:Adverse events that occurred during clinical trials of CYTOVENE-IV solution and CYTOVENE capsules are summarized below, according to the participating study subject population.

Subjects With AIDS: Three controlled, randomized, phase 3 trials comparing CYTOVENE-IV and CYTOVENE capsules for maintenance treatment of CMV retinitis have been completed. During these trials, CYTOVENE-IV or CYTOVENE capsules were prematurely discontinued in 9% of subjects because of adverse events. In a placebo-controlled, randomized, phase 3 trial of CYTOVENE capsules for prevention of CMV disease in AIDS, treatment was prematurely discontinued because of adverse events, new or worsening intercurrent illness, or laboratory abnormalities in 19.5% of subjects treated with CYTOVENE capsules and 16% of subjects receiving placebo. Laboratory data and adverse events reported during the conduct of these controlled trials are summarized below.

Laboratory Data:

	CMV Retinitis Treatment*		CMV Disease Prevention$
Treatment	CYTOVENE     Capsules# 3000 mg/day	CYTOVENE-IV## mg/kg/day	CYTOVENE     Capsules|| 3000 mg/day	Placebo&
Subjects, number	320	175	478	234
Neutropenia:    <500 ANC/µL    500 ­ <749    750 ­ <1000	18% 17% 19%	25% 14% 26%	10% 16% 22%	6%   7% 16%
Anemia:    Hemoglobin:    <6.5 g/dL    6.5 ­ <8.0    8.0 ­ <9.5	2% 10% 25%	5%  16% 26%	1%    5% 15%	<1%     3%   16%
Maximum Serum Creatinine:   >2.5 mg/dL   >1.5 ­ <2.5	1% 12%	2% 14%	1% 19%	2% 11%
*  Pooled data from Treatment Studies, ICM 1653, Study ICM 1774 and Study AVI 034. #   Mean time on therapy = 91 days, including allowed reinduction treatment periods ## Mean time on therapy = 103 days, including allowed reinduction treatment periods $  Data from Prevention Study, ICM 1654   ||   Mean time on ganciclovir = 269 days &  Mean time on placebo = 240 days  (See discussion of clinical trials under INDICATIONS AND USAGE.)

Adverse Events: The following table shows selected adverse events reported in 5% or more of the subjects in three controlled clinical trials during treatment with either CYTOVENE-IV solution (5 mg/kg/day) or CYTOVENE capsules (3000 mg/day), and in one controlled clinical trial in which CYTOVENE capsules (3000 mg/day) were compared to placebo for the prevention of CMV disease.

		Maintenance Treatment Studies		Prevention Study
Body System	Adverse Event	Capsules (n=326)	IV (n=179)	Capsules (n=478)	Placebo (n=234)
Body as a Whole     Digestive System   Hemic and  Lymphatic System Nervous System Other   Catheter Related*	Fever Infection Chills Sepsis Diarrhea Anorexia Vomiting Leukopenia Anemia Thrombocytopenia Neuropathy Sweating Pruritus Total Catheter Events   Catheter Infection   Catheter Sepsis	38%   9%   7%   4% 41% 15% 13% 29% 19%   6%   8% 11%   6%   6%   4%   1%	48% 13% 10% 15% 44% 14% 13% 41% 25%   6%   9% 12%   5% 22%   9%   8%	35%   8%   7%   3% 48% 19% 14% 17%   9%   3% 21% 14% 10% - - -	33%   4%   4%   2% 42% 16% 11%   9%   7%   1% 15% 12%   9% - - -
*Some of these events also appear under other body systems.

The following events were frequently observed in clinical trials but occurred with equal or greater frequency in placebo-treated subjects: abdominal pain, nausea, flatulence, pneumonia, paresthesia, rash.

Retinal Detachment: Retinal detachment has been observed in subjects with CMV retinitis both before and after initiation of therapy with ganciclovir. Its relationship to therapy with ganciclovir is unknown. Retinal detachment occurred in 11% of patients treated with CYTOVENE-IV solution and in 8% of patients treated with CYTOVENE capsules. Patients with CMV retinitis should have frequent ophthalmologic evaluations to monitor the status of their retinitis and to detect any other retinal pathology.

Transplant Recipients: There have been three controlled clinical trials of CYTOVENE-IV solution and one controlled clinical trial of CYTOVENE capsules for the prevention of CMV disease in transplant recipients. Laboratory data and adverse events reported during these trials are summarized below.

Laboratory Data: The following table shows the frequency of granulocytopenia (neutropenia) and thrombocytopenia observed:

Controlled Trials Â- Transplant Recipients
	CYTOVENE-IV				CYTOVENE Capsules
	Heart Allograft*		Bone Marrow Allograft#		Liver Allograft##
	CYTOVENE-IV (n=76)	Placebo (n=73)	CYTOVENE-IV (n=57)	Control (n=55)	CYTOVENE Capsules (n=150)	Placebo (n=154)
Neutropenia
Minimum ANC   <500/µL Minimum ANC   500-1000/µL	4% 3%	3% 8%	12% 29%	6% 17%	3% 3%	1% 2%
TOTAL ANC   <1000/µL	7%	11%	41%	23%	6%	3%
Thrombocytopenia
Platelet count   <25,000/µL Platelet count   25,000-50,000/µL	3% 5%	1% 3%	32% 25%	28% 37%	0% 5%	3% 3%
TOTAL Platelet   <50,000/µL	8%	4%	57%	65%	5%	6%
*  Study ICM 1496. Mean duration of treatment = 28 days #  Study ICM 1570 and ICM 1689. Mean duration of treatment = 45 days ## Study GAN040. Mean duration of ganciclovir treatment = 82 days (See discussion of clinical trials under INDICATIONS AND USAGE.)

The following table shows the frequency of elevated serum creatinine values in these controlled clinical trials:

Controlled Trials Â- Transplant Recipients
	CYTOVENE-IV						CYTOVENE Capsules
	Heart Allograft ICM 1496		Bone Marrow Allograft ICM 1570		Bone Marrow Allograft ICM 1689		Liver Allograft Study 040
Maximum  Serum  Creatinine    Levels	CYTOVENE-IV (n=76)	Placebo (n=73)	CYTOVENE-IV (n=20)	Control (n=20)	CYTOVENE-IV (n=37)	Placebo (n=35)	CYTOVENE Capsules (n=150)	Placebo (n=154)
Serum  Creatinine  >2.5mg/dL	18%	4%	20%	0%	0%	0%	16%	10%
Serum  Creatinine  >1.5 -<2.5  mg/dL	58%	69%	50%	35%	43%	44%	39%	42%

In 3 out of 4 trials, patients receiving either CYTOVENE-IV solution or CYTOVENE capsules had elevated serum creatinine levels when compared to those receiving placebo. Most patients in these studies also received cyclosporine. The mechanism of impairment of renal function is not known. However, careful monitoring of renal function during therapy with CYTOVENE-IV solution or CYTOVENE capsules is essential, especially for those patients receiving concomitant agents that may cause nephrotoxicity.

General: Other adverse events that were thought to be "probably" or "possibly" related to CYTOVENE-IV solution or CYTOVENE capsules in controlled clinical studies in either subjects with AIDS or transplant recipients are listed below. These events all occurred in at least 3 subjects.

Body as a Whole: abdomen enlarged, asthenia, chest pain, edema, headache, injection site inflammation, malaise, pain

Digestive System: abnormal liver function test, aphthous stomatitis, constipation, dyspepsia, eructation

Hemic and Lymphatic System: pancytopenia

Respiratory System: cough increased, dyspnea

Nervous System: abnormal dreams, anxiety, confusion, depression, dizziness, dry mouth, insomnia, seizures, somnolence, thinking abnormal, tremor

Skin and Appendages: alopecia, dry skin

Special Senses: abnormal vision, taste perversion, tinnitus, vitreous disorder

Metabolic and Nutritional Disorders: creatinine increased, SGOT increased, SGPT increased, weight loss

Cardiovascular System: hypertension, phlebitis, vasodilatation

Urogenital System: creatinine clearance decreased, kidney failure, kidney function abnormal, urinary frequency

Musculoskeletal System: arthralgia, leg cramps, myalgia, myasthenia

The following adverse events reported in patients receiving ganciclovir may be potentially fatal: gastrointestinal perforation, multiple organ failure, pancreatitis and sepsis.

Adverse Events Reported During Postmarketing Experience With CYTOVENE-IV and CYTOVENE Capsules: The following events have been identified during postapproval use of the drug. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to either the seriousness, frequency of reporting, the apparent causal connection or a combination of these factors:

acidosis, allergic reaction, anaphylactic reaction, arthritis, bronchospasm, cardiac arrest, cardiac conduction abnormality, cataracts, cholelithiasis, cholestasis, congenital anomaly, dry eyes, dysesthesia, dysphasia, elevated triglyceride levels, encephalopathy, exfoliative dermatitis, extrapyramidal reaction, facial palsy, hallucinations, hemolytic anemia, hemolytic uremic syndrome, hepatic failure, hepatitis, hypercalcemia, hyponatremia, inappropriate serum ADH, infertility, intestinal ulceration, intracranial hypertension, irritability, loss of memory, loss of sense of smell, myelopathy, oculomotor nerve paralysis, peripheral ischemia, pulmonary fibrosis, renal tubular disorder, rhabdomyolysis, Stevens-Johnson syndrome, stroke, testicular hypotrophy, Torsades de Pointes, vasculitis, ventricular tachycardia

At an oral dose of 1000 mg of CYTOVENE every 8 hours and didanosine, 200 mg every 12 hours, the steady-state didanosine AUC_0-12 increased 111 ± 114% (range: 10% to 493%) when didanosine was administered either 2 hours prior to or concurrent with administration of CYTOVENE (n=12 patients, 23 observations). A decrease in steady-state ganciclovir AUC of 21 ± 17% (range: -44% to 5%) was observed when didanosine was administered 2 hours prior to administration of CYTOVENE, but ganciclovir AUC was not affected by the presence of didanosine when the two drugs were administered simultaneously (n=12). There were no significant changes in renal clearance for either drug.

When the standard intravenous ganciclovir induction dose (5 mg/kg infused over 1 hour every 12 hours) was coadministered with didanosine at a dose of 200 mg orally every 12 hours, the steady-state didanosine AUC_0-12 increased 70 ± 40% (range: 3% to 121%, n=11) and C_max increased 49 ± 48% (range: -28% to 125%). In a separate study, when the standard intravenous ganciclovir maintenance dose (5 mg/kg infused over 1 hour every 24 hours) was coadministered with didanosine at a dose of 200 mg orally every 12 hours, didanosine AUC_0-12 increased 50 ± 26% (range: 22% to 110%, n=11) and C_max increased 36 ± 36% (range: -27% to 94%) over the first didanosine dosing interval. Didanosine plasma concentrations (AUC_12-24) were unchanged during the dosing intervals when ganciclovir was not coadministered. Ganciclovir pharmacokinetics were not affected by didanosine. In neither study were there significant changes in the renal clearance of either drug.

Zidovudine: At an oral dose of 1000 mg of CYTOVENE every 8 hours, mean steady-state ganciclovir AUC_0-8 decreased 17 ± 25% (range: -52% to 23%) in the presence of zidovudine, 100 mg every 4 hours (n=12). Steady-state zidovudine AUC_0-4 increased 19 ± 27% (range: -11% to 74%) in the presence of ganciclovir.

Since both zidovudine and ganciclovir have the potential to cause neutropenia and anemia, some patients may not tolerate concomitant therapy with these drugs at full dosage.

Probenecid: At an oral dose of 1000 mg of CYTOVENE every 8 hours (n=10), ganciclovir AUC_0-8 increased 53 ± 91% (range: -14% to 299%) in the presence of probenecid, 500 mg every 6 hours. Renal clearance of ganciclovir decreased 22 ± 20% (range: -54% to -4%), which is consistent with an interaction involving competition for renal tubular secretion.

Imipenem-cilastatin: Generalized seizures have been reported in patients who received ganciclovir and imipenem-cilastatin. These drugs should not be used concomitantly unless the potential benefits outweigh the risks.

Other Medications: It is possible that drugs that inhibit replication of rapidly dividing cell populations such as bone marrow, spermatogonia and germinal layers of skin and gastrointestinal mucosa may have additive toxicity when administered concomitantly with ganciclovir. Therefore, drugs such as dapsone, pentamidine, flucytosine, vincristine, vinblastine, adriamycin, amphotericin B, trimethoprim/sulfamethoxazole combinations or other nucleoside analogues, should be considered for concomitant use with ganciclovir only if the potential benefits are judged to outweigh the risks.

No formal drug interaction studies of CYTOVENE-IV or CYTOVENE and drugs commonly used in transplant recipients have been conducted. Increases in serum creatinine were observed in patients treated with CYTOVENE-IV plus either cyclosporine or amphotericin B, drugs with known potential for nephrotoxicity (see ADVERSE EVENTS). In a retrospective analysis of 93 liver allograft recipients receiving ganciclovir (5 mg/kg infused over 1 hour every 12 hours) and oral cyclosporine (at therapeutic doses), there was no evidence of an effect on cyclosporine whole blood concentrations.