August, 1998

Dear Health Care Professional:

After continuing to receive reports of renal failure associated with VISTIDE (cidofovir injection) use, Gilead Sciences, Inc. is distributing this letter to reinforce the importance of adherence to specific treatment guidelines when administering VISTIDE. These guidelines are summarized below, and are detailed in the attached Guidelines For Use of VESTIDE. Importantly, this information is included in the enclosed current prescribing information for VISTIDE. Additionally, this letter is also to alert providers to recent reports of anterior uveitis or iritis and hearing loss in patients receiving therapy with VISTIDE.

Cases of acute renal failure resulting in dialysis and/or contributing to death have been reported after as few as one or two doses of Vistide. Most patients had identifiable risk factors that increase the potential for nephrotoxicity associated with the use of VISTIDE, including non-compliance with dose modification criteria for VISTIDE, omission of probenecid administration prior to dosing with VISTIDE, failure to carefully monitor serum creatinine and/or urine protein prior to each infusion of VISTIDE, dehydration during therapy with VISTIDE, or recent/concomitant use of other agents with nephrotoxic potential. The risk of adverse renal events may be reduced by careful adherence to drug treatment guidelines outlined in the Guidelines For Use of Vistide and in the full prescribing information. These include:

• Initiation of therapy only in patients with adequate renal function (serum creatinine £ 1.5 mg/dL, creatinine clearance > 55 mL/min, and urine protein < 100 mg/dL)

• Monitoring of renal function prior to each dose of VISTIDE and modify or discontinue dosing as appropriate

• Prehydration with at least 1 liter of normal saline and ensure adequate fluid volume status

• Coadministration of all doses of oral probenecid (total 4 grams)

• Avoidance of concomitant nephrotoxic agents at least 7 days prior to starting therapy with VISTIDE

REPORTS OF UVEITIS/IRITIS

Cases of anterior uveitis have occurred during therapy with VISTIDE. In some of these cases, patients also experienced varying degrees of hypotony (decrease in intraocular pressure). Many patients who develop anterior uveitis are able to continue therapy with VISTIDE while receiving concomitant topical corticosteroids with or without cycloplegic therapy. Patients should be monitored for signs and symptoms of uveitis/iritis while receiving therapy with VISTIDE.

Three cases of hearing loss, with or without tinnitus, associated with administration of VISTIDE, have been reported. In two patients, symptoms that were reported within 24 to 48 hours of the infusion of VISTIDE declined over time until the next dose. Following discontinuation of therapy with VISTIDE the hearing impairment and tinnitus abated.

VISTIDE is indicated for the treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS). The recommended induction dose of VISTIDE is 5 mg/kg body weight (infused intravenously over 1 hr at a constant rate) administered once weekly for two consecutive weeks, followed by a maintenance dose of 5 mg/kg (infused intravenously over 1 hr at a constant rate) administered once every two weeks. Pre-dose monitoring of creatinine and urinalysis within 48 hours prior to each infusion of VISTIDE is essential. Properly timed intravenous prehydration with normal (0.9%) saline and oral probenecid must be used with each infusion of VISTIDE.

Gilead Sciences asks that health care professionals report any case of serious toxicity associated with administration of VISTIDE to Gilead's Department of Medical Information/Safety Surveillance by calling 1-800-GILEAD-5 or to the FDA's MedWatch program by calling 1-800-FDA-1088/FAX 1-800-FDA-0178.

Sharon F. Safrin, M.D.
Director of Clinical Research

1. Therapy with VISTIDE is contraindicated in patients with impaired renal function

Initiation of therapy with VISTIDE is contraindicated in patients with serum creatinine levels > 1.5 mg/dL, calculated creatinine clearance £ 55mL/min, or a urine protein ³ 100 mg/dL (equivalent to ³ 2+ proteinuria). Creatinine clearance can be calculated using the Cockcroft-Gault formula:

Males:
(140-age) x body weight (kg)
72 x [serum creatinine (mg/dL)]

Females:
(140-age) x body weight (kg) x 0.85
72 x [serum creatinine (mg/dL]

2. VISTIDE is contraindicated in patients who are receiving agents with nephrotoxic potential

An interval of at least seven days should elapse following the administration of agents with nephrotoxic potential prior to the initiation of therapy with VISTIDE and should not be used during the course of therapy. Examples of agents having potential nephrotoxicity include: amphotericin B, foscarnet, intravenous pentamidine, intravenous aminoglycoside antibiotics (e.g., gentamicin, tobramycin, amikacin), vancomycin, and non-steroidal anti-inflammatory agents.

3. Avoidance of dehydration is important in the prevention of potential nephrotoxicity

Intravenous prehydration with at least one liter of 0.9% (normal) saline should be administered prior to each infusion of VISTIDE, with additional intravenous normal saline administered during or after each infusion of VISTIDE when tolerated. Since patients with chronic diarrhea or AIDS-related wasting may have intravascular volume depletion, special attention should be given to repletion of fluids in these patients.

4. Oral probenecid must be administered in conjunction with VISTIDE therapy and is important in the prevention of potential nephrotoxicity

Three doses of probenecid must be administered orally with every infusion of VISTIDE: two grams 3 hours prior to infusion (i.e., four 500 mg tablets), 1 gram (i.e., two 500 mg tablets) at 2 hours after infusion and 1 gram (i.e., two 500 mg tablets) at 8 hours after infusion (for a total of 4 grams of probenecid with each infusion of VISTIDE).

5. Renal function must be monitored prior to each dose in patients receiving therapy with VISTIDE, and the dose must be reduced or discontinued if changes in renal function occur during therapy

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