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

Subjects With AIDS

Three controlled, randomized, phase 3 trials comparing CYTOVENE-IV and ganciclovir capsules for maintenance treatment of CMV retinitis have been completed. During these trials, CYTOVENE-IV or ganciclovir capsules were prematurely discontinued in 9% of subjects because of adverse events. Laboratory data and adverse events reported during the conduct of these controlled trials are summarized below.

Laboratory Data

Table 4: Selected Laboratory Abnormalities in Trials for Treatment of CMV Retinitis

  CMV Retinitis Treatment*
Treatment Ganciclovir Capsules
3000 mg/day
CYTOVENE-IV
5 mg/kg/day
Subjects, number 320 175
Neutropenia:
   < 500 ANC/µL 18% 25%
  500 – < 749 17% 14%
  750 – < 1000 19% 26%
Anemia Hemoglobin:
   < 6.5 g/dL 2% 5%
  6.5 – < 8.0 10% 16%
  8.0 – < 9.5 25% 26%
Maximum Serum Creatinine:
   ≥ 2.5 mg/dL 1% 2%
   ≥ 1.5 – < 2.5 12% 14%
* 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 (See Clinical Trials.)

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 ganciclovir capsules (3000 mg/day), and in one controlled clinical trial with CYTOVENE (ganciclovir) capsules (3000 mg/day).

Table 5: Selected Adverse Events Reported in ≥ 5% of Subjects in Three Randomized Phase 3 Studies Comparing Ganciclovir Capsules to CYTOVENE (ganciclovir) -IV Solution for Maintenance Treatment of CMV Retinitis

Body System Adverse Event Maintenance Treatment Studies
Capsules
(n=326)
IV
(n=179)
Body as a Whole Fever 38% 48%
Infection 9% 13%
Chills 7% 10%
Sepsis 4% 15%
Digestive System Diarrhea 41% 44%
Anorexia 15% 14%
Vomiting 13% 13%
Hemic and Lymphatic System Leukopenia 29% 41%
Anemia 19% 25%
Thrombocytopenia 6% 6%
Nervous System Neuropathy 8% 9%
Other Sweating 11% 12%
Pruritus 6% 5%
Catheter Related* Total Catheter Events 6% 22%
Catheter Infection 4% 9%
Catheter Sepsis 1% 8%
*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 ganciclovir 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 (ganciclovir) -IV solution 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:

Table 6: Controlled Trials – Transplant Recipients

  CYTOVENE-IV
Heart Allograft* Bone Marrow Allograft
CYTOVENE-IV
(n=76)
Placebo
(n=73)
CYTOVENE-IV
(n=57)
Control
(n=55)
Neutropenia
  Minimum ANC < 500/µL 4% 3% 12% 6%
  Minimum ANC 500-1000/µL 3% 8% 29% 17%
  TOTAL ANC ≤ 1000/µL 7% 11% 41% 23%
Thrombocytopenia
  Platelet count < 25,000/µL 3% 1% 32% 28%
  Platelet count25,000-50,000/µL 5% 3% 25% 37%
  TOTAL Platelet ≤ 50,000/µL 8% 4% 57% 65%
* Study ICM 1496. Mean duration of treatment = 28 days
Study ICM 1570 and ICM 1689. Mean duration of treatment = 45 days (See Clinical Trials.)

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

Table 7: Controlled Trials - Transplant Recipients

  CYTOVENE-IV
Heart Allograft
ICM 1496
Bone Marrow Allograft
ICM 1570
Bone Marrow Allograft
ICM 1689
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)
Serum Creatinine ≥ 2.5 mg/dL 18% 4% 20% 0% 0% 0%
Serum Creatinine ≥ 1.5 - < 2.5 mg/dL 58% 69% 50% 35% 43% 44%

In these three trials, patients receiving CYTOVENE (ganciclovir) -IV solution 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 (ganciclovir) -IV solution 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 ganciclovir 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 Ganciclovir 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