Drug Interactions between AccessPak for HIV PEP Expanded with Kaletra and Nolvadex

GENERALLY AVOID: Chronic coadministration of potent or moderate CYP450 2D6 inhibitors including certain antidepressants may reduce the effectiveness of tamoxifen. The proposed mechanism is inhibition of tamoxifen bioactivation via CYP450 2D6 to endoxifen (4-hydroxy-N-desmethyltamoxifen), the active metabolite that may be responsible for much of tamoxifen's antiestrogenic activity. This is consistent with studies that reported poorer clinical outcome (e.g., increased breast cancer recurrence; shorter relapse-free periods; lower rates of event-free survival) and decreased incidence/severity of hot flashes in patients treated with tamoxifen who have genetic polymorphisms of CYP450 2D6 resulting in reduced or absent enzyme activity. A similar relationship has been observed between endoxifen exposure and alterations in CYP450 2D6 metabolic status, whether due to CYP450 2D6 genetic variants or use of CYP450 2D6 inhibitors such as quinidine or SSRI antidepressants. In a study of 12 patients receiving tamoxifen adjuvant therapy, mean plasma concentrations of endoxifen decreased by more than 50% after four weeks of paroxetine 10 mg/day for hot flashes, and the effect was evident primarily in patients who carried the wild-type genotype for CYP450 2D6 (i.e., extensive metabolizers). In vitro, quinidine reduced the conversion to endoxifen by 79%. Potential clinical implications of this interaction were reported in a retrospective analysis of nearly 1,300 female breast cancer patients who were newly prescribed tamoxifen between 2003 and 2005 and were monitored for at least two years (mean 2.7 years). Women who used a moderate to potent CYP450 2D6 inhibitor (n=353) during tamoxifen therapy had a two-year breast cancer recurrence rate of 13.9%, compared to 7.5% for those not taking any CYP450 2D6 inhibitors (n=945). The average duration of concomitant tamoxifen and CYP450 2D6 inhibitor use was 340 days. In a subset analysis of patients taking tamoxifen with SSRI antidepressants, a breast cancer recurrence rate of 16% was reported for 213 women who used fluoxetine, paroxetine, or sertraline--SSRIs that are considered moderate to potent inhibitors of CYP450 2D6. This rate was 2.2 times higher than that for women taking tamoxifen without CYP450 2D6 inhibitors. In contrast, the breast cancer recurrence rate was 8.8% for 137 women using citalopram, escitalopram, or fluvoxamine, which was not statistically different than controls. An earlier, smaller study conducted by a group of Danish researchers also reported no reduction of tamoxifen effectiveness in association with citalopram or escitalopram use for up to five years. It is important to note that not all studies have found an association between CYP450 2D6 activity and tamoxifen clinical effects. In fact, a couple of studies even reported decreased risk of recurrence in patients treated with tamoxifen who have a common genetic variant of CYP450 2D6. Investigators suggest that the discrepancies may be due to differences in study designs, including sample size, different genetic models for the assessment of phenotypes, and stratification effects.

MANAGEMENT: Based on available data, patients treated with tamoxifen should avoid the chronic use of potent CYP450 2D6 inhibitors such as bupropion, fluoxetine, paroxetine and quinidine whenever possible, and preferably also moderate inhibitors such as adagrasib, duloxetine, and sertraline. If an antidepressant is required during treatment with tamoxifen, agents such as desvenlafaxine, fluvoxamine, milnacipran, levomilnacipran, mirtazapine, and venlafaxine may be considered, since they have mild to no effects on CYP450 2D6. Alternatively, aromatase inhibitors such as anastrozole, exemestane, and letrozole may be appropriate substitutes for tamoxifen in certain patients. In addition, it should be noted that rolapitant, a moderate CYP450 2D6 inhibitor, may reduce the effectiveness of tamoxifen for at least 28 days after administration of rolapitant.

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GENERALLY AVOID: Lopinavir in combination with ritonavir may cause dose-related 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 a study of 39 healthy adults who were administered lopinavir-ritonavir at a therapeutic dosage of 400 mg-100 mg twice daily and a supratherapeutic dosage of 800 mg-200 mg twice daily, the maximum mean time-matched difference in QTcF interval from placebo (after baseline correction) was 5.3 msec for the lower dosage and 15.2 msec for the supratherapeutic dosage in the 12 hours post-dose on treatment day 3 when exposures were approximately 1.5 and 3-fold higher, respectively, than those observed with recommended once-daily or twice-daily dosages of lopinavir-ritonavir at steady state. No subject experienced an increase in QTcF greater than 60 msec from baseline or a QTcF interval exceeding the potentially clinically relevant threshold of 500 msec. There have been cases of QT interval prolongation and torsade de pointes arrhythmia during postmarketing use of lopinavir-ritonavir, although causality could not be established. 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 lopinavir-ritonavir with other drugs that can prolong the QT interval should generally be avoided. Patients treated with any medication that can cause QT prolongation 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.

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MONITOR: Coadministration with ritonavir, with or without lopinavir, has been suggested in postmarketing reports to increase the proximal tubular intracellular concentrations of tenofovir and potentiate the risk of tenofovir-induced nephrotoxicity. The proposed mechanism is ritonavir inhibition of tenofovir renal tubular secretion into the urine via multidrug resistance protein MRP2. Analysis of data from a compassionate access study in which 271 patients with advanced HIV disease received the combination for a mean duration of 63 weeks revealed no clinically significant nephrotoxicity associated with coadministration. However, there have been case reports of renal failure associated with acute tubular necrosis, Fanconi's syndrome, and nephrogenic diabetes insipidus in patients treated with tenofovir disoproxil fumarate in combination with ritonavir. Some patients had incomplete recovery of renal function more than a year after cessation of tenofovir therapy. Ritonavir given in combination with lopinavir has also been reported to modestly increase the plasma concentrations of tenofovir. In contrast, both slight decreases and no change in lopinavir and ritonavir concentrations have been reported.

MANAGEMENT: Caution is advised if tenofovir disoproxil fumarate is prescribed with ritonavir. Renal function should be monitored regularly, including surveillance for signs of tubulopathy such as glycosuria, acidosis, increases in serum creatinine level, electrolyte disturbances (e.g., hypokalemia, hypophosphatemia), and proteinuria. The same precaution may be applicable during therapy with other protease inhibitors based on their similar pharmacokinetic profile, although clinical data are lacking. Nelfinavir reportedly does not alter the pharmacokinetics of tenofovir, or vice versa. Tenofovir administration should be discontinued promptly if nephropathy develops.

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MONITOR: Coadministration with ritonavir, with or without lopinavir, has been suggested in postmarketing reports to increase the proximal tubular intracellular concentrations of tenofovir and potentiate the risk of tenofovir-induced nephrotoxicity. The proposed mechanism is ritonavir inhibition of tenofovir renal tubular secretion into the urine via multidrug resistance protein MRP2. Analysis of data from a compassionate access study in which 271 patients with advanced HIV disease received the combination for a mean duration of 63 weeks revealed no clinically significant nephrotoxicity associated with coadministration. However, there have been case reports of renal failure associated with acute tubular necrosis, Fanconi's syndrome, and nephrogenic diabetes insipidus in patients treated with tenofovir disoproxil fumarate in combination with ritonavir. Some patients had incomplete recovery of renal function more than a year after cessation of tenofovir therapy. Ritonavir given in combination with lopinavir has also been reported to modestly increase the plasma concentrations of tenofovir. In contrast, both slight decreases and no change in lopinavir and ritonavir concentrations have been reported.

MANAGEMENT: Caution is advised if tenofovir disoproxil fumarate is prescribed with ritonavir. Renal function should be monitored regularly, including surveillance for signs of tubulopathy such as glycosuria, acidosis, increases in serum creatinine level, electrolyte disturbances (e.g., hypokalemia, hypophosphatemia), and proteinuria. The same precaution may be applicable during therapy with other protease inhibitors based on their similar pharmacokinetic profile, although clinical data are lacking. Nelfinavir reportedly does not alter the pharmacokinetics of tenofovir, or vice versa. Tenofovir administration should be discontinued promptly if nephropathy develops.

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