GANCICLOVIR- ganciclovir injection, solution

United States - English - NLM (National Library of Medicine)

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Active ingredient:
GANCICLOVIR (UNII: P9G3CKZ4P5) (GANCICLOVIR - UNII:P9G3CKZ4P5)
Available from:
EXELA PHARMA SCIENCES, LLC
INN (International Name):
GANCICLOVIR
Composition:
GANCICLOVIR 2 mg in 1 mL
Administration route:
INTRAVENOUS
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
GANCICLOVIR INJECTION is indicated for the treatment of cytomegalovirus (CMV) retinitis in immunocompromised adult patients, including patients with acquired immunodeficiency syndrome (AIDS) [see Clinical Studies (14)] .  GANCICLOVIR INJECTION is indicated for the prevention of CMV disease in adult transplant recipients at risk for CMV disease [see Clinical Studies (14 )] . GANCICLOVIR INJECTION is contraindicated in patients who have experienced a clinically significant hypersensitivity reaction (e.g., anaphylaxis) to ganciclovir, valganciclovir or acyclovir. Risk Summary Inanimal studies, ganciclovir caused maternal and fetal toxicity and embryo-fetal mortality in pregnant mice and rabbits as well as teratogenicity in rabbits at exposures two times the exposure at the recommended human dose (RHD) [see Data] . Although placental transfer of ganciclovir has been shown to occur based on ex vivo experiments with human placenta and on at least one case report in a pregnant woman, no adequate human data are a
Product summary:
GANCICLOVIR INJECTION is supplied as a sterile, unpreserved, colorless solution in a single-dose polymeric bag containing 500 mg ganciclovir in 250 mL of solution (2 mg/mL) sealed with a Twist Off port from Technoflex, and oversealed in an aluminum pouch (NDC 51754-2500-1), in cases of 10 (NDC 51754-2500-3). Follow guidelines for handling and disposal for cytotoxic drugs.1 The premix flexible plastic container bag contains no preservative; any unused portion should be discarded [see Dosage and Administration (2.6)] .   Gently shaking should redissolve any crystals that may have formed during transportation and/or storage at temperatures lower than recommended. The solution must be clear at the time of use. Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
Authorization status:
New Drug Application
Authorization number:
51754-2500-1, 51754-2500-3

GANCICLOVIR- ganciclovir injection, solution

EXELA PHARMA SCIENCES, LLC

----------

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use GANCICLOVIR INJECTION safely and

effectively. See full prescribing information for GANCICLOVIR INJECTION.

GANCICLOVIR INJECTION, for intravenous use

Initial U.S. Approval: 1989

WARNING: HEMATALOGIC TOXICITY, IMPAIRMENT OF FERTILITY, TERATOGENICITY, and

CARCINOGENICITY

See full prescribing information for complete boxed warning.

Hematologic Toxicity: Granulocytopenia, anemia, thrombocytopenia, and pancytopenia have been

reported in patients treated with ganciclovir. (5.1)

Impairment of Fertility: Based on animal data, GANCICLOVIR INJECTION may cause temporary or

permanent inhibition of spermatogenesis in males and suppression of fertility in females. (5.2)

Fetal Toxicity: Based on animal data, GANCICLOVIR INJECTION has the potential to cause birth

defects in humans. (5.3)

Mutagenesis and Carcinogenesis: Based on animal data, GANCICLOVIR INJECTION has the potential

to cause cancer in humans. (5.4)

INDICATIONS AND USAGE

GANCICLOVIR INJECTION is a nucleoside analogue CMV DNA polymerase inhibitor indicated for the:

Treatment of CMV retinitis in immunocompromised adult patients, including patients with acquired immunodeficiency

syndrome (AIDS). (1.1)

Prevention of CMV disease in adult transplant recipients at risk for CMV disease. (1.2)

DOSAGE AND ADMINISTRATION

Dosage in Adult Patients with Normal Renal Function (2.3, 2.4)

Treatment of CMV retinitis (2.3)

Induction: 5 mg/kg (given intravenously at a constant rate over 1 hour) every 12

hours for 14 to 21 days.

Maintenance: 5 mg/kg (given intravenously at a constant rate over 1 hour) once daily

for 7 days per week, or 6 mg/kg once daily for 5 days per week.

Prevention of CMV disease in

transplant recipients (2.4)

Induction: 5 mg/kg (given intravenously at a constant rate over 1 hour) every 12

hours for 7 to 14 days.

Maintenance: 5 mg/kg (given intravenously at a constant rate over 1 hour) once daily

for 7 days per week, or 6 mg/kg once daily for 5 days per week until 100 to 120 days

post-transplantation.

Adult patients with renal impairment: Adjust dosage based on creatinine clearance. (2.5)

DOSAGE FORMS AND STRENGTHS

Injection: 500 mg ganciclovir in 250 mL (2 mg per mL) solution in a single-dose bag for intravenous use. (3)

CONTRAINDICATIONS

Hypersensitivity to ganciclovir, valganciclovir or acyclovir. (4)

WARNINGS AND PRECAUTIONS

Hematologic toxicity: Granulocytopenia (neutropenia), anemia, thrombocytopenia, and pancytopenia have been

reported with use of ganciclovir. Avoid the use of GANCICLOVIR INJECTION if absolute neutrophil count is less than

500 cells/µL, hemoglobin is less than 8 g/dL, or platelet count is less than 25,000 cells/µL. Use with caution in patients

with pre-existing cytopenias or in patients receiving myelosuppressive drugs or irradiation. Monitor with frequent

complete blood and platelet counts. (5.1)

Impairment of renal function: Increased serum creatinine levels have been observed with the use of ganciclovir,

particularly in elderly patients and transplant patients receiving concomitant nephrotoxic drugs. Monitor renal function

during therapy with GANCICLOVIR INJECTION, particularly in elderly patients and in patients taking other

nephrotoxic drugs, and reduce dosage in patients with renal impairment. (5.2)

Impairment of fertility: Based on animal studies, GANCICLOVIR INJECTION may cause temporary or permanent

female and male infertility. (5.3)

Fetal toxicity: Based on findings in animal studies, GANCICLOVIR INJECTION may cause fetal toxicity. Females of

reproductive potential should use effective contraception during treatment and for at least 30 days following treatment

with GANCICLOVIR INJECTION. Males should practice barrier contraception during treatment and for at least 90 days

following treatment with GANCICLOVIR INJECTION. (5.4)

Mutagenicity and carcinogenicity: Based on animal studies, GANCICLOVIR INJECTION is potentially mutagenic and

carcinogenic. (5.5)

ADVERSE REACTIONS

Most common adverse reactions and laboratory abnormalities reported in at least 20% of patients were fever, diarrhea,

leukopenia, anemia, catheter-related events (including catheter infection and catheter sepsis), and elevated creatinine

levels. (6.1)

To report SUSPECTED ADVERSE REACTIONS, Contact Exela Pharma Sciences, LLC at 1-888-451-4321 or FDA

at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

Didanosine: Patients should be closely monitored for didanosine toxicity. (7)

Zidovudine: Potential to cause neutropenia and anemia. Monitor with frequent tests of white blood cell counts with

differential and hemoglobin levels. (7)

Probenecid: Ganciclovir dose may need to be reduced. Monitor for evidence of ganciclovir toxicity. (7)

Imipenem-cilastatin: Generalized seizures have been reported in patients with concomitant use of ganciclovir and

imipenem-cilastatin. (7)

Cyclosporine or amphotericin B: Monitor renal function. (5.2, 7)

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. (7)

USE IN SPECIFIC POPULATIONS

Lactation: Breastfeeding is not recommended. (8.2)

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 9/2017

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: HEMATALOGIC TOXICITY, IMPAIRMENT OF FERTILITY,

TERATOGENICITY, and CARCINOGENICITY

1 INDICATIONS AND USAGE

1.1 Treatment of CMV Retinitis

1.2 Prevention of CMV Disease in Transplant Recipients

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosing and Administration Information

2.2 Testing Before and During Treatment

2.3 Recommended Dosage for Treatment of CMV Retinitis in Adult Patients with Normal Renal

Function

2.4 Recommended Dosage for Prevention of CMV Disease in Adult Transplant Recipients with

Normal Renal Function

2.5 Recommended Dosage in Adult Patients with Renal Impairment

2.6 Handling and Disposal

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Hematologic Toxicity

5.2 Impairment of Renal Function

5.3 Impairment of Fertility

5.4 Fetal Toxicity

5.5 Mutagenesis and Carcinogenesis

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

12.4 Microbiology

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Treatment of CMV Retinitis

14.2 Prevention of CMV Disease in Transplant Recipients

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

WARNING: HEMATALOGIC TOXICITY, IMPAIRMENT OF FERTILITY,

TERATOGENICITY, and CARCINOGENICITY

Hematologic Toxicity: Granulocytopenia, anemia, thrombocytopenia, and pancytopenia

have been reported in patients treated with ganciclovir [see Warnings and Precautions

(5.1)].

Impairment of Fertility: Based on animal data, GANCICLOVIR INJECTION may cause

temporary or permanent inhibition of spermatogenesis in males and suppression of

fertility in females [see Warnings and Precautions (5.3)].

Fetal Toxicity: Based on animal data, GANCICLOVIR INJECTION has the potential to

cause birth defects in humans [see Warnings and Precautions (5.4)].

Mutagenesis and Carcinogenesis: Based on animal data, GANCICLOVIR INJECTION

has the potential to cause cancer in humans [see Warnings and Precautions (5.5)].

1 INDICATIONS AND USAGE

1.1 Treatment of CMV Retinitis

GANCICLOVIR INJECTION is indicated for the treatment of cytomegalovirus (CMV) retinitis in

Sections or subsections omitted from the full prescribing information are not listed.

GANCICLOVIR INJECTION is indicated for the treatment of cytomegalovirus (CMV) retinitis in

immunocompromised adult patients, including patients with acquired immunodeficiency syndrome

(AIDS) [see Clinical Studies (14)].

1.2 Prevention of CMV Disease in Transplant Recipients

GANCICLOVIR INJECTION is indicated for the prevention of CMV disease in adult transplant

recipients at risk for CMV disease [see Clinical Studies (14)].

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosing and Administration Information

Do not administer GANCICLOVIR INJECTION by rapid or bolus intravenous injection which may

increase toxicity as a result of excessive plasma levels.

The recommended dosage and infusion rate for GANCICLOVIR INJECTION should not be

exceeded.

Administration of GANCICLOVIR INJECTION should be accompanied by adequate hydration.

GANCICLOVIR INJECTION should only be infused into veins with adequate blood flow to permit

rapid dilution and distribution.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior

to administration, whenever solution and container permit.

2.2 Testing Before and During Treatment

Females of reproductive potential should undergo pregnancy testing before initiation of

GANCICLOVIR INJECTION [see Warnings and Precautions (5.4), Use in Specific Populations (8.1,

8.3)].

Complete blood counts with differential and platelet counts should be performed frequently,

especially in patients in whom ganciclovir or other nucleoside analogues have previously resulted

in cytopenias, or in whom absolute neutrophil counts are less than 1000 cells/μL at the beginning of

treatment [see Warnings and Precautions (5.1)].

All patients should be monitored for renal function before and during treatment with

GANCICLOVIR INJECTION and dosage should be adjusted as needed [see Dosage and

Administration (2.5), Warnings and Precautions (5.2)].

Patients with CMV retinitis should have frequent ophthalmological examinations during treatment with

GANCICLOVIR INJECTION to monitor disease status and for other retinal abnormalities [see Adverse

Reactions (6.1)].

2.3 Recommended Dosage for Treatment of CMV Retinitis in Adult Patients with Normal Renal

Function

Induction Dosage: The recommended initial dosage of GANCICLOVIR INJECTION for patients with

normal renal function is 5 mg/kg (given intravenously at a constant rate over 1 hour) every 12 hours for

14 to 21 days.

Maintenance Dosage: Following induction treatment, the recommended maintenance dosage of

GANCICLOVIR INJECTION is 5 mg/kg (given intravenously at a constant rate over 1 hour) once daily

for 7 days per week, or 6 mg/kg once daily for 5 days per week.

2.4 Recommended Dosage for Prevention of CMV Disease in Adult Transplant Recipients with

Normal Renal Function

Induction Dosage:The recommended initial dosage of GANCICLOVIR INJECTION 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.

Maintenance Dosage: Following induction, the recommended maintenance dosage of GANCICLOVIR

INJECTIONS is 5 mg/kg (given intravenously at a constant rate over 1 hour) once daily for 7 days per

week, or 6 mg/kg once daily for 5 days per week until 100 to 120 days post-transplantation.

2.5 Recommended Dosage in Adult Patients with Renal Impairment

For patients with renal impairment, refer to Table 1 for recommended doses of GANCICLOVIR

INJECTION for induction and maintenance dosage for treatment of CMV retinitis and prevention of

CMV disease in transplant patients. Monitor serum creatinine or creatinine clearance during treatment to

allow for dosage adjustments in patients with impaired renal function.

Table 1. Recommended Induction and Maintenance Dosage for Adult Patients with Renal

Impairment

Creatinine

Clearance*

(mL/min)

GANCICLOVIR

INJECTION

Induction

Dose (mg/kg)

Dos ing

Interval

(hours) for

Induction

GANCICLOVIR

INJECTION

Maintenance

Dose (mg/kg)

Dos ing

Interval

(hours) for

Maintenance

Greater than or equal

to 70

50-69

25-49

1.25

10-24

1.25

0.625

Less than 10

1.25

3 times per week,

following

hemodialysis

0.625

3 times per week,

following

hemodialysis

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

Dosing for patients undergoing hemodialysis should not exceed 1.25 mg per kg 3 times per week,

following each hemodialysis session. GANCICLOVIR INJECTION should be given shortly after

completion of the hemodialysis session, since hemodialysis has been shown to reduce plasma levels by

approximately 50% [see Clinical Pharmacology (12.3)].

2.6 Handling and Disposal

Because ganciclovir shares some of the properties of antitumor agents (i.e., carcinogenicity

and mutagenicity), procedures for proper handling and disposal for cytotoxic drugs should be

considered [see How Supplied/Storage and Handling (16)]. The premix flexible plastic container bag

contains no preservative; therefore, any unused portion should be discarded after each use.

3 DOSAGE FORMS AND STRENGTHS

Injection: 500 mg of ganciclovir in 250 mL (2 mg per mL) sterile, unpreserved, colorless solution in a

single-dose bag for intravenous use.

4 CONTRAINDICATIONS

GANCICLOVIR INJECTION is contraindicated in patients who have experienced a clinically

significant hypersensitivity reaction (e.g., anaphylaxis) to ganciclovir, valganciclovir or acyclovir.

5 WARNINGS AND PRECAUTIONS

5.1 Hematologic Toxicity

Granulocytopenia (neutropenia), anemia,thrombocytopenia, and pancytopenia have been observed in

patients treated with ganciclovir. The frequency andseverity of these events vary widely in different

patient populations [see Adverse Reactions (6.1)].GANCICLOVIR INJECTION is not recommended if

the absolute neutrophil count is less than 500 cells/μL, hemoglobin is less than 8 g/dL, or the platelet

count is less than 25,000 cells/μL. GANCICLOVIR INJECTION should also be used with caution in

patients with pre-existing cytopenias and in patients receiving myelosuppressive drugs or irradiation.

Neutropenia usually occurs during the first or second week of treatment but may occur at any time

during treatment. Cell counts usually begin to recover within 3 to 7 days after discontinuing drug.

Colony-stimulating factors have been shown to increase neutrophil and white blood cell counts in

patients receiving ganciclovir for treatment of CMV retinitis.

Due to the frequency of neutropenia, anemia and thrombocytopenia in patients receiving

GANCICLOVIR INJECTION, complete blood counts with differential and platelet counts should be

performed frequently, especially in patients in whom ganciclovir or other nucleoside analogues have

previously resulted in leukopenia, or in whom neutrophil counts are less than 1000 cells/µL at the

beginning of treatment [see Dosage and Administration (2.2)].

5.2 Impairment of Renal Function

Increased serum creatinine levels have been reported in elderly patients and in transplant patients

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), Use in Specific Populations (8.5)].

5.3 Impairment of Fertility

Based on animal 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 use of GANCICLOVIR INJECTION [see

Use in Specific Population (8.1), 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 [see Dosage and Administration (2.6),

should therefore be considered a potential carcinogen in humans [see Dosage and Administration (2.6),

Nonclinical Toxicology (13.1)].

6 ADVERSE REACTIONS

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

Hematologic Toxicity [see Warnings and Precautions (5.1)]

Impairment of Renal Function [see Warnings and Precautions (5.2)]

Impairment of Fertility [see Warnings and Precautions (5.3)]

Fetal Toxicity [see Warnings and Precautions (5.4)]

Mutagenesis and Carcinogenesis [see Warnings and Precautions (5.5)]

6.1 Clinical Trials Experience

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 the rates observed in practice.

Adverse Reactions in Patients with CMV Retinitis

Three controlled, randomized, phase 3 trials comparing intravenous ganciclovir and ganciclovir

capsules for maintenance treatment of CMV retinitis have been completed. During these trials, 9% of

subjects were prematurely discontinued 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)].

Table 2. Pooled Selected Adverse Events Reported in ≥ 5% of Subjects Comparing

Intravenous Ganciclovir to Ganciclovir Capsules for Maintenance Treatment of CMV

Retinitis

Adverse Event

Maintenance Treatment

Studies

Intravenous

Ganciclovir

(n=179)

Ganciclovir

Caps ules

(n=326)

Fever

Diarrhea

Leukopenia

Anemia

Total catheter events:

Catheter infection

Catheter sepsis

Other catheter related events

Sepsis

Anorexia

Vomiting

Infection

Sweating

Chills

Neuropathy

Thrombocytopenia

Pruritus

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 intravenous ganciclovir and in 8% of patients treated with

ganciclovir capsules.

Table 3. Selected Laboratory Abnormalities in Trials for Treatment of CMV Retinitis

Laboratory Abnormalities

CMV Retinitis Treatment*

Intravenous Ganciclovir†

5mg/kg/day

(N=175)

%

Ganciclovir Capsules‡

3000mg/day

(N=320)

%

Neutropenia with Absolute

Neutrophil Count (ANC) per µL:

<500

500 - <749

750 - <1000

Anemia with Hemoglobin (g/dL):

<6.5

6.5 - <8.0

8.0 - <9.5

Serum Creatinine (mg/dL):

≥2.5

≥1.5 - <2.5

* 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

Adverse Reactions in Transplant Recipients

There have been three controlled clinical trials of intravenous ganciclovir for the prevention of CMV

disease in transplant recipients. Selected laboratory abnormalities are summarized in Tables 4 and 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 [see Clinical Studies (14)].

Table 4. Laboratory Abnormalities in Controlled Trials – Transplant Recipients who

Received Intravenous Ganciclovir or Placebo

Laboratory Abnormalities

Heart Allograft*

Bone Marrow Allograft†

Intravenous

Ganciclovir

(N=76)

Placebo

(n=73)

Intravenous

Ganciclovir

(n=57)

Control

(n=55)

Neutropenia

Absolute Neutrophil Count

(ANC) per µL:

<500

<500-1000

TOTAL ANC

≤1000/µL

Thrombocytopenia

Platelet count per µL:

<25,000

25,000-50,000

TOTAL Platelet Count

≤50,000/µL

Table 5. Serum Creatinine Levels in Controlled Trials – Transplant Recipients who

Received Intravenous Ganciclovir or Placebo

Serum

Creatinine

Levels (mg/dL)

Heart Allograft

ICM 1496

Bone Marrow Allograft

ICM 1570

Bone Marrow Allograft

ICM 1689

Intravenous

Ganciclovir

(N=76)

Placebo

(n=73)

Intravenous

Ganciclovir

(n=20)

Placebo

(n=73)

Intravenous

Ganciclovir

(n=37)

Placebo

(n=35)

≥2.5

≥1.5 - <2.5

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

Other adverse reactions with intravenous ganciclovir 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.

Ear and labyrinth disorders: tinnitus

Eye disorders: abnormal vision, vitreous disorder

Gastrointestinal disorders: enlarged abdomen, aphthous stomatitis, constipation, dyspepsia, eructation,

gastrointestinal perforation, pancreatitis, dry mouth

General disorders and administration site conditions: asthenia, injection site inflammation, edema, malaise,

multiple organ failure, pain, chest pain

Blood and lymphatic system disorders: pancytopenia

Infections and infestations: sepsis

Investigations: abnormal liver function test, decreased creatinine clearance

Metabolism and nutritional disorders: weight loss

Musculoskeletal and connective tissue disorders: arthralgia, leg cramps, myalgia, myasthenia

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

Respiratory, thoracic and mediastinal disorders: increased cough, dyspnea

Nervous system disorders: confusion, dizziness, headache, insomnia, seizures, somnolence, abnormal

thinking, tremor, taste perversion

Psychiatric disorders: abnormal dreams, anxiety, depression

Skin and subcutaneous disorders: alopecia, dry skin

Vascular disorders: hypertension, phlebitis, vasodilation

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of intravenous

ganciclovir. Because these reactions are reported voluntarily from a population of uncertain size, it is

not always possible to reliably estimate their frequency or establish a causal relationship to drug

exposure.

Blood and lymphatic system disorders: hemolytic anemia

Cardiac disorders: cardiac arrest, cardiac conduction abnormality, torsades de pointes, ventricular

tachycardia

Congenital, familial and genetic disorders: congenital anomaly

Eye disorders: cataracts, dry eyes

Gastrointestinal disorders: intestinal ulceration

Hepatobiliary disorders: hepatic failure, cholestasis, cholelithiasis, hepatitis

Immune system disorders: anaphylactic reaction, allergic reaction, vasculitis

Investigations: increased blood triglycerides, increased blood antidiuretic hormone

Metabolism and nutrition disorders: acidosis, hypercalcemia, hyponatremia

Musculoskeletal and connective tissue disorders: arthritis, rhabdomyolysis

Nervous system disorders: dysesthesia, dysphasia, encephalopathy, extrapyramidal disorder, facial

palsy, intracranial hypertension, loss of memory, loss of smell, myelopathy, oculomotor nerve

paralysis, stroke

Renal and urinary disorders: hemolytic uremic syndrome, renal tubular disorder

Reproductive system and breast disorders: infertility, testicular hypotrophy

Respiratory, thoracic and mediastinal disorders: bronchospasm, pulmonary fibrosis

Psychiatric disorders: hallucinations, irritability

Skin and subcutaneous tissue disorders: exfoliative dermatitis, Stevens-Johnson syndrome

Vascular disorders: peripheral ischemia

7 DRUG INTERACTIONS

Established and other potentially significant drug interactions conducted with ganciclovir are listed in

Table 6 [see Clinical Pharmacology (12.3)].

Table 6. Established and Other Potentially Significant Drug Interactions with Ganciclovir

Name of the Concomitant

Drug

Change in the

Concentration of

Ganciclovir or

Concomitant Drug

Clinical Comment

Didanosine

↑ Didanosine

Patients should be closely monitored for

didanosine toxicity.

Zidovudine

↓ Ganciclovir

↑ Zidovudine

Dose reduction or interruption may be

needed because both zidovudine and

ganciclovir have the potential to cause

neutropenia and anemia. Monitor with

frequent tests of white blood cell counts

with differential and hemoglobin levels.

Probenecid

↑ Ganciclovir

GANCICLOVIR INJECTION dose may

need to be reduced. Monitor for evidence

of ganciclovir toxicity.

Imipenem-cilastatin

Unknown

Coadministration with imipenem-cilastatin

is not recommended because generalized

seizures have been reported in patients

who received ganciclovir and imipenem-

cilastatin.

Cyclosporine or amphotericin

Unknown

Monitor renal function when

GANCICLOVIR INJECTION is co-

administered with cyclosporine or

amphotericin B because of potential

increase in serum creatinine [see

Warnings and Precautions (5.2)].

Dapsone, pentamidine,

flucytosine, vincristine,

vinblastine, adriamycin,

amphotericin B,

trimethoprim/sulfamethoxazole

combinations or other

nucleoside analogues

Unknown

Co-administration with GANCICLOVIR

INJECTION should be considered only if

the potential benefits are judged to

outweigh the risks because of potential

additive toxicity.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Inanimal studies, ganciclovir caused maternal and fetal toxicity and embryo-fetal mortality in pregnant

mice and rabbits as well as teratogenicity in rabbits at exposures two times the exposure at the

recommended human dose (RHD) [see Data]. Although placental transfer of ganciclovir has been shown

to occur based on ex vivo experiments with human placenta and on at least one case report in a pregnant

woman, no adequate human data are available to establish whether GANCICLOVIR INJECTION poses

a risk to pregnancy outcomes. The background risk of major birth defects and miscarriage for the

indicated population is unknown. In the U.S. general population, the estimated background risk of major

birth defects and miscarriage in the clinically recognized pregnancies is 2-4% and 15−20%,

respectively.

Clinical considerations

Disease-associated maternal and/or fetal risk

Most maternal CMV infections are subclinical or they may be associated with a mononucleosis-like

syndrome. However, in immunocompromised patients, CMV infections are often symptomatic and are

associated with significant morbidity and mortality. The transmission of CMV to the fetus is a result of

maternal viremia and transplacental infection. CMV infection can also occur perinatally from mother to

infant by exposure to CMV in cervicovaginal secretions. Approximately 10% of infected newborns are

symptomatic at birth. Mortality in symptomatic infants is about 10%, and approximately 50 to 90% of

survivors experience significant problems, including sensorineural hearing loss, mental retardation, and

other neurologic deficits. The risk and severity of congenital CMV infection appear to be higher in

infants born to mothers with primary CMV infection than in those born to mothers with reactivation of

CMV infection.

Data

Animal Data

Daily intravenous doses of ganciclovir were administered to pregnant mice (108 mg/kg/day) and rabbits

(60 mg/kg/day), and also to female mice (90 mg/kg) prior to mating, during gestation, and during

lactation. Fetal resorptions were present in at least 85% of rabbits and mice. Additional 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 pre/postnatal development studies in mice,

there were maternal/fetal toxicity and embryolethality which included fetal effects of hypoplasia of the

testes and seminal vesicles in the male offspring, as well as pathologic changes in the nonglandular

region of the stomach. The systemic exposure (AUC) of ganciclovir during these studies was

approximately 2-times (pregnant mice and rabbits) and 1.7-times (pre/postnatal mice) the exposure in

humans at the RHD [see Nonclinical Toxicology (13.1)].

8.2 Lactation

Risk Summary

No data are available regarding the presence of ganciclovir in human milk, the effects on the breastfed

infant, or the effects on milk production. When ganciclovir was administered to lactating rats,

ganciclovir was present in milk [see Data]. Advise nursing mothers that breastfeeding is not

recommended during treatment with GANCICLOVIR INJECTION because of the potential for serious

adverse reactions in nursing infants. Furthermore, the Centers for Disease Control and Prevention

recommends that HIV-infected mothers not breastfeed their infants to avoid potential postnatal

transmission of HIV [see Warnings and Precautions (5.1, 5.3, 5.5), Nonclinical Toxicology (13.1)].

Data

Animal Data

Ganciclovir administered intravenously (at 0.13 mg/h) to lactating rats (on lactation day 15) resulted in

passive transfer into milk. The milk-to-serum ratio for ganciclovir at steady state was 1.6 ± 0.33.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Females of reproductive potential should undergo pregnancy testing before initiation of

GANCICLOVIR INJECTION [see Dosage and Administration (2.2), Use in Specific Populations (8.1)].

Contraception

Females

Because of the mutagenic and teratogenic potential of ganciclovir, females of reproductive potential

should be advised to use effective contraception during treatment and for at least 30 days following

treatment with GANCICLOVIR INJECTION [see Warnings and Precautions (5.3, 5.4), Nonclinical

Toxicology (13.1)].

Males

Because of its mutagenic potential, males should be advised to practice barrier contraception during and

for at least 90 days following, treatment with GANCICLOVIR INJECTION [see Warnings and

Precautions (5.3, 5.4), Nonclinical Toxicology (13.1)].

Infertility

GANCICLOVIR INJECTION at the recommended doses may cause temporary or permanent female and

male infertility [see Warnings and Precautions (5.3, 5.4), Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

Safety and efficacy of GANCICLOVIR INJECTION have not been established in pediatric patients.

A total of 120 pediatric patients with serious CMV infections participated in clinical trials.

Granulocytopenia and thrombocytopenia were the most common adverse reactions.

The pharmacokinetic characteristics of ganciclovir administered intravenously were studied in 27

neonates (aged 2 to 49 days) and 10 pediatric patients, aged 9 months to 12 years. In neonates, the

pharmacokinetic parameters after ganciclovir intravenous doses of 4 mg/kg (n=14) and 6 mg/kg (n=13)

were C

5.5 ± 1.6 and 7.0 ± 1.6 μg/mL, systemic clearance 3.14 ± 1.75 and 3.56 ± 1.27 mL/min/kg, and

of 2.4 hours (harmonic mean) for both doses, respectively.

In pediatric patients 9 months to 12 years of age, the pharmacokinetic characteristics of ganciclovir

were the same after single and multiple (every 12 hours) intravenous doses (5 mg/kg). The steady-state

volume of distribution was 0.64 ± 0.22 L/kg, C

was 7.9 ± 3.9 μg/mL, systemic clearance was 4.7 ±

2.2 mL/min/kg, and t

was 2.4 ± 0.7 hours.

Although the pharmacokinetics of intravenous ganciclovir in pediatric patients were similar to those

observed in adults, the safety and efficacy of ganciclovir at these exposures in pediatric patients have

not been established.

8.5 Geriatric Use

Clinical studies of ganciclovir did not include sufficient numbers of subjects aged 65 and over to

determine whether they respond differently from younger subjects. In general, dose selection for an

elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or

cardiac function, and of concomitant disease or other drug therapy. Ganciclovir is known to be

substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in

patients with impaired renal function. Because elderly patients are more likely to have decreased renal

function, care should be taken in dose selection. In addition, renal function should be monitored and

dosage adjustments should be made accordingly [see Dosage and Administration (2.5), Warnings and

Precautions (5.2), Use in Specific Populations (8.6)].

8.6 Renal Impairment

Dose reduction is recommended when administering GANCICLOVIR INJECTION to patients with

renal impairment [see Dosage and Administration (2.5), Warnings and Precautions (5.2), Adverse Reactions

(6.1)].

Hemodialysis has been shown to reduce plasma levels of ganciclovir by approximately 50%.

8.7 Hepatic Impairment

The safety and efficacy of ganciclovir have not been studied in patients with hepatic impairment.

10 OVERDOSAGE

Adverse reactions reported with overdosage of intravenous ganciclovir included irreversible

pancytopenia, acute renal failure requiring hemodialysis, neutropenia, thrombocytopenia, hepatitis, and

seizures.

Since ganciclovir is dialyzable, dialysis may be useful in reducing serum concentrations. Adequate

hydration should be maintained. The use of hematopoietic growth factors should be considered in

patients with cytopenias [see Dosage and Administration (2.5), Warnings and Precautions (5.1)].

11 DESCRIPTION

GANCICLOVIR INJECTION, 500 mg is a sterile, unpreserved solution for intravenous administration.

The appearance of the solution is clear and colorless. Each mL contains 2.0 mg of ganciclovir, 8.0 mg

of sodium chloride in water for injection, and may contain sodium hydroxide, and/or hydrochloric acid,

as required to adjust the pH to 7.5.

Ganciclovir, an antiviral agent, is a synthetic guanine derivative, 9-[[2-hydroxy-1-(hydroxymethyl)-

ethoxy]methyl]guanine. Ganciclovir is a white to off-white crystalline powder with a molecular formula

of C H N 0 and a molecular weight of 255.23. Ganciclovir is a polar hydrophilic compound with a

solubility of 2.6 mg/mL in water at 25°C and an n-octanol/water partition coefficient of 0.022. The pK s

for ganciclovir are 2.2 and 9.4.

The chemical structure of ganciclovir is:

The plastic container is fabricated from a multilayer film designed for medical use. The solution is in

contact with the inner polypropylene layer of the container. No components of the plastic container

material were found to migrate into the solution.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Ganciclovir is an antiviral drug with activity against cytomegalovirus (CMV) [see Microbiology (12.4)].

12.3 Pharmacokinetics

Absorption:

At the end of a 1-hour intravenous infusion of 5 mg/kg ganciclovir, total AUC ranged between 22.1 ±3.2

(n=16) and 26.8 ± 6.1 g·hr/mL (n=16) and C

ranged between 8.27 ± 1.02 (n=16) and 9.0 ± 1.4 g/mL

(n=16).

Distribution:

The steady-state volume of distribution of ganciclovir after intravenous administration was 0.74 ± 0.15

L/kg (n=98). Cerebrospinal fluid concentrations obtained 0.25 to 5.67 hours post-dose in 3 patients who

received 2.5 mg/kg ganciclovir intravenously every 8 hours or every 12 hours ranged from 0.31 to 0.68

g/mL representing 24% to 70% of the respective plasma concentrations. Binding to plasma proteins was

1% to 2% over ganciclovir concentrations of 0.5 and 51 g/mL.

Elimination:

Renal excretion of unchanged drug by glomerular filtration and active tubular secretion is the major

route of elimination of ganciclovir. In patients with normal renal function, 91.3 ± 5.0% (n=4) of

intravenously administered ganciclovir was recovered unchanged in the urine. Systemic clearance of

intravenously administered ganciclovir was 3.52 ± 0.80 mL/min/kg (n=98) while renal clearance was

3.20 ± 0.80 mL/min/kg (n=47), accounting for 91 ± 11% of the systemic clearance (n=47). Following

intravenous administration, ganciclovir half-life was 3.5 ± 0.9 hours (n=98) with linear

pharmacokinetics over the dose range of 1.6 to 5.0 mg/kg.

Specific Populations

Patients with Renal Impairment

The pharmacokinetics of ganciclovir following intravenous administration of ganciclovir were

evaluated in 10 immunocompromised patients with renal impairment who received doses ranging from

1.25 to 5.0 mg/kg (Table 7). Hemodialysis reduces plasma concentrations of ganciclovir by about 50%

after intravenous administration.

Table 7. Pharmacokinetics of Ganciclovir in Patients with Renal Impairment

Estimated

Creatinine

Clearance

(mL/min)

n

Dos e

Clearance

(mL/min)

Mean ± SD

Half-life

(hours )

Mean ± SD

50-79

3.2-5 mg/kg

128 ± 63

4.6 ± 1.4

25-49

3-5 mg/kg

57 ± 8

4.4 ± 0.4

<25

1.25-5 mg/kg

30 ± 13

10.7 ± 5.7

Race (Ethnicity) and Gender

The effects of race/ethnicity and gender were studied in subjects receiving a dose regimen of 1000 mg

every 8 hours. Although the numbers of Blacks (16%) and Hispanics (20%) were small, there appeared

to be a trend towards a lower steady-state C

and AUC

in these subpopulations as compared to

Caucasians. No definitive conclusions regarding gender differences could be made because of the

small number of females (12%); however, no differences between males and females were observed.

Drug Interactions

Didanosine

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

increased 70 ± 40% (range: 3% to 121%, n=11) and C

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

increased 50 ± 26% (range: 22% to 110%, n=11) and C

increased 36 ± 36% (range: -27% to 94%) over the first didanosine dosing interval. Ganciclovir

pharmacokinetics were not affected by didanosine. In both studies, there was no significant change in

the renal clearance of either drug.

Zidovudine

At an oral dose of 1000 mg of ganciclovir every 8 hours, mean steady-state ganciclovir AUC

decreased 17 ± 25% (range: -52% to 23%) in the presence of zidovudine, 100 mg every 4 hours (n=12).

Steady-state zidovudine AUC

increased 19 ± 27% (range: -11% to 74%) in the presence of

ganciclovir. No drug-drug interaction studies have been conducted with intravenous ganciclovir and

zidovudine.

Probenecid

At an oral dose of 1000 mg of ganciclovir every 8 hours (n=10), ganciclovir AUC

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. No drug-drug interaction studies have been conducted with

intravenous ganciclovir and probenecid.

Cyclosporine

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.

12.4 Microbiology

0-12

0-12

Antiviral Activity

Thciclovir is a synthetic analogue of 2'-deoxyguanosine, which inhibits replication of human CMV in

cell culture and in vivo. In CMV-infected cells, ganciclovir is initially phosphorylated to ganciclovir

monophosphate by the viral protein kinase, pUL97. Further phosphorylation occurs by cellular kinases

to produce ganciclovir triphosphate, which is then slowly metabolized intracellularly. As the

phosphorylation is largely dependent on the viral kinase, phosphorylation of ganciclovir occurs

preferentially in virus-infected cells. The virustatic activity of ganciclovir is due to inhibition of the

viral DNA polymerase, pUL54, by ganciclovir triphosphate.

Antiviral Activity

The median concentration of ganciclovir that inhibits CMV replication (EC

value) in cell culture

(laboratory strains or clinical isolates) has ranged from 0.08 to 13.6 micromolar (0.02 to 3.48 μg/mL).

Ganciclovir inhibits mammalian cell proliferation (CC

value) in cell culture at higher concentrations

ranging from 118 to 2840 micromolar (30 to 725 μg/mL). Bone marrow-derived colony-forming cells

are more sensitive [CC

value = 0.1 to 2.7 micromolar (0.028 to 0.7 μg/mL)]. The relationship between

the antiviral activity in cell culture and clinical response has not been established.

Resistance

Cell Culture: CMV isolates with reduced susceptibility to ganciclovir have been selected in cell

culture. Growth of CMV strains in the presence of ganciclovir resulted in the selection of amino acid

substitutions in the viral protein kinase pUL97 and the viral DNA polymerase pUL54.

In vivo: Viruses resistant to ganciclovir can arise after prolonged treatment or prophylaxis with

ganciclovir by selection of substitutions in pUL97 and/or pUL54. Limited clinical data are available on

the development of clinical resistance to ganciclovir and many pathways to resistance exist. The

possibility of viral resistance should be considered in patients who show poor clinical response or

experience persistent viral excretion during therapy.

CMV resistance to ganciclovir has been observed in individuals with AIDS and CMV retinitis who have

never received ganciclovir therapy. Viral resistance has also been observed in patients receiving

prolonged treatment for CMV retinitis with ganciclovir. In a controlled study of oral ganciclovir for

prevention of AIDS-associated CMV disease, 364 individuals had one or more cultures performed

after at least 90 days of ganciclovir treatment. Of these, 113 had at least one positive culture. The last

available isolate from each subject was tested for reduced sensitivity, and 2 of 40 were found to be

resistant to ganciclovir. These resistant isolates were associated with subsequent treatment failure for

retinitis.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis, Mutagenesis

Ganciclovir was carcinogenic in mice at the same mean drug exposure in humans as at the RHD (5

mg/kg). At the dose of 1000 mg/kg/day (1.4 times the exposure at the RHD) there was a significant

increase in the incidence of tumors of the preputial gland in males, forestomach (nonglandular mucosa)

in males and females, and reproductive tissues (ovaries, uterus, mammary gland, clitoral gland and

vagina) and liver in females. At the dose of 20 mg/kg/day (0.1 times the exposure at the RHD), a slightly

increased incidence of tumors was noted in the preputial and harderian glands in males, forestomach in

males and females, and liver in females. No carcinogenic effect was observed in mice administered

ganciclovir at 1 mg/kg/day (exposure estimated as 0.01 times the RHD). Except for histiocytic sarcoma

of the liver, ganciclovir-induced tumors were generally of epithelial or vascular origin. Although the

preputial and clitoral glands, forestomach and harderian glands of mice do not have human counterparts,

ganciclovir should be considered a potential carcinogen in humans.

Ganciclovir increased mutations in mouse lymphoma cells and DNA damage in human lymphocytes in

vitro at concentrations of 50 to 500 and 250 to 2000 μg/mL, respectively. In the mouse micronucleus

assay, ganciclovir was clastogenic at doses of 150 and 500 mg/kg (2.8 to 10 times the exposure at the

RHD) but not at doses of 50 mg/kg (exposure approximately comparable to the RHD). Ganciclovir was

not mutagenic in the Ames Salmonella assay at concentrations of 500 to 5000 μg/mL.

Impairment of Fertility

Ganciclovir caused decreased mating behavior, decreased fertility, and an increased incidence of

embryolethality in female mice following doses of 90 mg/kg/day (exposures approximately 1.7 times

the RHD). Ganciclovir caused decreased fertility in male mice and hypospermatogenesis in mice and

dogs following daily oral or intravenous administration of doses ranging from 0.2 to 10 mg/kg.

Systemic drug exposure (AUC) at the lowest dose showing toxicity in each species ranged from 0.03

to 0.1 times the exposure at the RHD.

14 CLINICAL STUDIES

14.1 Treatment of CMV Retinitis

In a retrospective, non-randomized, single-center analysis of 41 patients with AIDS and CMV retinitis

diagnosed by ophthalmologic examination between August 1983 and April 1988, treatment with

intravenous ganciclovir resulted in a delay in mean (median) time to first retinitis progression compared

to untreated controls [105 (71) days from diagnosis vs. 35 (29) days from diagnosis]. Patients in this

series received induction treatment of intravenous ganciclovir 5 mg/kg twice daily for 14 to 21 days

followed by maintenance treatment with either 5 mg/kg once daily, 7 days per week or 6 mg/kg once

daily, 5 days per week.

In a controlled, randomized trial conducted between February 1989 and December 1990, immediate

treatment with intravenous ganciclovir was compared to delayed treatment in 42 patients with AIDS and

peripheral CMV retinitis; 35 of 42 patients (13 in the immediate-treatment group and 22 in the delayed-

treatment group) were included in the analysis of time to retinitis progression. Based on masked

assessment of fundus photographs, the mean [95% CI] and median [95% CI] times to progression of

retinitis were 66 days [39, 94] and 50 days [40, 84], respectively, in the immediate-treatment group

compared to 19 days [11, 27] and 13.5 days [8, 18], respectively, in the delayed-treatment group.

Data from trials ICM 1653, ICM 1774, and AVI034, which were performed comparing intravenous to

oral ganciclovir for treatment of CMV retinitis in patients with AIDS, are shown in Table 8, and Figures

1, 2, and 3, and are discussed below.

Table 8. Population Characteristics in Studies ICM 1653, ICM 1774 and AVI 034

ICM 1653

(n=121)

ICM 1774

(n=225)

AVI 034

(n=159)

Median age (years)

Range

24-62

22-56

23-62

Males

116 (96%)

222 (99%)

148 (93%)

Females

5 (4%)

3 (1%)

10 (6%)

Asian

3 (3%)

5 (2%)

7 (4%)

Ethnicity

Black

11 (9%)

9 (4%)

3 (2%)

Caucasian

98 (81%)

186 (83%)

140 (88%)

Other

9 (7%)

25 (11%)

8 (5%)

Median CD4 Count

10.0

Range

0-141

0-80

0-320

Mean (SD) Observation

Time (days)

107.9 (43.0)

97.6 (42.5)

80.9 (47.0)

Trial ICM 1653

In this randomized, open-label, parallel group trial, conducted between March 1991 and

November1992, patients with AIDS and newly diagnosed CMV retinitis received a 3-week induction

course of intravenous ganciclovir, 5 mg/kg twice daily for 14 days followed by 5 mg/kg once daily for

1 additional week. Following the 21-day intravenous induction course, patients with stable CMV

retinitis were randomized to receive 20 weeks of maintenance treatment with either intravenous

ganciclovir, 5 mg/kg once daily, or ganciclovir capsules, 500 mg 6 times daily (3000 mg/day). The

study showed that the mean [95% CI] and median [95% CI] times to progression of CMV retinitis, as

assessed by masked reading of fundus photographs, were 57 days [44, 70] and 29 days [28, 43],

respectively, for patients on oral therapy compared to 62 days [50, 73] and 49 days [29, 61],

respectively, for patients on intravenous therapy. The difference [95% CI] in the mean time to

progression between the oral and intravenous therapies (oral - IV) was -5 days [-22, 12]. See Figure 1

for comparison of the proportion of patients remaining free of progression over time.

Trial ICM 1774

In this three-arm, randomized, open-label, parallel group trial, conducted between June 1991 and August

1993, patients with AIDS and stable CMV retinitis following from 4 weeks to 4 months of treatment

with intravenous ganciclovir were randomized to receive maintenance treatment with intravenous

ganciclovir, 5 mg/kg once daily, ganciclovir capsules, 500 mg 6 times daily, or ganciclovir capsules,

1000 mg three times daily for 20 weeks. The study showed that the mean [95% CI] and median [95% CI]

times to progression of CMV retinitis, as assessed by masked reading of fundus photographs, were 54

days [48, 60] and 42 days [31, 54], respectively, for patients on oral therapy compared to 66 days [56,

76] and 54 days [41, 69], respectively, for patients on intravenous therapy. The difference [95% CI] in

the mean time to progression between the oral and intravenous therapies (oral - IV) was -12 days [-24,

0]. See Figure 2 for comparison of the proportion of patients remaining free of progression over time.

Trial AVI 034

In this randomized, open-label, parallel group trial, conducted between June 1991 and February 1993,

patients with AIDS and newly diagnosed (81%) or previously treated (19%) CMV retinitis who had

tolerated 10 to 21 days of induction treatment with intravenous ganciclovir, 5 mg/kg twice daily, were

randomized to receive 20 weeks of maintenance treatment with either ganciclovir capsules, 500 mg 6

times daily or intravenous ganciclovir, 5 mg/kg/day. The mean [95% CI] and median [95% CI] times to

progression of CMV retinitis, as assessed by masked reading of fundus photographs, were 51 days [44,

57] and 41 days [31, 45], respectively, for patients on oral therapy compared to 62 days [52, 72] and 60

days [42, 83], respectively, for patients on intravenous therapy. The difference [95% CI] in the mean

time to progression between the oral and intravenous therapies (oral - IV) was -11 days [-24, 1]. See

Figure 3 for comparison of the proportion of patients remaining free of progression over time.

Comparison of other CMV retinitis outcomes between oral and intravenous formulations (development

of bilateral retinitis, progression into Zone 1, and deterioration of visual acuity), while not definitive,

showed no marked differences between treatment groups in these studies. Because of low event rates

among these endpoints, these studies are underpowered to rule out significant differences in these

endpoints.

Figure 1. ICM 1653: Time to Progression of CMV Retinitis

Figure 2. ICM 1774: Time to Progression of CMV Retinitis

Figure 3. AVI 034: Time to Progression of CMV Retinitis

14.2 Prevention of CMV Disease in Transplant Recipients

Intravenous ganciclovir was evaluated in three randomized, controlled trials of prevention of CMV

disease in organ transplant recipients.

Trial ICM 1496

In a randomized, double-blind, placebo-controlled study of 149 heart transplant recipients at risk for

CMV infection (CMV seropositive or a seronegative recipient of an organ from a CMV seropositive

donor), there was a reduction in the overall incidence of CMV disease in patients treated with

intravenous ganciclovir. Immediately post-transplant, patients received intravenous ganciclovir 5 mg/kg

twice daily for 14 days followed by 6 mg/kg once daily for 5 days/week for an additional 14 days.

Twelve of the 76 (16%) patients treated with intravenous ganciclovir vs. 31 of the 73 (43%) placebo-

treated patients developed CMV disease during the 120-day post-transplant observation period. No

significant differences in hematologic toxicities were seen between the two treatment groups [see

Adverse Reactions (6.1)].

Trial ICM 1689

In a randomized, double-blind, placebo-controlled study of 72 bone marrow transplant recipients with

asymptomatic CMV infection (CMV positive culture of urine, throat or blood) there was a reduction in

the incidence of CMV disease in patients treated with intravenous ganciclovir following successful

hematopoietic engraftment. Patients with virologic evidence of CMV infection received intravenous

ganciclovir 5 mg/kg twice daily for 7 days followed by 5 mg/kg once daily through day 100 post-

transplant. One of the 37 (3%) patients treated with intravenous ganciclovir vs 15 of the 35 (43%)

placebo-treated patients developed CMV disease during the study. At 6 months post-transplant, there

continued to be a reduction in the incidence of CMV disease in patients treated with intravenous

ganciclovir. Six of 37 (16%) patients treated with intravenous ganciclovir vs 15 of the 35 (43%)

placebo-treated patients developed disease through 6 months post-transplant. The overall rate of

survival was higher in the group treated with intravenous ganciclovir, both at day 100 and day 180 post-

transplant. Although the differences in hematologic toxicities were not statistically significant, the

incidence of neutropenia was higher in the group treated with intravenous ganciclovir [seeDosage and

Administration (2.4), Adverse Reactions (6.1)].

Trial ICM 1570

This was a randomized, unblinded trial which evaluated 40 allogeneic bone marrow transplant recipients

at risk for CMV disease. Patients underwent bronchoscopy and bronchoalveolar lavage (BAL) on day

35 post-transplant. Patients with histologic, immunologic or virologic evidence of CMV infection in the

lung were then randomized to observation or treatment with intravenous ganciclovir (5 mg/kg twice

daily for 14 days followed by 5 mg/kg once daily 5 days/week until day 120). Four of 20 (20%) patients

treated with intravenous ganciclovir and 14 of 20 (70%) control patients developed interstitial

pneumonia. The incidence of CMV disease was lower in the group treated with intravenous ganciclovir

[see Dosage and Administration (2.4)].

15 REFERENCES

1. “OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.

16 HOW SUPPLIED/STORAGE AND HANDLING

GANCICLOVIR INJECTION is supplied as a sterile, unpreserved, colorless solution in a single-dose

polymeric bag containing 500 mg ganciclovir in 250 mL of solution (2 mg/mL) sealed with a Twist Off

port from Technoflex, and oversealed in an aluminum pouch (NDC 51754-2500-1), in cases of 10 (NDC

51754-2500-3). Follow guidelines for handling and disposal for cytotoxic drugs.

The premix flexible plastic container bag contains no preservative; any unused portion should be

discarded [see Dosage and Administration (2.6)].

Gently shaking should redissolve any crystals that may have formed during transportation and/or storage

at temperatures lower than recommended. The solution must be clear at the time of use.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP

Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

Hematologic Toxicity

Inform patients of the potential for hematologic toxicity associated with the use of GANCICLOVIR

INJECTION including granulocytopenia (neutropenia), anemia and thrombocytopenia. Inform patients

that their blood counts will be closely monitored while on therapy [see Warnings and Precautions (5.1)].

Impairment of Renal Function

Inform patients that ganciclovir has been associated with decreased renal function and that serum

creatinine or creatinine clearance will be monitored carefully to allow for dosage adjustment in patients

with renal impairment [see Dosage and Administration (2.5), Warnings and Precautions (5.2)].

Impairment of Fertility

Inform patients that ganciclovir has caused decreased fertility in animals and may cause temporary or

permanent infertility in humans [see Warnings and Precautions (5.3), Use in Specific Populations (8.3)].

Pregnancy and Contraception

Inform women of childbearing potential that ganciclovir causes birth defects in animals. Advise female

patients to use effective contraception during treatment and for at least 30 days following treatment with

GANCICLOVIR INJECTION. Similarly, advise men to practice barrier contraception during and for at

least 90 days following treatment with GANCICLOVIR INJECTION [see Warnings and Precautions

(5.3), Use in Specific Populations (8.1, 8.3)].

Carcinogenicity

Inform patients that ganciclovir causes tumors in animals. Although there is no information from human

studies, ganciclovir should be considered a potential carcinogen [see Warnings and Precautions (5.5)].

Drug Interactions

Inform patients that GANCICLOVIR INJECTION may interact with other drugs. Advise patients to

report to their healthcare provider the use of any other medication [see Drug Interactions (7)].

Ophthalmological Examination in Patients with CMV Retinitis

Advise patients with CMV retinitis to have frequent ophthalmological examinations while being treated

with GANCICLOVIR INJECTION to monitor disease status and for other retinal abnormalities. More

frequent ophthalmological follow-up may be needed in some cases [see Dosage and Administration

(2.2), Adverse Reactions (6.1)].

Lactation

Advise nursing mothers that breastfeeding is not recommended during treatment with GANCICLOVIR

INJECTION because of the potential for serious adverse events in nursing infants and because HIV can

be passed to the baby in breast milk [see Use in Specific Populations (8.2)].

Manufactured and distributed by:

Exela Pharma Sciences

Lenoir, NC 28645

Principal Display Panel

NDC 51754-2500-1 250 mL

GANCICLOVIR INJECTION

500 mg per 250 mL (2 mg per mL)

0.8% sodium chloride solution

Single-dose for intravenous use only

Discard unused portion of drug

Bag Overwrap Label

GANCICLOVIR

ganciclovir injection, solution

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:51754-250 0

Route of Administration

INTRAVENOUS

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

GANCICLO VIR (UNII: P9 G3CKZ4P5) (GANCICLOVIR - UNII:P9 G3CKZ4P5)

GANCICLOVIR

2 mg in 1 mL

Inactive Ingredients

Ingredient Name

Stre ng th

SO DIUM CHLO RIDE (UNII: 451W47IQ8 X)

8 mg in 1 mL

EXELA PHARMA SCIENCES, LLC

SO DIUM HYDRO XIDE (UNII: 55X0 4QC32I)

HYDRO CHLO RIC ACID (UNII: QTT1758 2CB)

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:51754-250 0 -1

250 mL in 1 BAG; Type 0 : No t a Co mbinatio n Pro duct

0 2/28 /20 17

2

NDC:51754-250 0 -3

10 in 1 POUCH

0 2/28 /20 17

2

250 mL in 1 BAG; Type 0 : No t a Co mbinatio n Pro duct

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

NDA20 9 347

0 2/28 /20 17

Labeler -

EXELA PHARMA SCIENCES, LLC (831274399)

Registrant -

EXELA PHARMA SCIENCES, LLC (831274399)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

EXELA PHARMA SCIENCES, LLC

8 3127439 9

ma nufa c ture (51754-250 0 )

Revised: 10/2017

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