Ganciclovir for Injection: Indications, Dosage, Precautions, Adverse Effects
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Ganciclovir for Injection - Product Information

Manufacture: Fresenius Kabi USA, LLC
Country: Canada
Condition: Cytomegalovirus Infection, CMV Retinitis
Class: Antiviral agents
Form: Intravenous (IV), Powder
Ingredients: Ganciclovir sodium

Summary Product Information

Route of
Administration
Dosage Form/
Strength
Clinically Relevant Nonmedicinal
Ingredients
Intravenous Sterile lyophilized
powder, 500 mg
For a complete listing see Dosage Forms, Composition and Packaging section.

Indications and Clinical Use

Ganciclovir for Injection is indicated for the treatment of CMV retinitis in immunocompromised patients, including patients with acquired immunodeficiency syndrome (AIDS), iatrogenic suppression secondary to organ transplantation or those administered chemotherapy for neoplasia. Ganciclovir for Injection is also indicated for the prevention of CMV disease in transplant recipients at risk for CMV disease.

The diagnosis of CMV retinitis is primarily an ophthalmologic one and should be made by indirect ophthalmoscopy. Other conditions in the differential diagnosis of CMV retinitis include candidiasis, toxoplasmosis, histoplasmosis, retinal scars, and cotton wool spots, any of which may produce a retinal appearance similar to CMV. For this reason, it is essential that the diagnosis of CMV be established by an ophthalmologist familiar with the retinal presentation of these conditions. The diagnosis of CMV retinitis may be aided by culture of CMV from urine, blood, throat, or other sites, but a negative CMV culture does not rule out CMV retinitis.

Geriatrics

No studies on the efficacy or safety of ganciclovir specifically in elderly patients have been conducted. Since elderly individuals may have reduced renal function, ganciclovir should be administered to the elderly patients with care and with special consideration of their renal status (See Dosage and Administration, Recommended Dose and Dosage Adjustment, Renal Impairment).

Pediatrics

The safety and efficacy of ganciclovir in children has not been established. The use of ganciclovir warrants extreme caution due to the probability of long-term carcinogenicity and reproductive toxicity. Administration to children should be undertaken only after careful evaluation and only if the potential benefits of treatment outweigh these considerable risks.

Contraindications

Ganciclovir for Injection is contraindicated in patients who are hypersensitive to ganciclovir, valganciclovir or to any component of the product. Due to the similarity of the chemical structure of ganciclovir and that of acyclovir and valacyclovir, a cross-hypersensitivity reaction between these drugs is possible.

Warnings and Precautions

Serious Warnings and Precautions

The clinical toxicity of ganciclovir includes granulocytopenia, anemia and thrombocytopenia. In animal and in vitro studies, ganciclovir was mutagenic, teratogenic, carcinogenic and caused aspermatogenesis; therefore, it should be considered a potential teratogen and carcinogen in humans.

Ganciclovir for Injection is indicated for use only in immunocompromised patients, where the potential benefit outweighs the risks stated herein.

The safety and efficacy of ganciclovir have not been evaluated for congenital or neonatal CMV disease, nor for treatment of CMV infection in non-immunocompromised individuals (see Indications and Clinical Use).

General

In clinical studies with ganciclovir sodium for injection, the maximum single dose studied has been 6 mg/kg infused intravenously over one hour. Larger doses have resulted in increased toxicity. It is likely that more rapid infusions would also result in increased toxicity.

Administration of Ganciclovir for Injection should be accompanied by adequate hydration. Since ganciclovir is excreted by the kidneys, normal clearance depends on adequate renal function. IF RENAL FUNCTION IS IMPAIRED, DOSAGE ADJUSTMENTS ARE REQUIRED. Such adjustments should be based on measured or estimated creatinine clearance values (see Dosage and Administration, Recommended Dose and Dosage Adjustment, Renal Impairment).

For patients on hemodialysis (CrCl < 10 mL/min), it is recommended that intravenous ganciclovir be used (see Dosage and Administration, Recommended Dose and Dosage Adjustment, Renal Impairment).

Hemodialysis reduces plasma concentrations of ganciclovir by approximately 50% (see Dosage and Administration, Recommended Dose and Dosage Adjustment, Hemodialysis).

Carcinogenesis and Mutagenesis

Ganciclovir caused point mutations and chromosomal damage in mammalian cells in vitro and invivo, but did not cause point mutations in bacterial or yeast cells, dominant lethality in mice, or morphologically transformed cells in vitro.

In a study conducted over 18 months, ganciclovir was carcinogenic in the mouse after oral doses of 20 and 1,000 mg/kg/day [approximately 0.1x and 1.4x, respectively, based on area under the plasma concentration curve (AUC) comparisons]. The principally affected tissues at the dose of 1,000 mg/kg/day were the preputial gland in males, forestomach (nonglandular mucosa) in males and females, and reproductive tissues and liver in females. At a dose of 20 mg/kg/day, slightly increased tumor incidences occurred in the preputial and harderian glands in males, forestomach in males and females, and liver in females. All ganciclovir-induced tumours were of epithelial or vascular origin except for histiocytic sarcoma of the liver. No carcinogenic effect occurred at 1 mg/kg/day (estimated as 0.01x the human dose based on AUC comparison). The preputial and clitoral glands, forestomach and harderian glands of mice have no human counterpart. Ganciclovir should be considered a potential carcinogen in humans.

Hematologic

Ganciclovir for Injection should not be administered if the absolute neutrophil count is less than 500 cells/μL or the platelet count is less than 25,000 cells/μL or the hemoglobin is less than 80 g/L. Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, bone marrow depression and aplastic anemia have been observed in patients treated with ganciclovir sodium for injection. The frequency and severity of these events vary widely in different patient populations (see Warnings and Precautions, Monitoring and Laboratory Tests; Dosage and Administration, Recommended Dose and Dosage Adjustments, Patients with Severe Leukopenia, Neutropenia, Anemia, Thrombocytopenia and/or Pancytopenia; Adverse Reactions). Ganciclovir for Injection should, therefore, be used with caution in patients with pre-existing cytopenias, or with a history of cytopenic reactions to other drugs, chemicals, or irradiation.

Neutropenia

Neutropenia typically occurs during the first or second week of induction therapy and prior to administration of a total cumulative dose of 200 mg/kg of ganciclovir sodium for injection but may occur at any time during treatment. Evidence of recovery of cell counts usually occurs within 3 to 7 days after discontinuing the drug. Colony stimulating factors have been shown to increase neutrophil and white blood cell counts in patients receiving ganciclovir sodium for injection for treatment of CMV retinitis.

Thrombocytopenia

Thrombocytopenia (platelet count of less than 50,000 cells/μL) was observed in patients treated with ganciclovir sodium for injection. Immunodeficient patients without AIDS were more likely to develop lowered platelet counts than those with AIDS. Patients with initial platelet counts less than 100,000 cells/μL were also at increased risk of this toxicity of ganciclovir sodium for injection.

Renal

It is possible that probenecid, as well as other drugs which inhibit renal tubular secretion or resorption, may reduce renal clearance of ganciclovir and could increase its plasma half-life.

Use in Patients with Renal Impairment

Ganciclovir for injection, should be used with caution in patients with impaired renal function. Both the plasma half-life of ganciclovir as well as peak plasma levels are increased in patients with elevated serum creatinine levels.

Patients Undergoing Hemodialysis

Hemodialysis reduces plasma concentrations of ganciclovir by approximately 50% after i.v. administration (see Dosage and Administration, Recommended Dose and Dosage Adjustment, Hemodialysis).

Sexual Function/Reproduction

Animal data indicate that administration of ganciclovir caused inhibition of spermatogenesis and subsequent infertility, which were reversible at lower doses and irreversible at higher doses (see Warnings and Precautions, Carcinogenesis and Mutagenesis). Although clinical data have not yet been obtained regarding this effect, it is considered probable that ganciclovir sodium for injection at the recommended doses may cause temporary or permanent inhibition of spermatogenesis in humans. Animal data also indicate that suppression of fertility in females may occur.

Because of the mutagenic and teratogenic potential of ganciclovir, women of childbearing potential should be advised to use effective contraception during treatment with ganciclovir for injection. Similarly, men should be advised to practice barrier contraception during and for at least 90 days following treatment with ganciclovir for injection (see Warnings and Precautions, Carcinogenesis and Mutagenesis).

Ganciclovir for injection is considered to be a potential teratogen and carcinogen in humans with the potential to cause birth defects and cancers (see Storage and Stability, Special Handling Instructions).

Female mice exhibited decreased fertility, decreased mating behaviour, and increased embryolethality after daily intravenous doses of 90 mg/kg (approximately 1.7x the mean drug exposure in humans following the dose of 5 mg/kg, based on AUC comparisons).

In male mice, fertility was decreased after daily intravenous doses of ≥ 2 mg/kg and daily oral doses of ≥ 10 mg/kg. These effects were reversible after daily intravenous doses of 2 mg/kg and daily oral doses of 10 mg/kg, but were irreversible or incompletely reversible after daily intravenous doses of 10 mg/kg and daily oral doses of 100 or 1,000 mg/kg. Ganciclovir has also caused hypospermatogenesis in rats after daily oral doses of ≥ 100 mg/kg and in dogs after daily intravenous and oral doses of ≥ 0.4 mg/kg and 0.2 mg/kg, respectively.

Ganciclovir has been shown to be embryotoxic in rabbits and mice following intravenous administration, and teratogenic in rabbits. Fetal resorptions were present in at least 85% of rabbits and mice administered 60 mg/kg/day and 108 mg/kg/day (2x the human exposure based on AUC comparisons), respectively. Effects observed in rabbits included: fetal growth retardation, embryolethality, teratogenicity and/or maternal toxicity. Teratogenic changes included cleft palate, anophthalmia/microphthalmia, aplastic organs (kidney and pancreas), hydrocephaly and brachygnathia. In mice, effects observed were maternal/fetal toxicity and embryolethality.

Daily intravenous doses of 90 mg/kg ganciclovir administered to female mice prior to mating, during gestation, and during lactation caused hypoplasia of the testes and seminal vesicles in the month-old male offspring, as well as pathologic changes in the nonglandular region of the stomach. The drug exposure in mice as estimated by the AUC was approximately 1.7x the human AUC.

Skin

Initially reconstituted solutions of ganciclovir for injection have a high pH (pH 11). Despite further dilution in intravenous fluids, phlebitis and/or pain may occur at the site of intravenous infusion. Care must be taken to infuse solutions containing ganciclovir for injection only into veins with adequate blood flow to permit rapid dilution and distribution (see Dosage and Administration).

Special Populations

Animal data indicate that administration of ganciclovir caused inhibition of spermatogenesis and subsequent infertility, which were reversible at lower doses and irreversible at higher doses (see Warnings and Precautions, Sexual Function/Reproduction). Although clinical data have not yet been obtained regarding this effect, it is considered probable that ganciclovir for injection at the recommended doses may cause temporary or permanent inhibition of spermatogenesis in humans. Animal data also indicate that suppression of fertility in females may occur.

Because of the mutagenic and teratogenic potential of ganciclovir, women of childbearing potential should be advised to use effective contraception during treatment with ganciclovir for injection. Similarly, men should be advised to practice barrier contraception during and for at least 90 days following treatment with ganciclovir for injection (see Warnings and Precautions, Sexual Function/Reproduction).

Ganciclovir for injection is considered to be a potential teratogen and carcinogen in humans with the potential to cause birth defects and cancers (see Storage and Stability, Special Handling Instructions).

Pregnant Women

The safety of ganciclovir for use in human pregnancy has not been established. The use of ganciclovir should be avoided in pregnant woman unless the benefit to the mother outweighs the potential risk to the fetus.

Data obtained using an ex vivo human placental model show that ganciclovir crosses the placenta and that simple diffusion is the most likely mechanism of transfer. The transfer was not saturable over a concentration range of 1 to 10 mg/mL and occurred by passive diffusion.

Nursing Women

It is not known if ganciclovir is excreted in human milk. Since many drugs are, and because carcinogenic and teratogenic effects occurred in animals treated with ganciclovir, the possibility of serious adverse reactions from ganciclovir in nursing infants is considered likely. Ganciclovir should not be given to breast-feeding mothers. Mothers should be instructed to discontinue the drug or discontinue nursing if they are receiving ganciclovir.

Pediatrics Use

The safety and efficacy of ganciclovir in children has not been established. The use of ganciclovir warrants extreme caution due to the probability of long-term carcinogenicity and reproductive toxicity. Administration to children should be undertaken only after careful evaluation and only if the potential benefits of treatment outweigh these considerable risks.

There has been very limited clinical experience using ganciclovir sodium for injection for the treatment of CMV retinitis in patients under the age of 12 years.

The safety and efficacy of ganciclovir have not been evaluated for congenital or neonatal CMV disease, nor for treatment of CMV infection in non-immunocompromised individuals (see Indications and Clinical Use).

Use in the Elderly

No studies on the efficacy or safety of ganciclovir specifically in elderly patients have been conducted. Since elderly individuals may have reduced renal function, ganciclovir should be administered to elderly patients with care and with special consideration of their renal status (see Dosage and Administration, Recommended Dose and Dosage Adjustment, Renal Impairment).

Use in Patients with Renal Impairment

Ganciclovir should be used with caution in patients with impaired renal function. Both the plasma half-life of ganciclovir as well as peak plasma levels are increased in patients with elevated serum creatinine levels.

Patients Undergoing Hemodialysis

Hemodialysis reduces plasma concentrations of ganciclovir by approximately 50% after i.v. administration (See Dosage and Administration, Recommended Dose and Dosage Adjustments, Hemodialysis).

Patients with HIV and CMV Retinitis

Ganciclovir is not a cure for CMV retinitis, and immunocompromised patients may continue to experience progression of retinitis during or following treatment. Patients should be advised to have ophthalmologic follow- up examinations at a minimum of every 4 to 6 weeks while being treated with ganciclovir. Some patients will require more frequent follow-up.

Patients with HIV may be receiving zidovudine (ZDV); patients should be counselled that as zidovudine and ganciclovir each have the potential to cause neutropenia and anemia, some patients may not tolerate concomitant therapy (see Drug Interactions).

Transplant Recipients

Transplant recipients should be counselled regarding the high frequency of impaired renal function in transplant recipients who received ganciclovir sodium for injection in controlled clinical trials, particularly in patients receiving concomitant administration of nephrotoxic agents such as cyclosporine and amphotericin B. Although the specific mechanism of this toxicity, which in most cases was reversible, has not been determined, the higher rate of renal impairment in patients receiving ganciclovir sodium for injection compared with those who received placebo in the same trials may indicate that ganciclovir sodium for injection played a significant role.

Monitoring and Laboratory Tests

Due to the frequency of neutropenia, anemia or thrombocytopenia observed in patients receiving ganciclovir (see Adverse Reactions), it is recommended that complete blood counts and platelet counts be performed frequently, especially in patients in whom ganciclovir or other nucleoside analogs have previously resulted in leukopenia, or in whom pretreatment neutrophil counts are less than 1,000 cells/μL at the beginning of treatment. In patients with severe leukopenia, neutropenia, anemia and/or thrombocytopenia, it is recommended that treatment with hematopoietic growth factors and/or dose interruption be considered (see Dosage and Administration: Patient Monitoring, Reduction of Dose).

Because dosing modifications based on creatinine clearance are required in patients with renal impairment and because of the incidence of increased serum creatinine levels observed in transplant recipients treated with ganciclovir, patients should have serum creatinine or creatinine clearance monitored carefully (see Adverse Reactions and Dosage and Administration, Patient Monitoring).

Adverse Reactions

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Adverse events that occurred during clinical trials of ganciclovir sodium for injection are summarized below, according to the participating study subject population.

Adverse events seen in studies using ganciclovir sodium for injection might also occur in studies using ganciclovir capsules, and vice versa.

HIV-1 Infected Subjects

The safety of ganciclovir sodium for injection in HIV-1 infected patients was studied in several clinical trials. The pooled safety information of the use of ganciclovir sodium for injection for the treatment of CMV disease in HIV infected patients in six clinical trials is displayed below. The data is shown in comparison to the control arm (oral placebo plus intravitreal ganciclovir implant) of one of these studies. Clinical adverse events, which occurred in ≥ 2% of patients taking intravenous ganciclovir, regardless of causal relationship or seriousness, however, at a greater frequency than in the control arm, are summarized in Table 1.

Table 1 ‒ Percentage of Patients with Adverse Events Occurring in ≥ 2% of All Patients Receiving Intravenous Ganciclovir
Body Systems
Adverse Events
Intravenous Ganciclovir
n = 412
Control
n = 119
Hemic and lymphatic system    
Neutropenia 25.7% 11.8%
Anemia 19.7% 16.8%
Thrombocytopenia 6.6% 5.0%
Leukopenia 3.2% 0.8%
Lymphadenopathy 2.9% 1.7%
Gastrointestinal    
Diarrhea 26.5% 24.4%
Nausea - 21.8%
Vomiting - 12.6%
Abdominal pain 9.0% 7.6%
Flatulence - 1.7%
Loose stools - 1.7%
Dysphagia 2.7% 1.7%
Esophageal candidiasis 2.2% 1.7%
Body as a whole    
Pyrexia 35.9% 35.3%
Headache 18.7% 16.0%
Candida 10.4% 4.2%
Injection site infection 8.0% 0.8%
Sepsis 6.1% 3.4%
Sepsis secondary 5.8% -
Anorexia 4.9% -
Mycobacterium avium complex 4.9% 4.2%
Pain 4.6% 2.5%
Chest pain 4.4% 3.4%
Malaise - 0.8%
Asthenia - 0.8%
Blood culture positive 3.2% 1.7%
Injection site inflammation 2.2% -
Central and peripheral nervous
system
   
Confusion - 2.5%
Hypoesthesia 3.2% 1.7%
Anxiety 2.4% 1.7%
Skin and appendages    
Pruritus 3.2% 2.5%
Respiratory system    
Cough 16.0% 15.1%
Pneumocystis carinii pneumonia 7.3% 2.5%
Productive cough 3.6% 2.5%
Upper respiratory tract infection - 0.8%
Lower respiratory tract infection - 1.7%
Sinus congestion 3.4% 2.5%
Metabolic and nutritional
disorders
   
Blood alkaline phophatase
increased
4.4% 4.2%
Blood creatinine increased 3.2% 1.7%
Musculoskeletal system    
Arthralgia 2.4% 1.7%

Retinal Detachment

Retinal detachment has been observed in subjects with CMV retinitis both before and after initiation of therapy with ganciclovir sodium for injection. The relationship of retinal detachment to therapy with ganciclovir sodium for injection is unknown. Retinal detachment occurred in 11% of patients treated with ganciclovir sodium for injection 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.

Laboratory abnormalities reported from three clinical trials in HIV infected patients taking oral or intravenous ganciclovir as maintenance treatment for CMV retinitis are listed below. Three hundred twenty-six patients receiving ganciclovir capsules and 179 patients receiving ganciclovir sodium for injection were eligible for the laboratory abnormality analysis.

Table 2: Laboratory Data
Minimum ANC, Hemoglobin, and Platelets and Maximum Serum Creatinine Values during Treatment with ganciclovir sodium for injection and ganciclovir capsules in Three Controlled Clinical Trials*
  % of subjects
Oral Ganciclovir Capsules†
(3,000 mg/day)
(n = 326)
% of subjects
Intravenous Solution‡
5 mg/kg/day
(n = 179)
Neutropenia [n(%)]
ANC/μL
   
< 500 18.4 25.1
500 to < 750 16.6 14.3
750 to < 1,000 19.1 26.3
Anemia [n(%)]
Hemoglobin g/dL
   
< 6.5 1.6 4.6
6.5 to < 8.0 10.0 16.0
8.0 to < 9.5 24.7 25.7
Thrombocytopenia
Platelets/μL
   
< 25,000 1.3 2.9
25,000 to < 50,000 8.1 5.1
50,000 to < 100,000 20.0 22.9
Serum Creatinine (SeCr)
SeCr mg/dL
   
≥ 2.5 0.9 1.7
≥ 1.5 to < 2.5 12.2 13.9

* Data from Study ICM 1653, Study ICM 1774, and Study AVI034 pooled

† Mean time on therapy = 103 days, including allowed reinduction treatment periods

‡ Mean time on therapy = 91 days, including allowed reinduction treatment periods

Overall, patients treated with ganciclovir sodium for injection experienced lower minimum ANCs and hemoglobin levels, consistent with more neutropenia and anemia, compared with those who received ganciclovir capsules; P = 0.024 for neutropenia; P = 0.027 for anemia.

For the majority of subjects, maximum serum creatinine levels were less than 1.5 mg/dL and no difference was noted between ganciclovir sodium for injection and ganciclovir capsule for the occurrence of renal impairment. Serum creatinine elevations ≥ 2.5 mg/dL occurred in < 2% of all subjects and no significant differences were noted in the time from the start of maintenance to the occurrence of elevations in serum creatinine values.

Transplant Recipients

Several clinical trials have investigated intravenous ganciclovir for the treatment or prevention of CMV disease in transplant patients.

Summarized below are clinical adverse events, which occurred in ≥ 5% of patients taking i.v. ganciclovir in three pooled bone marrow studies, regardless of causal relationship or seriousness. Adverse events, which occurred in a higher frequency in the placebo/observational control arm compared to the i.v. ganciclovir arm, have not been included in Table 3 below.

Table 3: Adverse Events Occurring in ≥ 5% of Patients Taking IV Ganciclovir
Body system
Adverse event
Bone Marrow Transplant Patients
(ICM 1308, 1570 and 1689)
IV Ganciclovir
(n = 122)
Placebo/observational control
(n = 120)
Hemic and lymphatic system    
Pancytopenia 31% 25%
Leukopenia 20% 7%
Body as a whole    
Headache 15% 13%
Mucous membrane disorder 14% 13%
Pyrexia 11% 8%
Rigors 7% 4%
Sepsis 7% 2%
Anorexia 7% 5%
Face edema 5% 2%
Gastrointestinal system    
Diarrhea 24% 23%
Nausea 20% 19%
Dyspepsia 8% 6%
Abdominal distension 8% 6%
Metabolic and nutritional disorders    
Blood creatinine increased 16% 13%
Hepatic function abnormal 11% 10%
Blood magnesium decreased 11% 10%
Hypocalcemia 9% 8%
Hypokalemia 9% 8%
Central and peripheral nervous system    
Tremor 8% 7%
Confusion 5% 3%
Skin and appendages    
Dermatitis exfoliative 10% 9%
Respiratory system    
Rhinitis 9% 5%
Dyspnea 6% 4%
Cardiovascular system    
Tachycardia 16% 15%
Hypotension 11% 7%
Urogenital system    
Hematuria present 16% 13%
Special senses    
Eye hemorrhage 5% 3%
Musculoskeletal system    
Myalgia 5% 3%

Clinical adverse events, which occurred in ≥ 5% of patients taking i.v. ganciclovir in a placebo controlled heart transplant study (ICM 1496), regardless of causal relationship or seriousness, but which occurred in a higher frequency in the i.v. ganciclovir arm (n = 76) compared to the placebo arm (n = 73), are listed below.

Body as a whole: headache (18%), infection (18%)

Metabolic and nutritional disorders: edema (9%)

Central and peripheral nervous system: confusion (5%), peripheral neuropathy (7%)

Respiratory system: pleural effusion (5%)

Cardiovascular system: hypertension (20%)

Urogenital system: renal impairment (14%), renal failure (12%)

Less Common Clinical Trial Adverse Drug Reactions (< 1%)

Relevant adverse events, which are not listed above, as they did not fulfil the criteria for inclusion into any of the tables of previous sections, are given below.

Body as a Whole: cachexia, dehydration, fatigue, injection site abscess, injection site edema, injection site hemorrhage, injection site pain, injection site thrombosis, malaise, photosensitivity reaction.

Gastrointestinal System: pancreatitis, gastrointestinal disorder, gastrointestinal hemorrhage, eructation, esophagitis, fecal incontinence, gastritis, mouth ulceration, tongue disorder.

Hemic and Lymphatic System: aplastic anemia, bone marrow depression, eosinophilia, splenomegaly.

Central and Peripheral Nervous System: hallucinations, psychotic disorder, euphoric mood, emotional disturbance, hyperkinetic syndrome, myoclonic jerks, abnormal dreams, agitation, amnesia, ataxia, coma, convulsion, dry mouth, hypertonia, libido decreased, nervousness, somnolence, thinking abnormal.

Skin and Appendages: dermatitis, acne, alopecia, dry skin, herpes simplex, urticaria.

Special Senses: retinal detachment, vision abnormal, earache, blindness, deafness, eye pain, glaucoma, tinnitus, vitreous disorder.

Metabolic and Nutritional Disorders: blood creatine phosphokinase increased, blood glucose decreased, blood lactic dehydrogenase increased.

Cardiovascular System: arrhythmia (including ventricular arrhythmia), thrombophlebitis deep, phlebitis, migraine.

Urogenital System: impotence, urinary frequency.

Musculoskeletal System: myasthenic syndrome.

Infections: events related to bone marrow depression and immune system compromise such as local and systemic infections and sepsis.

Bleeding Complications: potentially life-threatening bleeding associated with thrombocytopenia.

Hepatic System: hepatitis, jaundice.

Abnormal Hematologic and Clinical Chemistry Findings

Laboratory data from three controlled clinical trials of ganciclovir sodium for injection for the prevention of CMV disease in transplant recipients are summarized below.

Table 4: Laboratory Data
Neutropenia and Thrombocytopenia in Trials for the Prevention of CMV Disease in Transplant Recipients
  Ganciclovir Intravenous*
Heart Allograft§ Bone Marrow Allograft†
Ganciclovir Placebo Ganciclovir Placebo
Subjects (number) n = 76 n = 73 n = 57 n = 55
Neutropenia
(ANC/μL)
       
< 500 4% 3% 12% 6%
500 – 1,000 3% 8% 29% 17%
Thrombocytopenia
(platelets/μL)
       
< 25,000 3% 1% 32% 28%
25,000 – 50,000 5% 3% 25% 37%

§ Study ICM 1496: Mean duration of treatment = 28 days

† Studies ICM 1570 and ICM 1689: Mean duration of treatment = 45 days * ganciclovir sodium for injection

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

Table 5: Laboratory Data
Elevated Serum Creatinine Values in Trials for the Prevention of CMV Disease in Transplant Recipients
  Ganciclovir Intravenous*
Heart Allograft Bone Marrow Allograft
ICM 1496 ICM 1570 ICM 1689
Maximum Serum
Creatinine Levels
Ganciclovir
(n = 76)
Placebo
(n = 73)
Ganciclovir
(n = 20)
Control
(n = 20)
Ganciclovir
(n = 37)
Placebo
(n = 35)
Serum Creatinine
(≥ 2.5 mg/dL)
18% 4% 20% 0% 0% 0%
Serum Creatinine
(≥ 1.5 to < 2.5 mg/dL)
58% 69% 50% 35% 43% 44%

* ganciclovir sodium for injection

Patients receiving ganciclovir sodium for injection 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 ganciclovir sodium for injection is essential, especially for those patients receiving concomitant agents that may cause nephrotoxicity.

Post-Market Adverse Drug Reactions

The following adverse events have been reported since the marketing introduction of ganciclovir sodium for injection and are not listed under adverse reactions above. 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, 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, ischemia, loss of memory, loss of sense of smell, myelopathy, peripheral oculomotor nerve paralysis, pulmonary fibrosis, renal tubular disorder, rhabdomyolysis, Stevens-Johnson syndrome, stroke, testicular hypotrophy, Torsades de Pointes, vasculitis, ventricular tachycardia.

Adverse events from postmarketing spontaneous reports with ganciclovir that were reported in HIV infected or other immunocompromised patients such as transplant recipients, which are not mentioned in any section above, and for which a causal relationship cannot be excluded, are: anaphylaxis, decreased fertility in males.

Adverse events that have been reported during the postmarketing period are consistent with those seen in clinical trials with ganciclovir.

Drug Interactions

Ganciclovir

Binding of ganciclovir to plasma proteins is only about 1% ‒ 2%, and drug interactions involving binding site displacement are not anticipated.

Probenecid

At a dose of 1,000 mg of ganciclovir capsules every 8 hours, ganciclovir serum concentrations increased 45% in the presence of probenecid, 500 mg every 6 hours. Renal clearance of ganciclovir decreased 22%, which is consistent with an interaction involving competition for renal tubular secretion. Patients taking probenecid and ganciclovir capsules should be closely monitored for ganciclovir toxicity.

Zidovudine

At a dose of 1,000 mg of ganciclovir capsules every 8 hours, there was a trend for decreased ganciclovir AUC in the presence of zidovudine, 100 mg every 4 hours (18%), but the decrease was not statistically significant. There was a statistically significant increase in AUC for zidovudine (15%) in the presence of ganciclovir.

Since both zidovudine and ganciclovir have the potential to cause neutropenia and anemia, many patients will not tolerate combination therapy with these two drugs at full dosage strength. However, studies with ganciclovir sodium for injection for the treatment of CMV retinitis in AIDS showed no difference in the rate of severe neutropenia (ANC < 0.5 x 109 cells/L) or of severe anemia (hemoglobin < 8.0 g/dL), with or without concomitant zidovudine.

Didanosine

At an oral dose of 1,000 mg of ganciclovir capsules every 8 hours, the steady state AUC0-12 for didanosine, 200 mg every 12 hours, increased approximately 80% when didanosine was administered 2 hours prior to or concurrently with administration of ganciclovir capsules. Decreased steady state AUC (23%) was observed for ganciclovir in the presence of didanosine when the drug was administered 2 hours prior to administration of ganciclovir capsules, but AUC was not affected by the presence of didanosine when the two drugs were administered simultaneously. There were no significant changes in renal clearance for either drug.

When the standard ganciclovir sodium for injection induction dose (5 mg/kg infused over 1 hour every 12 hours) was co-administered with didanosine at a dose of 200 mg orally every 12 hours, the steady state didanosine AUC0-12 increased 70 ± 40% (range, 3 to 121%, n = 11) and Cmax increased 49 ± 48% (range, -28 to 125%). In a separate study, when the standard ganciclovir sodium for injection maintenance dose (5 mg/kg infused over 1 hour every 24 hours) was co-administered with didanosine at a dose of 200 mg orally every 12 hours, didanosine AUC0-12 increased 50 ± 26% (range, 22 to 110%, n = 11) and Cmax increased 36 ± 36% (range, -27 to 94%) over the first didanosine dosing interval. Didanosine plasma concentrations (AUC12-24 were unchanged during the dosing intervals when ganciclovir sodium for injection was not co-administered. Ganciclovir pharmacokinetics were not affected by didanosine. In neither study were there significant changes in the renal clearance of either drug.

This increase in didanosine plasma concentration cannot be explained by competition for renal tubular secretion, as there was an increase in the percentage of didanosine dose excreted. This increase could arise from either increased bioavailability or decreased metabolism. However, given the increase in didanosine plasma concentrations in the presence of ganciclovir, patients should be closely monitored for didanosine toxicity.

Didanosine has been associated with pancreatitis. In three controlled trials, pancreatitis was reported in 2% of patients taking didanosine and ganciclovir sodium for injection. The rates of pancreatitis were similar in the intravenous solution and capsule groups.

Other than laboratory abnormalities, concomitant treatment with zidovudine, didanosine, or zalcitabine did not appear to affect the type or frequency of reported adverse events, with the exception of moderately increased rates of diarrhea. Among patients taking ganciclovir sodium for injection, the diarrhea rates were 51% and 49% respectively with didanosine versus 39% and 35% respectively, without didanosine.

Zalcitabine

Zalcitabine increased the AUC0-8 of oral ganciclovir by 13%. There were no statistically significant changes in any of the other pharmacokinetic parameters assessed. Additionally, there were no clinically relevant changes in zalcitabine pharmacokinetics in the presence of oral ganciclovir although a small increase in the elimination rate constant was observed.

Stavudine

No statistically significant pharmacokinetic interaction was observed when stavudine and oral ganciclovir were given in combination.

Trimethoprim

Trimethoprim statistically significantly decreased the renal clearance of oral ganciclovir by 16.3% and this was associated with a statistically significant decrease in the terminal elimination rate and corresponding increase in half-life by 15%. However, these changes are unlikely to be clinically significant, as AUC0-8 and Cmax were unaffected. The only statistically significant change in trimethoprim pharmacokinetic parameters when co-administered with ganciclovir was an increase in Cmin. However, this is unlikely to be of clinical significance and no dose adjustment is recommended.

Cyclosporin

There was no evidence that introduction of ganciclovir affects the pharmacokinetics of cyclosporin based on the comparison of cyclosporin trough concentrations. However, there was some evidence of increases in the maximum serum creatinine value observed following initiation of ganciclovir therapy.

Imipenem-cilastatin

Generalized convulsions have been reported in patients who received ganciclovir sodium for injection and imipenem-cilastatin. These drugs should not be used concomitantly unless the potential benefits outweigh the risks.

Mycophenolate Mofetil

Following single -dose administration to twelve stable renal transplant patients, no pharmacokinetic interaction was observed between mycophenolate mofetil (1.5 g) and ganciclovir sodium for injection (5 mg/kg). Mean (±SD) ganciclovir AUC and Cmax were 54.3 (±19.0) μg·h/mL and 11.5 (±1.8) μg/mL, respectively after co-administration of the two drugs, compared to 51.0 (±17.0) μg·h/mL and 10.6 (±2.0) μg/mL, respectively after administration of ganciclovir sodium for injection alone. The mean (±SD) AUC and Cmax of MPA (active metabolite of mycophenolate) after co-administration were 80.9 (±21.6) μg·h/mL and 27.8 (±13.9) μg/mL, respectively compared to values of 80.3 (±16.4) μg·h/mL and 30.9 (±11.2) μg/mL, respectively after administration of mycophenolate mofetil alone. However, based on the known effects of renal impairment on the pharmacokinetics of ganciclovir and mycophenlate, it is anticipated that co- administration of these agents (which have the potential to compete for mechanisms of renal tubular secretion) will result in increases in ganciclovir concentration and MPAG (inactive metabolite of mycophenolate). In patients with renal impairment in which ganciclovir and mycophenolate are co-administered, the dose recommendations for ganciclovir should be observed and patients monitored carefully.

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. In addition, toxicity may be enhanced when ganciclovir is co-administered with other drugs known to be associated with renal impairment. Therefore, drugs known to be myelosuppressive or associated with renal impairment such as dapsone, pentamidine, flucytosine, vincristine, vinblastine, adriamycin, amphotericin B, trimethoprim/sulfamethoxazole combinations or other nucleoside analogues, or hydroxyurea, should be considered for concomitant use with ganciclovir only if the potential benefits are judged to outweigh the risks.

Allograft recipients treated with ganciclovir sodium for injection in three controlled clinical studies also received a variety of concomitant medications, including amphotericin B, azathioprine, cyclosporine, muromonab-CD3 (OKT3), and/or prednisone. Increases in serum creatinine were observed in patients treated with ganciclovir plus either cyclosporine or amphotericin B, drugs with known potential for nephrotoxicity (see Adverse Reactions). 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.

Dosage and Administration

Dosing Considerations

DO NOT ADMINISTER GANCICLOVIR FOR INJECTION BY RAPID OR BOLUS INTRAVENOUS INJECTION. THE TOXICITY OF GANCICLOVIR MAY BE INCREASED AS A RESULT OF EXCESSIVE PLASMA LEVELS.

INTRAMUSCULAR OR SUBCUTANEOUS INJECTION MAY RESULT IN SEVERE TISSUE IRRITATION DUE TO THE HIGH pH (APPROXIMATELY 11) OF GANCICLOVIR FOR INJECTION SOLUTIONS.

Recommended Dose and Dosage Adjustment

THE RECOMMENDED DOSE FOR GANCICLOVIR FOR INJECTION SHOULD NOT BE EXCEEDED. THE RECOMMENDED INFUSION RATE FOR GANCICLOVIR FOR INJECTION SOLUTION SHOULD NOT BE EXCEEDED.

Because of individual patient variations in the clinical response of CMV disease and the sensitivity to the myelosuppressive effects of ganciclovir sodium for injection, the treatment of each patient with Ganciclovir for Injection should be individualized on a case by case basis. Changes in dose should be based on regular clinical evaluations as well as on regular hematologic monitoring.

For Treatment of CMV Retinitis

Induction Treatment

The recommended dose of ganciclovir for injection for patients with normal renal function is 5 mg/kg every 12 hours for 14 to 21 days, given as a constant intravenous infusion over one hour.

Maintenance Treatment

Following the induction treatment, the recommended dose of ganciclovir for injection is 5 mg/kg given as an intravenous infusion over one hour, once per day for seven days each week, or 6 mg/kg once per day for five days each week.

For patients who experience progression of CMV retinitis while receiving maintenance treatment with ganciclovir for injection, reinduction treatment using the twice daily regimen of ganciclovir for injection is recommended.

For the Prevention of CMV Disease in Transplant Recipients

The recommended initial dose for patients with normal renal function is 5 mg/kg (given intravenously at a constant rate over 1 hour) every 12 hours for 7 to 14 days, followed by either 5 mg/kg once per day if on a seven-day weekly regimen, or 6 mg/kg once per day if on a five-day weekly regimen.

The duration of treatment with ganciclovir for injection in transplant recipients is dependent upon the duration and degree of immunosuppression. In controlled clinical trials in bone marrow allograft recipients, treatment with ganciclovir sodium for injection was continued until day 100 to 120 post-transplantation. CMV disease occurred in several patients who discontinued treatment with ganciclovir sodium for injection prematurely. In heart allograft recipients, the onset of newly diagnosed CMV disease occurred after treatment with ganciclovir sodium for injection was stopped at day 28 post-transplant, suggesting that continued dosing may be necessary to prevent late occurrence of CMV disease in this patient population.

Patients with Severe Leukopenia, Neutropenia, Anemia, Thrombocytopenia and/or Pancytopenia

Severe leukopenia, neutropenia, anemia, thrombocytopenia, bone marrow depression and aplastic anemia have been observed in patients treated with ganciclovir. Therapy should not be initiated if the absolute neutrophil count is less than 500 cells/mL or the platelet count is less than 25,000/mL or the hemoglobin is less than 80 g/L (see Warnings and Precautions, Hematologic; Monitoring and Laboratory Tests; and Adverse Reactions).

Patient Monitoring

Due to the frequency of leukopenia, granulocytopenia (neutropenia), anemia, thrombocytopenia, pancytopenia, bone marrow depression, and aplastic anemia in patients receiving ganciclovir (see Adverse Reactions), it is recommended that complete blood counts and platelet counts be performed frequently, especially in patients in whom ganciclovir or other nucleoside analogues have previously resulted in cytopenia, or in whom neutrophil counts are less than 1,000 cells/μL at the beginning of treatment. Patients should have serum creatinine or creatinine clearance values followed carefully to allow for dosage adjustments in renally impaired patients (see Dosage and Administration, Recommended Dose and Dosage Adjustment, Renal Impairment).

Reduction of Dose

Dosage reductions in renally impaired patients are required for ganciclovir for injection (see Renal Impairment section). Dosage reductions should also be considered for patients with neutropenia, anemia and/or thrombocytopenia. Ganciclovir for injection should not be administered in patients with severe neutropenia (ANC less than 500/μL) or severe thrombocytopenia (platelets less than 25,000/μL) or severe anemia (hemoglobin less than 80 g/L).

Renal Impairment

For patients with impairment of renal function (see Warnings and Precautions), refer to the table below for recommended doses of ganciclovir for injection and adjust the dosing interval as indicated.

Induction and Maintenance Doses of Ganciclovir for Injection in Renal Impairment
Creatinine
Clearance*
(mL/min)
Induction Dose
(mg/kg)
Dosing Interval
(hours)
Maintenance Dose
(mg/kg)
Dosing Interval
(hours)
≥ 70 5.0 12 5.0 24
50 to 69 2.5 12 2.5 24
25 to 49 2.5 24 1.35 24
10 to 24 1.25 24 0.625 24
< 10 1.25 3 times per week,
following
hemodialysis
0.625 3 times per week,
following
hemodialysis

Hemodialysis

Dosing for patients undergoing hemodialysis should not exceed 1.25 mg/kg three times per week, following each hemodialysis session. Ganciclovir for injection should be given shortly after completion of the hemodialysis session, since hemodialysis has been shown to reduce plasma levels by approximately 50%.

* Creatinine clearance can be related to serum creatinine by the formula below:

Creatinine clearance for females = 0.85 x male value

Creatinine Clearance in SI units (mL/S) = 0.01667 x value obtained from the above formula in traditional units (mL/min).

Administration

Infusion concentrations greater than 10 mg/mL are not recommended. Do not administer ganciclovir for injection by rapid or bolus intravenous injection. It should be given by constant intravenous infusion over 1 hour.

Reconstitution

Reconstitution of Sterile Lyophilized Powder: Reconstitute by injecting sterile water for injection into the vial.

Vial Size Volume of Diluent to be
Added to Vial
Approximate
Available Volume
Nominal Concentration per mL
500 mg 10 mL 10.29 mL 50 mg/mL

Shake well until dissolved.

DO NOT USE BACTERIOSTATIC WATER FOR INJECTION CONTAINING PARABENS, SINCE THESE ARE INCOMPATIBLE WITH GANCICLOVIR SODIUM STERILE POWDER AND MAY CAUSE PRECIPITATION.

The reconstituted solution should be inspected for particulate matter or discolouration prior to proceeding with admixture preparation.

Admixture Preparation: The reconstituted solution is further diluted in one of the solutions listed below for intravenous infusion.

Solutions for intravenous infusion: normal saline, dextrose 5% in water, Ringer's injection, lactated Ringer's injection.

Overdosage

For management of a suspected drug overdose, please contact your regional Poison Control Centre immediately.

Overdosage with intravenous ganciclovir has been reported in both adults and children below 2 years of age. In two cases of overdosage in adults, no adverse events were reported after patients received either one dose of 3,500 mg or 7 doses of 11 mg/kg over a 3-day period. Similarly, the following overdoses in pediatric patients did not result in adverse events: a single dose of 500 mg (72.5 mg/kg) followed by 48 hours of peritoneal dialysis (4-month old), single dose of approximately 60 mg/kg followed by exchange transfusion (18-month old), two doses of 500 mg instead of 31 mg (21-month old).

Reports of overdoses with intravenous ganciclovir have been received from clinical trials and during postmarketing experience. In some of these cases, no adverse events were reported. The majority of patients experienced one or more of the following adverse events:

Hematological toxicity: pancytopenia, bone marrow depression, medullary aplasia, leukopenia, neutropenia, granulocytopenia

Hepatotoxicity: hepatitis, liver function disorder

Renal Toxicity: worsening of hematuria in a patient with pre-existing renal impairment, acute renal failure, elevated creatinine

Gastrointestinal toxicity: abdominal pain, diarrhea, vomiting

Neurotoxicity: generalized tremor, convulsion

In addition, one adult received 0.4 mL (instead of 0.1 mL) ganciclovir by intravitreal injection, and experienced temporary loss of vision and central retinal artery occlusion secondary to increased intraocular pressure related to the injected fluid volume.

Overdose Experience with Valganciclovir

One adult developed fatal bone marrow depression (medullary aplasia) after several days of dosing that was at least 10-fold greater than recommended for the patient’s degree of renal impairment (decreased creatinine clearance).

Treatment

Hemodialysis may be useful in reducing serum concentrations, given that it reduces plasma concentrations of ganciclovir by approximately 50% (see Dosage and Administration, Recommended Dose and Dosage Adjustment, Hemodialysis). Adequate hydration should be maintained. The use of hematopoietic growth factors should be considered.

Action and Clinical Pharmacology

Mechanism of Action

Ganciclovir is a synthetic nucleoside analogue of guanine which inhibits the replication of herpes viruses both in vitro and in vivo.

Intracellular ganciclovir is phosphorylated to ganciclovir monophosphate by a cellular deoxyguanosine kinase. Further phosphorylation occurs by several cellular kinases to produce ganciclovir triphosphate. It has been shown in vitro that the levels of ganciclovir triphosphate are as much as 100-fold greater in CMV-infected cells than in non-infected cells. Thus, there is a preferential phosphorylation of ganciclovir in virus -infected cells. In virus-infected cells, ganciclovir triphosphate is metabolized slowly, with 60 to 70% remaining intracellularly 18 hours after removal of ganciclovir from the extracellular fluid. The antiviral activity of ganciclovir is the result of inhibition of viral DNA synthesis by two modes: (1) ganciclovir triphosphate competitively inhibits dGTP incorporation into DNA by DNA polymerase and (2) incorporation of ganciclovir triphosphate into viral DNA causes subsequent termination or very limited viral DNA elongation.

Ganciclovir inhibits mammalian cell proliferation in vitro at concentrations from 10 to 60 μg/mL, with bone marrow colony forming cells being most sensitive (IC50 of 10 μg/mL).

Pharmacokinetics

The pharmacokinetics of ganciclovir sodium for injection have been evaluated in immunocompromised patients with serious CMV disease. In patients with normal renal function, the plasma half-life was 2.9 ± 1.3 hours. Dose-independent kinetics were demonstrated over the range of 1.6 to 5.0 mg/kg. Renal excretion through both glomerular filtration and active tubular secretion is the major route of elimination of ganciclovir (see Warnings and Precautions, Special Populations, Use in Patients with Renal Impairment). At the end of a one-hour intravenous infusion of 5 mg/kg ganciclovir sodium for injection, total ganciclovir area under the serum concentration vs. time curve (AUC) ranged between 22.1 ± 3.2 (n = 16) and 26.8 ± 6.1 μg·hr/mL (n = 16) and maximum serum concentration (Cmax) ranged between 8.27 ± 1.02 (n = 16) and 9.0 ± 1.4 μg/mL (n = 16).

Storage and Stability

Stability and Storage Recommendations

Store at room temperature (15 °C ‒ 30 °C), avoid excessive heat above 40 °C (104 °F). The reconstituted solution in the vial may be stored at room temperature up to 12 hours and should not be refrigerated.

Ganciclovir for Injection, when reconstituted with sterile water for injection, further diluted with 0.9% sodium chloride injection, and stored refrigerated at 5 °C in polyvinyl chloride (PVC) bags, remain physically and chemically stable for 14 days. However, because Ganciclovir for Injection is reconstituted with nonbacteriostatic sterile water, it is recommended that the infusion solution be used within 24 hours of dilution to reduce the risk of bacterial contamination. The further diluted solutions should be stored under refrigeration. Freezing is not recommended.

Special Handling Instructions

Caution should be exercised in the handling and preparation of Ganciclovir for Injection. Avoid ingestion, inhalation or direct contact with the skin and mucous membranes. Ganciclovir for injection should be considered a potential teratogen and carcinogen in humans. Ganciclovir for injection solutions are alkaline (pH approximately 11). The use of latex gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If the solution contacts the skin or mucous membranes, wash thoroughly with soap and water; rinse eyes for at least 15 minutes with plain water.

Several guidelines for the handling and disposal of hazardous pharmaceuticals (including cytotoxic drugs) are available (e.g., CSHP, 1991). Disposal of ganciclovir for injection should follow provincial, municipal, and local hospital guidelines or requirements.

Dosage Forms, Composition and Packaging

Ganciclovir for Injection: Each 10 mL vial contains ganciclovir sodium equivalent to 500 mg of ganciclovir. The sodium content is 46 mg (2 mEq).

C315110 Ganciclovir for Injection sterile powder is supplied in 10 mL clear glass vials, containing ganciclovir sodium equivalent to 500 mg of ganciclovir. 25 vials per tray.