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4.2     Posology and method of administration

Paediatric patients:

Valcyte is not recommended for use in the paediatric population due to insufficient data on safety and efficacy (see sections 4.4 and 5.3). The safety and efficacy of Valcyte in pediatric patients have not been established in adequate and well-controlled clinical studies. Currently available data are described in section 4.8, 5.1 and 5.2 but no recommendation on a posology can be made.

4.8         Undesirable effects

Paediatrics

There are very limited paediatric data on the exposure to valganciclovir (see also sections 5.1 and 5.2). Following a summary of all adverse events which occurred in more than 10% (very common) of the total paedriatric population on treatment:

5.1     Pharmacodynamic properties

Paediatrics

A phase II pharmacokinetic and safety study in paediatric solid organ transplant recipients (aged 4 months to 16 years, n = 63) receiving valganciclovir once daily for up to 100 days according to a dosing algorithm produced exposures similar to that in adults (see section 5.2). Follow up after treatment was 12 weeks. CMV D/R serology status at baseline was D+/R- in 40%, D+/R+ in 38%, D-/R+ in 19% and D-/R- in 3% of the cases. Presence of CMV virus was reported in 7 patients. The observed adverse drug reactions were of similar nature as those in adults (see 4.8). These data are too limited to allow conclusions regarding efficacy or posology recommendations for paediatric patients.

The pharmacokinetics and safety of single dose valganciclovir (dose range 14-16-20 mg/kg/dose) was studied in 24 neonates (aged 8-34 days) with symptomatic congenital CMV disease (see section 5.2). The neonates received 6 weeks of antiviral treatment, whereas 19 of the 24 patients received up to 4 weeks of treatment with oral valganciclovir, in the remaining 2 weeks they received i.v. ganciclovir. The 5 remaining patients received i.v. ganciclovir for the most time of the study period. This treatment indication is not recommended presently for valganciclovir. The design of the study and obtained results are too limited to allow appropriate efficacy and safety conclusions on valganciclovir.

5.2     Pharmacokinetic properties

Pediatric patients

In a phase II pharmacokinetic and safety study in paediatric solid organ transplant recipients (aged 4 months to 16 years, n = 63) valganciclovir was given once daily for up to 100 days. Pharmacokinetics parameters were similar across organ type and age range and comparable with adults. Population pharmacokinetic modeling suggested that bioavailability was approximately 60%. Clearance was positively influenced by both body surface area and renal function. The mean total clearance was 5.3 L/hr (88.3 mL/min) for a patient with creatinine clearance of 70.4 mL/min. The following table shows the mean C_max, t ½ and AUC values including standard deviations for the relevant paediatric age groups compared to adult data:

* Extracted from study report PV 16000

The once daily dose of Valcyte was based on body surface area (BSA) and creatinine clearance (CrCl) derived from a modified Schwartz formula, and was calculated using the equation below:

Pediatric Dose (mg) = 7 x BSA x CrCl (calculated using the modified Schwartz formula)

where

where k = 0.45 for patients aged < 2 years, 0.55 for boys aged 2 to < 13 years and girls aged 2 to 16 years, and 0.7 for boys aged 13 to 16 years.

The dose should not exceed the adult 900 mg dose. In addition, if the calculated Schwartz creatinine clearance exceeds 150 mL/min/1.73m², then a maximum value of 150 mL/min/1.73m² should be used in the equation. It should be noted that the paediatric dosage algorithm was developed based on pharmacokinetic data only and has not been verified in efficacy and safety studies (see 5.1).

Ganciclovir pharmacokinetics were also evaluated in 24 neonates aged 8 to 34 days with symptomatic congenital CMV disease. All patients received 6 mg/kg intravenous ganciclovir twice daily. Patients were then treated with oral valganciclovir, where the dose of valganciclovir powder for oral solution ranged from 14 mg/kg to 20 mg/kg twice daily.  A dose of 16 mg/kg twice daily of valganciclovir powder for oral solution provided comparable ganciclovir exposure as 6 mg/kg intravenous ganciclovir twice daily in neonates, and also achieved ganciclovir exposure similar to the effective adult 5 mg/kg intravenous dose. The following table shows the mean AUC, C_max, and t ½ values including standard deviations compared adult data:

 GAN = Ganciclovir, i.v.

VAL = Valganciclovir, oral

The pharmacokinetic modeling suggested that the typical value of clearance (L/hr), volume of distribution (L), and bioavailability of ganciclovir in neonates were 0.146 x Weight^1.68, 1.15 x Weight, and 54%, respectively. These data are too limited to allow conclusions regarding efficacy or posology recommendations for pediatric patients with congenital CMV infection.

10.     DATE OF REVISION OF THE TEXT

June 2010June 2011

Underlined text has been added, text with strike through deleted:

4.2     Posology and method of administration

Prevention of CMV disease in solid organ transplantation:

For kidney transplant patients, the recommended dose is 900 mg once daily , starting within 10 days of transplantation and continuing until 200100 days post transplantation. Prophylaxis may be continued until 200 days post-transplantation (see sections 4.4, 4.8 and 5.1).

For patients who have received a solid organ transplant other than kidney, the recommended dose is 900 mg once daily, starting within 10 days of transplantation and continuing until 100 days post transplantation.

4.4     Special warnings and precautions for use

When extending prophylaxis beyond 100 days the possible risk of developing leucopenia and neutropenia should be taken into account (see sections 4.2, 4.8 and 5.1).

4.8         Undesirable effects

5.1     Pharmacodynamic properties

A double-blind, placebo controlled study has been conducted in 326 kidney transplant patients at high risk of CMV disease (D+/R-) to assess the efficacy and safety of extending Valcyte CMV prophylaxis from 100 to 200 days post-transplant. Patients were randomized (1:1) to receive Valcyte tablets (900 mg od) within 10 days of transplantation either until Day 200 post-transplant or until Day 100 post-transplant followed by 100 days of placebo.

The proportion of patients who developed CMV disease during the first 12 months post-transplant is shown in the table below.

Percentage of Kidney Transplant Patients with CMV Disease¹, 12 Month ITT Population ^A

¹ CMV Disease is defined as either CMV syndrome or tissue invasive CMV.  ² Confirmed CMV is a clinically confirmed case of CMV disease.  Patients were assumed to have CMV disease if there was either no week 52 assessment orand no confirmation of CMV disease before this time point.

^A The results found up to 24 months were in line with the up to 12 month results: Confirmed or assumed CMV disease was 48.5% in the 100 days treatment arm versus 34.2% in the 200 days treatment arm; difference between the treatment groups was 14.3% [3.2 %; 25.3%].

Significantly less high risk kidney transplant patients developed CMV disease following CMV prophylaxis with Valcyte until Day 200 post-transplant compared to patients who received CMV prophylaxis with Valcyte until Day 100 post-transplant.

The graft survival rate as well as the incidence of biopsy proven acute rejection was similar in both treatment groups. The graft survival rate at 12 months post-transplant was 98.12 % (160/163) for the 100 day dosing regimen and 98.21 % (152/155) for the 200 day dosing regimen. Up to 24 month post-transplant, four additional cases of graft loss were reported, all in the 100 days dosing group. The incidence of biopsy proven acute rejection at 12 months post-transplant was 17.2% (28/163) for the 100 day dosing regimen and 11.0% (17/155) for the 200 day dosing regimen. Up to 24 month post-transplant, one additional case has been reported in the 200 days dosing group.

Extending prophylaxis study from 100 to 200 days post-transplant

Genotypic analysis was performed on the UL54 and UL97 genes derived from virus extracted from 72 patients who met the resistance analysis criteria: patients who experienced a positive viral load (>600 copies/mL) at the end of prophylaxis and/or patients who had confirmed CMV disease up to 12 months (52 weeks) post-transplant. Three patients in each treatment group had a known ganciclovir resistance mutation.