Drug Interactions between AccessPak for HIV PEP Expanded with Kaletra and Hypaque Cysto

GENERALLY AVOID: Concomitant use of intravascular radiocontrast media with other nephrotoxic agents may potentiate the risk of contrast-induced nephropathy and renal impairment. Contrast-induced nephropathy is most commonly defined as an increase in serum creatinine >=0.5 mg/dL or 25% from baseline within 24 to 72 hours of intravascular contrast administration in the absence of alternative etiologies, although nephropathy may occur up to a week after contrast exposure. Pathogenesis has not been fully elucidated, but may involve renal hypoperfusion and ischemia, direct cytotoxicity on tubular epithelial cells, and generation of reactive oxygen species. While the condition is usually transient and asymptomatic, it can be associated with increased risk of renal failure, dialysis, prolonged hospitalization, significant long-term morbidity, and mortality. Patients at increased risk of developing contrast-induced nephropathy include those with diabetes (especially diabetic nephropathy), preexisting renal insufficiency (serum creatinine >1.5 mg/dL or GFR <60 mL/min/1.73 m2), volume depletion (e.g., diuretic use), advanced age (>70 years), congestive heart failure, multiple myeloma, hypoalbuminemia, and concomitant use of nephrotoxic agents (e.g., aminoglycosides; polypeptide, glycopeptide, and polymyxin antibiotics; amphotericin B; aminosalicylates; antiviral/antiretroviral agents such as acyclovir, adefovir, cidofovir, foscarnet, and tenofovir; antineoplastics such as aldesleukin, cisplatin, clofarabine, ifosfamide, streptozocin, and high intravenous dosages of methotrexate; chelating agents such as deferasirox, deferoxamine, edetate disodium, and edetate calcium disodium; immunosuppressants such as cyclosporine, everolimus, sirolimus, and tacrolimus; intravenous bisphosphonates; intravenous pentamidine; high dosages and/or chronic use of nonsteroidal anti-inflammatory agents; gallium nitrate; lithium; penicillamine). The incidence has been reported to be approximately 10% to 30% in patients with risk factors, and as high as 90% in diabetics with chronic kidney disease. Intraarterial administration of contrast media is also associated with increased risk of nephropathy relative to intravenous administration.

MANAGEMENT: Alternative imaging techniques that do not require contrast should be considered in patients who are at increased risk for contrast-induced nephropathy. Otherwise, experts recommend discontinuing other nephrotoxic drugs 1 to 2 days before administration of contrast media, depending on the clinical feasibility of doing so. The smallest effective dose (100 mL or less) of a nonionic, low-osmolar (e.g., iohexol, iomeprol, iopamidol, iopental, iopromide, ioversol) or iso-osmolar (e.g., iodixanol, iotrolan) contrast medium should be used whenever possible, since the risk of nephrotoxicity may be increased with increasing contrast dose, osmolarity, and ionicity. Some studies suggest a lower risk for iso-osmolar contrasts compared to low-osmolar contrasts, although data are limited. Serum creatinine levels should be measured before contrast administration (if procedure is not urgent) and continued for 24 to 48 hours after. In addition, patients should be adequately hydrated with either intravenous normal saline or sodium bicarbonate starting 3 (outpatient) to 6 (inpatient) hours before and continued for 6 to 24 hours after procedure. Oral fluids are also beneficial, but not as effective as intravenous hydration. N-acetylcysteine the day before and day of contrast administration, or theophylline up to 30 minutes before contrast administration, have also been used in high-risk or critically ill patients. Preferably, a nephrologist should be consulted to optimize prophylactic measures for preventing contrast-induced nephropathy in high-risk patients and to guide treatment if the condition occurs. Any repeat procedures with contrast media, if necessary, should not occur until at least 48 to 72 hours after the previous contrast exposure and renal function has fully recovered.

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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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