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Drug Administration]](https://webarchive.library.unt.edu/eot2008/20081028115620im_/http://www.fda.gov/icon/header.gif){kind=icon}
September, 1996
Dear Health Care Professional,
Gilead Sciences, Inc., has become aware of several reports of severe renal impairment associated with the use of VISTIDE® (cidofovir injection). VISTIDE is indicated for the treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS). At least two cases of acute renal failure resulting in dialysis and/or contributing to death, associated with the administration of only one or two doses of VISTIDE, have recently been reported. This letter is being sent to health care providers to reinforce the importance of appropriate patient selection, treatment administration and monitoring of VISTIDE therapy in order to ensure that VISTIDE is used safely, and to alert providers about two new contraindications for VISTIDE. The package insert for VISTIDE and all of our communications clearly state that renal impairment is the major toxicity of VISTIDE. Gilead Sciences requests that other cases of nephrotoxicity possibly associated with VISTIDE be reported to Gilead Sciences or the FDA's MedWatch program.
The reports noted above were associated with risk factors for nephrotoxicity, including preexisting mild renal insufficiency, and VISTIDE administration proximal to completion of aminoglycoside therapy in a patient with preexisting normal serum creatinine. The VISTIDE Product Information describes factors that can contribute to the development of renal insufficiency which includes dosing outside the recommended guidelines, preexisting renal disease, failure to properly monitor indices of renal function during treatment, and concomitant administration of agents with nephrotoxic potential. Listed below are guidelines to ensure the proper selection of patients, proper administration of VISTIDE and proper patient monitoring. Items l and 2 of the guidelines are two new contraindications for VISTIDE. For more complete information, please refer to the attachment provided.
The package labeling for VISTIDE clearly states that renal impairment is the major toxicity of VISTIDE. The insert has been revised to emphasize further the importance of appropriate patient selection, treatment administration and monitoring when using VISTIDE; a copy of the revised package insert is enclosed with this letter. Also enclosed with this letter is an attachment that emphasizes steps to reduce the incidence of nephrotoxicity, as well as a patient log for monitoring patients receiving VISTIDE therapy.
Gilead Sciences asks that health care professionals report any case of nephrotoxicity or other serious toxicity associated with VISTIDE administration to Gilead Sciences, Inc., 1-800-GILEAD-5 or to the FDA's MEDWATCH program at 1-800-FDA-1088/fax 1-800-FDA-0178.
Sincerely,
Howard S. Jaffe, M.D.
Senior Vice President
Drug Development
VISTIDE is contraindicated in patients with serum creatinine levels > 1.5 mg/dL, creatinine clearance </= 55 mL/min, or a urine protein >/= 100 mg/dL (equivalent to >/= 2+ proteinuria). Because serum creatinine in patients with advanced AIDS and CMV retinitis may not provide a complete picture of your patients' underlying renal status, it is important to utilize the Cockcroft-Gault formula to more precisely estimate creatinine clearance (CrCl). As creatinine clearance is dependent on serum creatinine and patient weight, it is necessary to calculate clearance prior to initiating VISTIDE. CrCl (mL/min) should be calculated according to the following formula:
Males: (140 - age) x weight (in kg) / 72 x serum creatinine (in mg/dL)
Females: (140 - age) x weight (in kg) x O.85 / 72 x serum creatinine (in mg/dL)
VISTIDE has not been studied in patients with moderate to severe renal impairment and appropriate induction and maintenance doses have not been established.
Concomitant administration of VISTIDE with agents having nephrotoxic potential is contraindicated. VISTIDE has not been studied in patients receiving concomitant therapy with agents having nephrotoxic potential such as foscarnet, amphotericin B, aminoglycoside antibiotics (e.g., tobramycin, gentamicin, or amikacin), vancomycin, non-steroidal anti-inflammatory agents, and intravenous pentamidine. Patients should undergo a "wash-out" period of at least 7 days following the administration of the above agents prior to receiving VISTIDE. Importantly, clinical trials have provided evidence that previous exposure to foscarnet, an agent with known nephrotoxic potential, may increase the risk of VISTIDE-related nephrotoxicity. Therefore, VISTIDE therapy should only be used in patients who have received foscarnet when the potential benefits exceed the potential risks.
Special attention must be given to the hydration status of patients receiving VISTIDE. Patients with intravascular volume depletion may be at increased risk of nephrotoxicity. Because chronic diarrhea, poor fluid intake, and HIV-1 related wasting may be part of your patients' underlying medical condition, repletion and maintenance of volume status in such patients is necessary to minimize the potential for nephrotoxicity.
The recommended dosage, frequency, or infusion rate of VISTIDE must not be exceeded. The recommended induction dose of VISTIDE is 5 mg/kg body weight (given as an intravenous infusion at a constant rate over 1 hr) administered once weekly for two consecutive weeks.
The recommended maintenance dose of VISTIDE is 5mg/kg body weight (given as an intravenous infusion at a constant rate over 1 hr) administered once every two weeks.
The VISTIDE dose must be reduced or discontinued if changes in renal function occur during therapy. For increases of 0.3 to 0.4 mg/dL in serum creatinine above baseline, the VISTIDE dose must be reduced from 5 mg/kg to 3 mg/kg. VISTIDE must be discontinued for an increase in serum creatinine of 0.5 mg/dL above baseline or development of 3+ proteinuria. Patients with 2+ proteinuria should be observed carefully, and dose reduction or temporary interruption considered.
Properly timed intravenous pre-hydration with normal saline and oral probenecid must be used with each VISTIDE infusion. Patients must receive at least one liter of 0.9% (normal) saline solution intravenously prior to each infusion of VISTIDE. The saline should be infused over a one to two hour period immediately before the VISTIDE infusion. Patients who can tolerate the additional fluid load should receive a second liter, initiated either during the VISTIDE infusion or immediately afterwards, infused over a 1 to 3 hour period.
Probenecid must be administered orally with each VISTIDE dose. Two grams must be administered 3 hours prior to the VISTIDE dose and one gram administered at 2 hours and again at 8 hours after the completion of the one hour VISTIDE infusion (for a total of 4 grams of probenecid). Failure to comply with this regimen may increase the risk of nephrotoxicity.
Renal function (serum creatinine and urine protein) must be monitored prior to each dose of VISTIDE and the dose of VISTIDE reduced or treatment discontinued for changes in renal function as appropriate. Serum creatinine and urine protein must be assessed during the 48 hour period immediately preceding the VISTIDE infusion. Because patients with advanced AIDS and CMV retinitis are at risk for the development of acute medical problems, close monitoring is necessary to help reduce the risk of nephrotoxicity. We strongly recommend the use of laboratory flow sheets (contact Gilead Sciences for a copy) to ensure that close monitoring of renal function is performed.
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