GANCICLOVIR: Package Insert and Label Information

GANCICLOVIR- ganciclovir injection, solution
EXELA PHARMA SCIENCES, LLC

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 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
CreatinineClearance*(mL/min)GANCICLOVIRINJECTIONInductionDose (mg/kg)DosingInterval(hours) for InductionGANCICLOVIRINJECTIONMaintenanceDose (mg/kg)DosingInterval(hours) for Maintenance
Greater than or equal to 70512 5 24
50-692.5122.5 24
25-492.524 1.2524
10-241.2524 0.62524
Less than 101.253 times per week,followinghemodialysis 0.6253 times per week,followinghemodialysis

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

Creatinine Clearance Formulas
(click image for full-size original)

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 considered1 [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 and severity 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), 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 RetinitisThree 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 TreatmentStudies
IntravenousGanciclovir(n=179) GanciclovirCapsules(n=326)
Fever 48% 38%
Diarrhea

44%

41%
Leukopenia 41% 29%
Anemia 25% 19%
Total catheter events: 22% 6%
Catheter infection 9% 4%
Catheter sepsis 8% 1%
Other catheter related events 5% 1%
Sepsis 15% 4%
Anorexia 14% 15%
Vomiting 13% 13%
Infection 13% 9%
Sweating 12% 11%
Chills 10% 7%
Neuropathy 9% 8%
Thrombocytopenia 6% 6%
Pruritus 5% 6%

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

25%

18%
500 — <749 14% 17%
750 — <1000 16% 19%
Anemia with Hemoglobin (g/dL):
<6.5 5% 2%
6.5 — <8.0 16% 10%
8.0 — <9.5 26% 25%
Serum Creatinine (mg/dL):
≥2.5 2% 1%
≥1.5 — <2.5 14% 12%

* 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 RecipientsThere 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†
IntravenousGanciclovir(N=76) Placebo(n=73) IntravenousGanciclovir(n=57) Control(n=55)
Neutropenia

Absolute Neutrophil Count

(ANC) per µL:

<500

4%

3% 12% 6%
<500-1000 3% 8% 29% 17%

TOTAL ANC

≤1000/µL

7% 11% 41% 23%
Thrombocytopenia
Platelet count per µL:
<25,000 3% 1% 32% 28%
25,000-50,000 5% 3% 25% 37%
TOTAL Platelet Count ≤50,000/µL 8% 4% 57% 65%
Table 5. Serum Creatinine Levels in Controlled Trials – Transplant Recipients who Received Intravenous Ganciclovir or Placebo
SerumCreatinineLevels (mg/dL) Heart AllograftICM 1496 Bone Marrow AllograftICM 1570 Bone Marrow AllograftICM 1689
Intravenous Ganciclovir (N=76) Placebo(n=73) IntravenousGanciclovir(n=20) Placebo(n=73) IntravenousGanciclovir(n=37) Placebo(n=35)

≥2.5

18% 14% 20% 0% 0% 0%
≥1.5 — <2.5 58% 69% 50% 35% 43% 44%

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

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