Drug Interactions between citalopram and emtricitabine / lopinavir / ritonavir / tenofovir disoproxil

GENERALLY AVOID: Citalopram can cause dose-dependent 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. The maximum mean difference from placebo in the individually corrected QTc (QTcNi) interval for healthy subjects (n=119) evaluated in a randomized, double-blind, crossover, escalating multiple-dose study for citalopram (20 mg/day for 9 days, 40 mg/day for 4 days, and then 60 mg/day for 9 days) was 8.5 msec for 20 mg and 18.5 msec for 60 mg. Based on the established exposure-response relationship, prolongation of the QTcNi interval was estimated to be 12.6 msec for citalopram 40 mg. Cases of QT prolongation and ventricular arrhythmia including torsade de pointes have been reported during postmarketing use, predominantly in patients of female gender, with hypokalemia, or with preexisting QT-prolongation or other cardiac disease. 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 those noted in postmarketing use with citalopram. The extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s). In addition, when two or more medications with similar adverse effect profiles are given concurrently, the likelihood of experiencing these adverse reactions may be increased. For example, the risk of experiencing central nervous system (CNS) and/or respiratory depressant effects may be increased when citalopram is combined with another agent that could also cause these adverse reactions, particularly in those who are already at an increased risk, such as the elderly or debilitated patients.

MANAGEMENT: The use of citalopram is not recommended in patients receiving other drugs that prolong the QT interval and is considered contraindicated by some authorities. Likewise, citalopram should be avoided in patients with congenital long QT syndrome, bradycardia, hypokalemia, hypomagnesemia, recent acute myocardial infarction, or uncompensated heart failure unless the benefits outweigh the risks for a particular patient. If treatment with citalopram is considered clinically necessary or beneficial in these patients, the labeling recommends that the dosage not exceed 40 mg/day, unless the patient has hepatic impairment, is greater than 60 years of age, and/or is a poor metabolizer of CYP450 2C19 in which case the dosage should not exceed 20 mg/day. Patients at risk for significant electrolyte disturbances should have serum potassium and magnesium assessed at baseline and periodically during treatment. If hypokalemia or hypomagnesemia is found, it should be corrected prior to initiation of treatment and periodically monitored. Regular ECG monitoring is also advised, and persistent QTc measurements greater than 500 msec should prompt discontinuation of the medication(s). 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. Additionally, when citalopram is used in combination with other drugs that cause CNS and/or respiratory depression, patients should be monitored for potentially excessive or prolonged CNS and respiratory depression. Ambulatory patients should be counseled to avoid hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their doctor if they experience excessive or prolonged CNS effects that interfere with their normal activities. The product labeling of the concomitant medication should be consulted for further guidance, such as specific dosage adjustment and/or management recommendations should serious adverse reactions occur.

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.

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.

Coadministration with inhibitors of CYP450 3A4 is not expected to significantly affect the pharmacokinetics of citalopram or escitalopram, both of which are partially metabolized by the isoenzyme. Administration of racemic citalopram (40 mg) in combination with the potent CYP450 3A4 inhibitor ketoconazole (200 mg) decreased the ketoconazole peak plasma concentration (Cmax) by 21% and systemic exposure (AUC) by 10%, but did not significantly affect the pharmacokinetics of citalopram. Likewise, coadministration of a single 20 mg dose of escitalopram with a single 600 mg dose of ritonavir, another potent CYP450 3A4 inhibitor, did not affect the pharmacokinetics of either drug. Because citalopram and escitalopram are both metabolized by multiple isoenzymes (CYP450 2C19, 3A4, and 2D6), inhibition of a single isoenzyme may not appreciably decrease their clearance.