Ganciclovir: Package Insert and Label Information (Page 2 of 6)

5.2 Renal Impairment

Ganciclovir Injection should be used with caution in patients with impaired renal function because the half-life and plasma/serum concentrations of ganciclovir will be increased due to reduced renal clearance. If renal function is impaired, dosage adjustments are recommended Ganciclovir Injection should be used with caution in patients with impaired renal function because the half-life and plasma/serum concentrations of ganciclovir will be increased due to reduced renal clearance. If renal function is impaired, dosage adjustments are recommended [see Dosage and Administration (2.5), Use in Specific Populations (8.5, 8.6)] .

Increased serum creatinine levels have been reported in elderly patients and in transplant recipients receiving concomitant nephrotoxic medications (i.e., cyclosporine and amphotericin B). Monitoring renal function during therapy with Ganciclovir Injection is essential, especially for elderly patients and those patients receiving concomitant agents that may cause nephrotoxicity . Increased serum creatinine levels have been reported in elderly patients and in transplant recipients receiving concomitant nephrotoxic medications (i.e., cyclosporine and amphotericin B). Monitoring renal function during therapy with Ganciclovir Injection is essential, especially for elderly patients and those patients receiving concomitant agents that may cause nephrotoxicity [see Dosage and Administration (2.5), Drug Interactions (7), Use in Specific Populations (8.5)] .

5.3 Impairment of Fertility

Based on animal data and limited human data, Ganciclovir Injection at the recommended human dose (RHD) may cause temporary or permanent inhibition of spermatogenesis in males, and may cause suppression of fertility in females. Advise patients that fertility may be impaired with the use of Ganciclovir Injection [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].

5.4 Fetal Toxicity

Ganciclovir Injection may cause fetal toxicity when administered to pregnant women based on findings in animal studies. Systemic exposure of ganciclovir in animals at approximately 2 times the RHD caused fetal growth retardation, embryolethality, teratogenicity, and/or maternal toxicity. Teratogenic changes in animals included cleft palate, anophthalmia/microphthalmia, aplastic organs (kidney and pancreas), hydrocephaly and brachygnathia. Women of childbearing potential should be advised to use effective contraception during treatment and for at least 30 days following treatment with Ganciclovir Injection. Similarly, men should be advised to practice barrier contraception during and for at least 90 days following treatment with Ganciclovir Injection [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].

5.5 Mutagenesis and Carcinogenesis

Animal data indicate that ganciclovir is mutagenic and carcinogenic. Ganciclovir Injection should therefore be considered a potential carcinogen in humans Animal data indicate that ganciclovir is mutagenic and carcinogenic. Ganciclovir Injection should therefore be considered a potential carcinogen in humans [see Dosage and Administration (2.7), Nonclinical Toxicology (13.1)] .

6 ADVERSE REACTIONS

The following serious adverse reactions are discussed in greater detail in other sections of the labeling:

6.1 Clinical Trial Experience in Adult Patients

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect rates observed in practice. The most common adverse reactions and laboratory abnormalities reported in at least 20% of patients were pyrexia, diarrhea, leukopenia, nausea, anemia, asthenia, headache, cough, decreased appetite, dyspnea, abdominal pain, sepsis, hyperhidrosis, and blood creatinine increased.

Selected adverse reactions that occurred during clinical trials of Ganciclovir Injection are summarized below, according to the participating study patient population.

Three controlled, randomized, phase 3 trials comparing Ganciclovir Injection and ganciclovir capsules for maintenance treatment of CMV retinitis have been completed. During these trials, Ganciclovir Injection or ganciclovir capsules were prematurely discontinued in 9% of subjects because of adverse reactions. Selected adverse reactions and laboratory abnormalities reported during the conduct of these controlled trials are summarized in Table 2 and Table 3, respectively Adverse Reactions in Patients with CMV Retinitis: Three controlled, randomized, phase 3 trials comparing Ganciclovir Injection and ganciclovir capsules for maintenance treatment of CMV retinitis have been completed. During these trials, Ganciclovir Injection or ganciclovir capsules were prematurely discontinued in 9% of subjects because of adverse reactions. Selected adverse reactions and laboratory abnormalities reported during the conduct of these controlled trials are summarized in Table 2 and Table 3, respectively [see Clinical Studies (14.1)] .

Table 2. Pooled Selected Adverse Reactions Reported in ≥ 5% of Subjects Comparing Ganciclovir Injection to Ganciclovir Capsules for Maintenance Treatment of CMV Retinitis
Maintenance Treatment Studies
Adverse Reaction Ganciclovir Injection (n=179) Ganciclovir Capsules (n=326)
Pyrexia 48% 38%
Diarrhea 44% 41%
Leukopenia 41% 29%
Anemia 25% 19%
Total catheter events 22% 6%
Catheter infection 9% 4%
Catheter sepsis 8% 1%
Other catheter related events 5% 1%
Sepsis 15% 4%
Decreased appetite 14% 15%
Vomiting 13% 13%
Infection 13% 9%
Hyperhidrosis 12% 11%
Chills 10% 7%
Neuropathy peripheral 9% 8%
Thrombocytopenia 6% 6%
Pruritus 5% 6%

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 Ganciclovir Injection 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 Ganciclovir Injection and in 8% of patients treated with ganciclovir capsules.

Table 3. Selected Laboratory Abnormalities in Trials for Treatment of CMV Retinitis
CMV Retinitis Treatment *
Laboratory Abnormalities Ganciclovir Injection 5 mg/kg/day (N=175) % Ganciclovir Capsules 3000 mg/day (N=320) %
*
Pooled data from Treatment Studies: ICM 1653, ICM 1774 and AVI 034
Mean time on therapy = 103 days, including allowed re-induction treatment periods
Mean time on therapy = 91 days, including allowed re-induction treatment periods
Neutropenia with Absolute Neutrophil Count (ANC) per mcL:
< 500 25% 18%
500 < 749 14% 17%
750 < 1000 26% 19%
Anemia with Hemoglobin (g/dL):
< 6.5 g/dL 5% 2%
6.5 < 8.0 16% 10%
8.0 < 9.5 26% 25%
Serum Creatinine (mg/dL):
≥ 2.5 2% 1%
≥ 1.5 – < 2.5 14% 12%

There have been three controlled clinical trials of Ganciclovir Injection for the prevention of CMV disease in transplant recipients. Selected laboratory abnormalities are summarized in Table 4 and Table 5 below. Adverse Reactions in Transplant Recipients: There have been three controlled clinical trials of Ganciclovir Injection for the prevention of CMV disease in transplant recipients. Selected laboratory abnormalities are summarized in Table 4 and Table 5 below.

Table 4 shows the frequency of neutropenia and thrombocytopenia and Table 5 shows the frequency of elevated serum creatinine values observed in these trials Table 4 shows the frequency of neutropenia and thrombocytopenia and Table 5 shows the frequency of elevated serum creatinine values observed in these trials [see Clinical Studies (14.2)] .

Table 4. Laboratory Abnormalities in Controlled Trials Transplant Recipients who Received Ganciclovir Injection, Placebo or Control
Ganciclovir Injection
Heart Allograft * Bone Marrow Allograft
Ganciclovir Injection (n=76) Placebo (n=73) Ganciclovir Injection (n=57) Control (n=55)
*
Study ICM 1496. Mean duration of treatment = 28 days
Study ICM 1570 and ICM 1689. Mean duration of treatment = 45 days
Neutropenia
Absolute Neutrophil Count (ANC) per mcL
< 500 4% 3% 12% 6%
500-1000 3% 8% 29% 17%
Total ANC
≤ 1000/mcL 7% 11% 41% 23%
Thrombocytopenia
Platelet count per mcL
< 25,000 3% 1% 32% 28%
25,000-50,000 5% 3% 25% 37%
Total Platelet Count
≤ 50,000/mcL 8% 4% 57% 65%
Table 5. Serum Creatinine Levels in Controlled Trials — Transplant Recipients who Received Ganciclovir Injection or Placebo
Serum Creatinine Levels (mg/dL) Heart Allograft ICM 1496 Bone Marrow Allograft ICM 1570 Bone Marrow Allograft ICM 1689
Ganciclovir Injection (n=76) Placebo Ganciclovir Injection Control Ganciclovir Injection Placebo
(n=73) (n=20) (n=20) (n=37) (n=35)
≥ 2.5 mg/dL 18% 4% 20% 0% 0% 0%
≥ 1.5 — < 2.5 58% 69% 50% 35% 43% 44%

Other Adverse Reactions in Clinical Trials in Patients with CMV Retinitis and in Transplant Recipients

Adverse drug reactions with Ganciclovir Injection or ganciclovir capsules in controlled clinical studies in either subjects with AIDS or transplant recipients are listed below Adverse drug reactions with Ganciclovir Injection or ganciclovir capsules in controlled clinical studies in either subjects with AIDS or transplant recipients are listed below [see Clinical Studies (14)]. All these events occurred in at least 3 subjects.

pancytopenia, bone marrow failure Blood and lymphatic disorders: pancytopenia, bone marrow failure

arrhythmia Cardiac disorders: arrhythmia

: tinnitus, ear pain, deafness Ear and labyrinth disorders: tinnitus, ear pain, deafness

: visual impairment, vitreous disorders, eye pain, conjunctivitis, macular edema Eye disorders: visual impairment, vitreous disorders, eye pain, conjunctivitis, macular edema

: nausea, abdominal pain, dyspepsia, flatulence, constipation, mouth ulceration, dysphagia, abdominal distention, pancreatitis, gastrointestinal perforation, eructation, dry mouth Gastrointestinal disorders: nausea, abdominal pain, dyspepsia, flatulence, constipation, mouth ulceration, dysphagia, abdominal distention, pancreatitis, gastrointestinal perforation, eructation, dry mouth

: fatigue, injection site inflammation, edema, pain, malaise, asthenia, chest pain, multiple organ failure General disorders and administration site conditions: fatigue, injection site inflammation, edema, pain, malaise, asthenia, chest pain, multiple organ failure

: hypersensitivity Immune system disorders: hypersensitivity

candida infections including oral candidiasis, upper respiratory infection, influenza, urinary tract infection, cellulitis Infections and infestations: candida infections including oral candidiasis, upper respiratory infection, influenza, urinary tract infection, cellulitis

: blood alkaline phosphatase increased, hepatic function abnormal, aspartate aminotransferase increased, alanine aminotransferase increased, creatinine clearance decreased Investigations: blood alkaline phosphatase increased, hepatic function abnormal, aspartate aminotransferase increased, alanine aminotransferase increased, creatinine clearance decreased

weight decreased Metabolism and nutrition disorders: weight decreased

back pain, myalgia, arthralgia, muscle spasms, leg cramps, myasthenia Musculoskeletal and connective tissue disorders: back pain, myalgia, arthralgia, muscle spasms, leg cramps, myasthenia

headache, insomnia, dizziness, paresthesia, hypoesthesia, seizure, somnolence, dysgeusia (taste disturbance), tremor Nervous system disorders: headache, insomnia, dizziness, paresthesia, hypoesthesia, seizure, somnolence, dysgeusia (taste disturbance), tremor

depression, confusional state, anxiety, agitation, psychotic disorder, thinking abnormal, abnormal dreams Psychiatric disorders: depression, confusional state, anxiety, agitation, psychotic disorder, thinking abnormal, abnormal dreams

kidney failure, renal function abnormal, urinary frequency, hematuria Renal and urinary disorders: kidney failure, renal function abnormal, urinary frequency, hematuria

cough, dyspnea Respiratory, thoracic and mediastinal disorders: cough, dyspnea

dermatitis, alopecia, dry skin, urticaria, rash Skin and subcutaneous tissues disorders: dermatitis, alopecia, dry skin, urticaria, rash

: hypotension, hypertension, phlebitis, vasodilation Vascular disorders: hypotension, hypertension, phlebitis, vasodilation

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