Valganciclovir (Page 5 of 9)

8.7 Hepatic Impairment

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

10 OVERDOSAGE

Experience with Valganciclovir Tablets: An overdose of valganciclovir could also possibly result in increased renal toxicity [see Dosage and Administration ( 2.5), Use in Specific Populations ( 8.6) ]. Because ganciclovir is dialyzable, dialysis may be useful in reducing serum concentrations in patients who have received an overdose of valganciclovir [see Clinical Pharmacology ( 12.3) ]. Adequate hydration should be maintained. The use of hematopoietic growth factors should be considered [see Warnings and Precautions (5.1) and see Clinical Pharmacology ( 12.3) ].

Reports of adverse reactions after overdoses with valganciclovir, some with fatal outcomes, have been received from clinical trials and during postmarketing experience. The majority of patients experienced one or more of the following adverse events:

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

Hepatotoxicity: hepatitis, liver function disorder

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

Gastrointestinal toxicity: abdominal pain, diarrhea, vomiting

Neurotoxicity: generalized tremor, seizure

11 DESCRIPTION

Valganciclovir tablets USP contains valganciclovir hydrochloride USP, a hydrochloride salt of the L-valyl ester of ganciclovir that exists as a mixture of two diastereomers. Ganciclovir is a synthetic guanine derivative active against CMV.

Valganciclovir hydrochloride USP is available as a 450 mg tablet for oral administration. Each tablet contains 496.3 mg of valganciclovir hydrochloride USP (corresponding to 450 mg of valganciclovir), and the inactive ingredients crospovidone, magnesium stearate, microcrystalline cellulose and povidone. The film-coat applied to the tablets contains hypromellose, iron oxide red, polyethylene glycol, polysorbate and titanium dioxide.

Valganciclovir hydrochloride USP is a white to almost white powder with a molecular formula of C 14 H 22 N 6 O 5 •HCl and a molecular weight of 390.71. The chemical name for valganciclovir hydrochloride USP is L-Valine, 2[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]-3-hydroxypropyl ester, monohydrochloride. Valganciclovir hydrochloride USP is a polar hydrophilic compound with a saturation solubility of 6029 mg/mL in water at 25°C and an n-octanol/water partition coefficient of 0.00701 at pH 5.1. The pKa for valganciclovir hydrochloride USP is 7.2.

The chemical structure of valganciclovir hydrochloride USP is:

structure
(click image for full-size original)

All doses in this insert are specified in terms of valganciclovir.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

12.3 Pharmacokinetics

Valganciclovir is a prodrug of ganciclovir. Valganciclovir C max and AUC are approximately 1% and 3% of those of ganciclovir, respectively.

Pharmacokinetics in Adults: The pharmacokinetics of ganciclovir after administration of valganciclovir tablets have been evaluated in HIV- and CMV-seropositive patients, patients with AIDS and CMV retinitis, and in solid organ transplant patients (Table 10).

Table 10 Ganciclovir Pharmacokinetics * in Healthy Volunteers and HIV-positive/CMV-positive Adults Administered Valganciclovir Tablets 900 mg Once Daily with Food.
*
Data were obtained from single and multiple dose studies in healthy volunteers, HIV-positive patients, and HIV-positive/CMV-positive patients with and without retinitis. Patients with CMV retinitis tended to have higher ganciclovir plasma concentrations than patients without CMV retinitis.

PK parameter

N

Value (Mean ± SD)

AUC 0-24h (mcg h/mL)

57

29.1 ± 9.7

C max (mcg/mL)

58

5.61 ± 1.52

Absolute oral bioavailability (%)

32

59.4 ± 6.1

Elimination half-life (hr)

73

4.08 ± 0.76

Renal clearance (mL/min/kg)

20

3.21 ± 0.75 (1 study, n=20)

The systemic ganciclovir exposures attained following administration of 900 mg valganciclovir tablets once daily were comparable across kidney, heart and liver transplant recipients (Table 11).

Table 11 Ganciclovir Pharmacokinetics in Solid Organ Transplant Recipients Administered Valganciclovir Tablets 900 mg Once Daily with Food.
*
Includes kidney-pancreas

Parameter

Value (Mean ± SD)

Heart Transplant Recipients (N=17)

Liver Transplant Recipients (N=75)

Kidney Transplant Recipients * (N=68)

AUC 0-24h (mcg h/mL)

40.2 ± 11.8

46.0 ± 16.1

48.2 ± 14.6

C max (mcg/mL)

4.9 ± 1.1

5.4 ± 1.5

5.3 ± 1.5

Elimination half-life (hr)

6.58 ± 1.50

6.18 ± 1.42

6.77 ± 1.25

The pharmacokinetic parameters of ganciclovir following 200 days of valganciclovir administration in high-risk kidney transplant patients were similar to those previously reported in solid organ transplant patients who received valganciclovir for 100 days.

Absorption, Distribution, Metabolism, and Excretion The pharmacokinetic (PK) properties of valganciclovir are provided in Table 12.

Table 12 Pharmacokinetic Properties of Ganciclovir and Valganciclovir Associated with Valganciclovir Tablets.
*
Steady state ganciclovir PK was assessed after administration of valganciclovir tablets (875 mg once daily) were administered with a high fat meal containing approximately 600 total calories (31.1 g fat, 51.6 g carbohydrates and 22.2 g protein) to 16 HIV-positive subjects.

Valganciclovir

Ganciclovir

Absorption

T max (h) median (min-max) (fed conditions)

2.18 1.7h to 3.0h

Food effect (high fat meal/fasting): PK parameter ratio and 90% confidence interval *

C max : 1.14 (0.95, 1.36) AUC: 1.30 (1.07, 1.51) * T max : ↔

Distribution

% Bound to human plasma proteins ( ex vivo)

Unknown

1 to 2% over 0.5 to 51 mcg/mL

Cerebrospinal fluid penetration

Unknown

Yes

Metabolism

Hydrolyzed by intestinal and liver esterases

No significant metabolism

Elimination

Dose proportionality

AUC was dose proportional under fed conditions across a valganciclovir dose range of 450 to 2625 mg

Major route of elimination

Metabolism to ganciclovir

Glomerular filtration and active tubular secretion

t 1/2 (h)

See Tables 10 and 11

% Of dose excreted in urine

Unknown

% Of dose excreted in feces

Unknown

Specific Populations:Renal Impairment: The pharmacokinetics of ganciclovir from a single oral dose of 900 mg valganciclovir tablets were evaluated in 24 otherwise healthy individuals with renal impairment. Decreased renal function results in decreased clearance of ganciclovir and increased terminal half-life (Table 13).

Table 13 Pharmacokinetics of Ganciclovir from a Single Oral Dose of 900 mg Valganciclovir Tablets
*
Creatinine clearance calculated from 24-hour urine collection.

Estimated Creatinine Clearance * (mL/min)

N

Apparent Clearance (mL/min) Mean ± SD

AUC last (mcg·h/mL) Mean ± SD

Half-life (hours) Mean ± SD

51 to 70 21 to 50 11 to 20 ≤10

6 6 6 6

249 ± 99 136 ± 64 45 ± 11 12.8 ± 8

49.5 ± 22.4 91.9 ± 43.9 223 ± 46 366 ± 66

4.85 ± 1.4 10.2 ± 4.4 21.8 ± 5.2 67.5 ± 34

Hemodialysis reduces plasma concentrations of ganciclovir by about 50% following valganciclovir administration. Adult patients receiving hemodialysis (CrCl less than 10 mL/min) cannot use valganciclovir tablets because the daily dose of valganciclovir tablets required for these patients is less than 450 mg [see Dosage and Administration ( 2.5) and Use in Specific Populations ( 8.6) ].

Pharmacokinetics in Pediatric Patients: The pharmacokinetics of ganciclovir were evaluated following the administration of valganciclovir in 63 pediatric solid organ transplant patients aged 4 months to 16 years and in 16 pediatric heart transplant patients less than 4 months of age. In these studies, patients received oral doses of valganciclovir (either valganciclovir for oral solution or tablets) to produce exposure equivalent to an adult 900 mg dose [see Dosage and Administration (2.3), Adverse Reactions (6.1), Use in Specific Populations (8.4), Clinical Studies (14.2)].

In studies using the pediatric valganciclovir dosing algorithm, the pharmacokinetics of ganciclovir were similar across organ types and age ranges (Table 14). Relative to adult transplant patients ( Table 11), AUC values in pediatric patients were somewhat increased, but were within the range considered safe and effective in adults.

Table 14 Ganciclovir Pharmacokinetics by Age in Pediatric Solid Organ Transplant Patients Administered Valganciclovir Tablets
*
Ages ranged from 26 to 124 days

Organ

Age group

PK Parameter Mean (SD)

< 4 months

4 months to ≤ 2 years

> 2 to < 12 years

≥ 12 years

Heart (N=26)

N

14 *

6

2

4

AUC 0-24h (mcg∙h/mL) C max (mcg/mL) t 1/2 (h)

66.3 (20.5) 10.8 (3.30) 3.5 (0.87)

55.4 (22.8) 8.2 (2.5) 3.8 (1.7)

59.6 (21) 12.5 (1.2) 2.8 (0.9)

60.6 (25) 9.5 (3.3) 4.9 (0.8)

Kidney (N=31)

N

2

10

19

AUC 0-24h (mcg·h/mL) C max (mcg/mL) t 1/2 (h)

NA

67.6 (13) 10.4 (0.4) 4.5 (1.5)

55.9 (12.1) 8.7 (2.1) 4.8 (1)

47.8 (12.4) 7.7 (2.1) 6 (1.3)

Liver (N=17)

N

9

6

2

AUC 0-24h (mcg·h/mL) C max (mcg/mL) t 1/2 (h)

NA

69.9 (37) 11.9 (3.7) 2.8 (1.5)

59.4 (8.1) 9.5 (2.3) 3.8 (0.7)

35.4 (2.8) 5.5 (1.1) 4.4 (0.2)

N= number of patients, NA=not applicable

Pharmacokinetics in Geriatric Patients: The pharmacokinetic characteristics of valganciclovir in elderly patients have not been established.

Drug Interactions:In vivo drug-drug interaction studies were not conducted with valganciclovir. However, because valganciclovir is rapidly and extensively converted to ganciclovir, interactions associated with ganciclovir will be expected for valganciclovir [see Drug Interactions (7) ].

Table 15 and Table 16 provide a listing of established drug interaction studies with ganciclovir. Table 15 provides the effects of coadministered drug on ganciclovir plasma pharmacokinetic parameters, whereas Table 16 provides the effects of ganciclovir on plasma pharmacokinetic parameters of coadministered drug.

Table 15 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 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 every 8 hours

10

AUC ↑ 53 ± 91% (range: -14% to 299%) Ganciclovir renal clearance ↓ 22 ± 20% (range: -54% to -4%)

Table 16 Results of Drug Interaction Studies with Ganciclovir: Effects of Ganciclovir on Pharmacokinetic Parameters of Co administered 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 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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