Valcyte Adverse Reactions

Clinical Trials: Valganciclovir is a prodrug of ganciclovir, which is rapidly converted to ganciclovir after oral administration. The undesirable effects known to be associated with ganciclovir usage can therefore be expected to occur with Valcyte. All of the adverse drug reactions observed in Valcyte clinical studies have been previously observed with ganciclovir.
Therefore, adverse drug reactions reported with IV or oral ganciclovir (no longer available) or with valganciclovir are included in the table of adverse reactions (see Tables 5a and 5b).
In patients treated with valganciclovir/ganciclovir the most serious and frequent adverse drug reactions are hematological reactions and include neutropenia, anemia and thrombocytopenia.
The frequencies presented in the table of adverse reactions are derived from a pooled population of patients (n=1704) receiving maintenance therapy with ganciclovir (GAN 1697, GAN 1653, GAN 2304, GAN 1774, GAN 2226, AVI 034, GAN 041) or valganciclovir (WV15376, WV15705). Exception is made for anaphylactic reaction, agranulocytosis and granulocytopenia the frequencies of which are derived from post-marketing experience. Frequencies are presented as percentages and as CIOMS frequency categories defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) and very rare (<1/10,000).
The overall safety profile of ganciclovir/valganciclovir is consistent in HIV and transplant populations except that retinal detachment has only been reported in patients with CMV retinitis. However, there are some differences in the frequency of certain reactions. Valganciclovir is associated with a higher risk of diarrhea compared to intravenous ganciclovir. Pyrexia, candida infections, depression, severe neutropenia (ANC <500/μl) and skin reactions are reported more frequently in patients with HIV. Renal and hepatic dysfunction are reported more frequently in organ transplant recipients. (See Tables 5a and 5b.)

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Description of selected adverse reactions: Neutropenia: The risk of neutropenia is not predictable on the basis of the number of neutrophils before treatment. Neutropenia usually occurs during the first or second week of induction therapy. The cell count usually normalizes within 2 to 5 days after discontinuation of the drug or dose reduction (see Precautions).
Thrombocytopenia: Patients with low baseline platelet counts (<100,000/μl) have an increased risk of developing thrombocytopenia. Patients with iatrogenic immunosuppression due to treatment with immunosuppressive drugs are at greater risk of thrombocytopenia than patients with HIV (see Precautions). Severe thrombocytopenia may be associated with potentially life-threatening bleeding.
Influence of treatment duration or indication on adverse reactions: Severe neutropenia (ANC <500/μl) is seen more frequently in CMV retinitis patients (16%) undergoing treatment with valganciclovir than in solid organ transplant patients receiving valganciclovir or oral ganciclovir. In patients receiving valganciclovir or oral ganciclovir until Day 100 post-transplant the incidence of severe neutropenia was 5% and 3% respectively, whilst in patients receiving valganciclovir until Day 200 post-transplant the incidence of severe neutropenia was 10%.
There was a greater increase in serum creatinine seen in solid organ transplant patients treated until Day 100 or Day 200 post-transplant with both valganciclovir and oral ganciclovir when compared to CMV retinitis patients. However, impaired renal function is a feature more frequent in solid organ transplantation patients.
The overall safety profile of Valcyte did not change with the extension of prophylaxis up to 200 days in high risk kidney transplant patients. Leukopenia was reported with a slightly higher incidence in the 200 days arm while the incidence of neutropenia, anemia and thrombocytopenia were similar in both arms.
Laboratory Abnormalities: Laboratory abnormalities reported in adult CMV retinitis patients and SOT patients receiving valganciclovir until Day 100 post-transplant are listed in Table 6. The incidence of laboratory abnormalities was comparable with the extension of prophylaxis up to 200 days in high risk kidney transplant patients.
Laboratory abnormalities reported in pediatric SOT patients are listed in Table 7. The incidence of severe neutropenia (ANC<500/μL) was higher in pediatric kidney transplant patients treated until Day 200 as compared to pediatric kidney transplant patients treated until Day 100 and to adults kidney transplant patients treated until Day 100 or Day 200. (See Tables 6 and 7.)

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Pediatric patients: Valcyte has been studied in 179 pediatric solid organ transplant patients who are at risk of developing CMV disease (aged 3 weeks to 16 years) and in 133 neonates with symptomatic congenital CMV disease (aged 2 to 31 days), with duration of ganciclovir exposure ranging from 2 to 200 days (see Pharmacology: Pharmacodynamics: Clinical Efficacy Studies under Actions).
The overall safety profile was similar in pediatric patients as compared to adults. Neutropenia was also reported with slightly higher incidence in the two pediatric studies as compared to adults but neutropenia and infectious adverse events were generally not correlated in the pediatric populations.
In kidney transplant pediatric patients, prolongation of valganciclovir exposure to 200 days was not associated with increased incidence of adverse events.
Congenital CMV: Congenital CMV is not an approved indication for Valcyte. However, studies conducted in neonates and infants with congenital CMV do provide safety data in this patient population. Studies suggest that the safety of Valcyte and Cymevene appear consistent with the known safety profile of valganciclovir/ganciclovir. The primary toxicity is neutropenia, in one study 9 of 24 subjects (38%) developed Grade 3 or 4 neutropenia while on ganciclovir therapy (one patient required treatment cessation). Most events were manageable with continuation of antiviral therapy. Growth (head circumference, weight and height) of all neonates, who had growth measurements recorded, increased over time in this non-comparative study. The most frequent treatment-related AEs associated with oral valganciclovir were neutropenia, anemia, liver function abnormality and diarrhea, all seen more frequently in the placebo group. The only treatment-related SAEs were neutropenia and anemia, both seen more frequently in the placebo arm. No statistically or clinically significant differences were observed in the rate of growth (average head circumference, weight and length) over time at each time point between the two treatment groups.
Postmarketing Experience: Safety reports from the postmarketing setting are consistent with safety data from clinical trials with valganciclovir and ganciclovir (see Tables 5a and 5b as previously mentioned).