Ganciclovir: Package Insert and Label Information (Page 4 of 6)

8.5 Geriatric Use

Clinical studies of Ganciclovir Injection 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 Injection 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 renal clearance decreases with age, Ganciclovir Injection should be administered to elderly patients with special consideration of their renal status. Renal function should be monitored and dosage adjustments should be made accordingly Clinical studies of Ganciclovir Injection 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 Injection 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 renal clearance decreases with age, Ganciclovir Injection should be administered to elderly patients with special consideration of their renal status. 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 Dose reduction is recommended when administering Ganciclovir Injection to patients with renal impairment [see Dosage and Administration (2.5), and Warnings and Precautions (5.2)] .

8.7 Hepatic Impairment

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

10 OVERDOSAGE

Reports of adverse reactions after overdoses with Ganciclovir Injection Reports of adverse reactions after overdoses with Ganciclovir Injection , some with fatal outcomes, have been received from clinical trials and during postmarketing experience. One or more of the following adverse reactions has been reported with overdoses:

myelosuppression including pancytopenia, leukopenia, neutropenia, granulocytopenia, thrombocytopenia, bone marrow failure Hematological toxicity: myelosuppression including pancytopenia, leukopenia, neutropenia, granulocytopenia, thrombocytopenia, bone marrow failure

hepatitis, liver function disorder Hepatotoxicity: hepatitis, liver function disorder

worsening of hematuria in a patient with pre-existing renal impairment, acute kidney injury, elevated creatinine Renal toxicity: worsening of hematuria in a patient with pre-existing renal impairment, acute kidney injury, elevated creatinine

abdominal pain, diarrhea, vomiting Gastrointestinal toxicity: abdominal pain, diarrhea, vomiting

seizure Neurotoxicity: seizure

Since ganciclovir is dialyzable, dialysis may be useful in reducing serum concentrations in patients who have received an overdose of Ganciclovir Injection . Adequate hydration should be maintained. The use of hematopoietic growth factors should be considered in patients with cytopenias . Since ganciclovir is dialyzable, dialysis may be useful in reducing serum concentrations in patients who have received an overdose of Ganciclovir Injection [see Clinical Pharmacology (12.3)] . Adequate hydration should be maintained. The use of hematopoietic growth factors should be considered in patients with cytopenias [see Warnings and Precautions (5.1)] .

11 DESCRIPTION

Ganciclovir Injection Ganciclovir Injection contains ganciclovir, in the form of the sodium salt for intravenous injection. Ganciclovir is a synthetic guanine derivative active against cytomegalovirus (CMV).

Chemically, ganciclovir is 9-[[2-hydroxy-1-(hydroxymethyl)-ethoxy]methyl]guanine and ganciclovir sodium is 9-[[2-hydroxy-1-(hydroxymethyl)-ethoxy]methyl]guanine, monosodium salt. The chemical structures of ganciclovir sodium and ganciclovir are:Chemically, ganciclovir is 9-[[2-hydroxy-1-(hydroxymethyl)-ethoxy]methyl]guanine and ganciclovir sodium is 9-[[2-hydroxy-1-(hydroxymethyl)-ethoxy]methyl]guanine, monosodium salt. The chemical structures of ganciclovir sodium and ganciclovir are:

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Ganciclovir is a white to off-white crystalline powder. 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. Ganciclovir is a white to off-white crystalline powder. 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 a s for ganciclovir are 2.2 and 9.4.

Ganciclovir Injection (ganciclovir), formulated as monosodium salt, using sodium hydroxide as a salt forming agent, is a sterile solution. At physiological pH, ganciclovir sodium exists as the un-ionized form with a solubility of approximately 6 mg/mL at 37°C.Ganciclovir Injection (ganciclovir), formulated as monosodium salt, using sodium hydroxide as a salt forming agent, is a sterile solution. At physiological pH, ganciclovir sodium exists as the un-ionized form with a solubility of approximately 6 mg/mL at 37°C.

Each vial contains ganciclovir sodium equivalent to 500 mg ganciclovir.Each vial contains ganciclovir sodium equivalent to 500 mg ganciclovir.

Inactive ingredients may include hydrochloric acid (QS) and sodium hydroxide (QS) added to adjust the pH.Inactive ingredients may include hydrochloric acid (QS) and sodium hydroxide (QS) added to adjust the pH.

All doses in this package insert are specified in terms of ganciclovir.All doses in this package insert are specified in terms of ganciclovir.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Ganciclovir is an antiviral drug with activity against 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 mcg∙hr/mL (n=16) and C max ranged between 8.27 ± 1.02 (n=16) and 9.0 ± 1.4 mcg/mL (n=16).

Distribution

The steady-state volume of distribution of ganciclovir after intravenous administration was 0.74 ± 0.15 L/kg (n=98). Ganciclovir diffuses across the placenta. 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 mcg/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 mcg/mL.

Elimination

When administered intravenously, ganciclovir exhibits linear pharmacokinetics over the range of 1.6 to 5.0 mg/kg. 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 unmetabolized 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). Half-life was 3.5 ± 0.9 hours (n=98) following intravenous administration.

Specific Populations

Pharmacokinetics in Patients with Renal Impairment

The pharmacokinetics following intravenous administration of Ganciclovir Injection solution were evaluated in 10 immunocompromised patients with renal impairment who received doses ranging from 1.25 to 5.0 mg/kg. Decreased renal function results in decreased clearance of ganciclovir (Table 7).

Table 7. Ganciclovir Pharmacokinetics in Patients with Renal Impairment
Estimated Creatinine Clearance (mL/min) n Dose Clearance (mL/min) Mean ± SD Half-life (hours) Mean ± SD
50-79 4 3.2-5 mg/kg 128 ± 63 4.6 ± 1.4
25-49 3 3-5 mg/kg 57 ± 8 4.4 ± 0.4
< 25 3 1.25-5 mg/kg 30 ± 13 10.7 ± 5.7

Plasma concentrations of ganciclovir are reduced by about 50% during a 4 hour hemodialysis session .

Pharmacokinetics in Geriatric Patients

The pharmacokinetic profiles of Ganciclovir Injection in patients 65 years of age and older have not been established. As ganciclovir is mainly renally excreted and since renal clearance decreases with age, a decrease in ganciclovir total body clearance and a prolongation of ganciclovir half-life can be anticipated in patients 65 years of age and older [see Dosage and Administration (2.5), Use in Specific Populations (8.5)].

Drug Interaction Studies

Table 8 and Table 9 provide a listing of established drug interaction studies with ganciclovir. Table 8 provides the effects of coadministered drug on ganciclovir plasma pharmacokinetic parameters, whereas Table 9 provides the effects of ganciclovir on plasma pharmacokinetic parameters of coadministered drug.

Table 8. Results of Drug Interaction Studies with Ganciclovir: Effects of Coadministered Drug on Ganciclovir Pharmacokinetic Parameters
Coadministered Drug Ganciclovir Dosage N Ganciclovir Pharmacokinetic (PK) Parameter
Mycophenolate mofetil (MMF) 1.5 g single dose 5 mg/kg IV single dose 12 No effect on ganciclovir PK parameters observed (patients with normal renal function)
Trimethoprim 200 mg once daily 1000 mg orally every 8 hours 12 No effect on ganciclovir PK parameters observed.
Didanosine 200 mg every 12 hours simultaneously administered with ganciclovir 5 mg/kg IV twice daily 11 No effect on ganciclovir PK parameters observed
5 mg/kg IV once daily 11 No effect on ganciclovir PK parameters observed
Probenecid 500 mg every 6 hours 1000 mg orally every 8 hours 10 AUC ↑ 53 ± 91% (range: -14% to 299%) Ganciclovir renal clearance ↓ 22 ± 20% (range: -54% to -4%)
Table 9. Results of Drug Interaction Studies with Ganciclovir: Effects of Ganciclovir on Pharmacokinetic Parameters of Coadministered Drug
Coadministered Drug Ganciclovir Dosage N Coadministered Drug Pharmacokinetic (PK) Parameter
Oral cyclosporine at therapeutic doses 5 mg/kg infused over 1 hour every 12 hours 93 In a retrospective analysis of liver allograft recipients, there was no evidence of an effect on cyclosporine whole blood concentrations.
Mycophenolate mofetil (MMF) 1.5 g single dose 5 mg/kg IV single dose 12 No PK interaction observed (patients with normal renal function)
Trimethoprim 200 mg once daily 1000 mg orally every 8 hours 12 No effect on trimethoprim PK parameters observed.
Didanosine 200 mg every 12 hours 5 mg/kg IV twice daily 11 AUC 0-12 ↑70 ± 40% (range: 3% to 121%) C max ↑49 ± 48% (range: -28% to 125%)
Didanosine 200 mg every 12 hours 5 mg/kg IV once daily 11 AUC 0-12 ↑50 ± 26% (range: 22% to 110%) C max ↑36 ± 36% (range: -27% to 94%)

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