twice daily for 9 consecutive days and a single 200 mg dose in the morning on day 10, with food. The largest mean increase in QTc interval was 19 msec. This was observed on day 10, 48 hours after administration of the morning dose of lonafarnib 200 mg. 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). Moreover, 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 lonafarnib with other agents that can prolong the QT interval should generally be avoided. If coadministration is necessary, clinical and laboratory monitoring should be considered. Patients should have an electrocardiogram obtained prior to initiating lonafarnib therapy, at regular intervals during treatment, and when clinically indicated. Serum electrolytes should be obtained prior to and during treatment with lonafarnib. Serum electrolyte abnormalities (e.g. hypokalemia, hypomagnesemia) should be corrected as clinically indicated, in accordance with current local practice guidelines. In addition to electrolyte management, lonafarnib treatment should be withheld if the QTc interval is greater than or equal to 500 msec until the QTc interval is less than 470 msec. Once the QTc interval is less than 470 msec, lonafarnib may be resumed at the same dosage. 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. Additional consultation with individual product labeling, as well as relevant institutional protocols, may be advisable for further guidance.

Generally avoid

Grapefruit, grapefruit juice, grapefruit hybrids, starfruit, and Seville oranges may increase the plasma concentrations of lonafarnib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice, but has been reported for other CYP450 3A4 inhibitors. When a single oral dose of lonafarnib (50 mg) was administered following pretreatment with the potent CYP450 3A4 inhibitor ketoconazole (200 mg once daily for 5 days) in healthy study subjects, lonafarnib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 270% and 425%, respectively, compared to lonafarnib administered alone. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high-dose, double-strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low-dose, single-strength) have typically demonstrated moderate inhibition. Increased exposure to lonafarnib may increase the risk and/or severity of adverse effects such as nausea, vomiting, diarrhea, anorexia, electrolyte disturbances, liver enzyme elevations, myelosuppression, infection, and hypertension. Lonafarnib alone prolongs the QTc interval, and increased exposure to lonafarnib may potentiate the risk of ventricular arrhythmias such as torsades de pointes, and sudden death.

Adjust dosing interval

Food does not have clinically relevant effects on the oral bioavailability of lonafarnib. When a single 75 mg oral dose of lonafarnib was administered with a high-fat meal (952 calories; approximately 43% from fat) in healthy subjects, lonafarnib Cmax and AUC decreased by 55% and 29%, respectively, compared to administration under fasted conditions. When administered with a low-fat meal (421 calories; approximately 12% from fat), lonafarnib Cmax decreased by 25% and AUC decreased by 21% relative to fasting. However, administration with food may help improve gastrointestinal tolerance to lonafarnib, which may commonly cause nausea, vomiting, diarrhea, and abdominal pain.

Management

Patients should avoid consumption of grapefruit, grapefruit juice, grapefruit hybrids, starfruit, and Seville oranges during treatment with lonafarnib. Additionally, lonafarnib should be administered with the morning and evening meals and an adequate amount of water. Consultation with product labeling may be advisable for further guidance.

Generally avoid

Due to their estrogenic effect, isoflavones present in soy such as genistein and daidzein may stimulate breast tumor growth and antagonize the antiproliferative action of tamoxifen. Supportive data are derived primarily from in vitro and animal studies. In vitro, low concentrations of these phytoestrogens have been found to promote DNA synthesis and reverse the inhibitory effect of tamoxifen on estrogen-dependent breast cancer cell proliferation. In contrast, high concentrations of genistein greater than 10 microM/L have been found to enhance tamoxifen effects by inhibiting breast cancer cell growth. It is not known if these high concentrations are normally achieved in humans. Plasma concentrations below 4 microM/L have been observed in healthy volunteers given a soy diet for one month or large single doses of genistein. These concentrations are comparable to the low plasma concentrations associated with tumor stimulation reported in animals. In a study of 155 female breast cancer survivors with substantially bothersome hot flashes, a product containing 50 mg of soy isoflavones (40% to 45% genistein; 40% to 45% daidzein; 10% to 20% glycitein) taken three times a day was found to be no more effective than placebo in reducing hot flashes. No toxicity or recurrence of breast cancer was reported during the 9-week study period. Green tea does not appear to have significant effects on the pharmacokinetics of tamoxifen or its primary active metabolite, endoxifen. In a study consisting of 14 patients who have been receiving tamoxifen treatment at a stable dose of 20 mg (n=13) or 40 mg (n=1) once daily for at least 3 months, coadministration with green tea supplements twice daily for 14 days resulted in no significant differences in the pharmacokinetics of either tamoxifen or endoxifen with respect to peak plasma concentration (Cmax), systemic exposure (AUC), and trough plasma concentration (Cmin) compared to administration of tamoxifen alone. The combination was well tolerated, with all reported adverse events categorized as mild (grade 1) and none categorized as serious or severe (grade 3 or higher) during the entire study. Although some adverse events such as headache, polyuria, gastrointestinal side effects (e.g., constipation, dyspepsia), and minor liver biochemical disturbances were reported more often during concomitant treatment with green tea, most can be attributed to the high dose of green tea used or to the caffeine in green tea. The green tea supplements used were 1000 mg in strength and contained 150 mg of epigallocatechin-3-gallate (EGCG), the most abundant and biologically active catechin in green tea. According to the investigators, the total daily dose of EGCG taken by study participants is equivalent to the amount contained in approximately 5 to 6 cups of regular green tea. However, it is not known to what extent the data from this study may be applicable to other preparations of green tea such as infusions, since the bioavailability of EGCG and other catechins may vary between preparations.

Management

Until more information is available, patients treated with tamoxifen may consider avoiding or limiting the consumption of soy-containing products. Consumption of green tea and green tea extracts during tamoxifen therapy appears to be safe.