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.
Table 4: Selected Laboratory Abnormalities in Trials for Treatment of CMV Retinitis
|CMV Retinitis Treatment*|
|Treatment|| Ganciclovir Capsules†
|< 500 ANC/µL||18%||25%|
|500 – < 749||17%||14%|
|750 – < 1000||19%||26%|
|< 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.)
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|
|Body as a Whole||Fever||38%||48%|
|Hemic and Lymphatic System||Leukopenia||29%||41%|
|Catheter Related*||Total Catheter Events||6%||22%|
|*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 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.
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.
The following table shows the frequency of granulocytopenia (neutropenia) and thrombocytopenia observed:
Table 6: Controlled Trials – Transplant Recipients
|Heart Allograft*||Bone Marrow Allograft†|
|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%|
|Platelet count < 25,000/µL||3%||1%||32%||28%|
|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
| Heart Allograft
| Bone Marrow Allograft
| Bone Marrow Allograft
|Maximum Serum Creatinine Levels|| CYTOVENE-IV
|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.
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