Adverse reactions : תופעות לוואי

4.8     Undesirable effects
 a     Summary of the safety profile
Valganciclovir is a prodrug of ganciclovir, which is rapidly and extensively metabolised to ganciclovir after oral administration. The undesirable effects known to be associated with ganciclovir use can be expected to occur with valganciclovir. All of the adverse drug reactions observed in valganciclovir clinical studies have been previously observed with ganciclovir. Therefore, adverse drug reactions reported with IV or oral ganciclovir (formulation no longer available) or with valganciclovir are included in the table of adverse drug reactions below.

In patients treated with valganciclovir/ganciclovir The most serious and frequent adverse drug reactions are haematological reactions and include neutropenia, anaemia and thrombocytopenia – see section 4.4.

The frequencies presented in the table of adverse reactions are derived from a pooled population of patients (n=1704) receiving maintenance therapy with ganciclovir or valganciclovir. Exception is made for anaphylactic reaction, agranulocytosis and granulocytopenia, the frequencies of which are derived from post-marketing experience. Adverse reactions are listed according to MedDRA system organ class. Frequency categories are defined using the following convention: 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).


VALCYTE®                                                                            Valcyte PI version 3 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 diarrhoea 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.
 b   Tabulated list of adverse drug reactions

ADR                                                                         Frequency (MedDRA)                                                                    Category System Organ Class
Infections and infestations:
Candida infections including oral candidiasis.                              Very common Upper respiratory tract infection
Sepsis                                                                      Common Influenza
Urinary tract infection
Cellulitis
Blood and lymphatic disorders:
Neutropenia                                                                 Very common Anaemia
Thrombocytopenia                                                            Common Leukopenia
Pancytopenia
Bone marrow failure                                                         Uncommon Aplastic anaemia                                                            Rare Agranulocytosis*
Granulocytopenia*
Immune system disorders:
Hypersensitivity                                                            Common Anaphylactic reaction*                                                      Rare Metabolic and nutrition disorders:
Decreased appetite                                                          Very common Weight decreased                                                            Common Psychiatric disorders:
Depression                                                                  Common Confusional state
Anxiety
Agitation                                                                   Uncommon Psychotic disorder
Thinking abnormal
Hallucinations
Nervous system disorders:
Headache                                                                    Very common Insomnia                                                                    Common Neuropathy peripheral
Dizziness
VALCYTE®                                                         Valcyte PI version 3 ADR                                                        Frequency
(MedDRA)                                                   Category
System Organ Class
Paraesthesia
Hypoaesthesia
Seizure
Dysgeusia (taste disturbance)
Tremor                                                     Uncommon
Eye disorders:
Visual impairment                                          Common
Retinal detachment**
Vitreous floaters
Eye pain
Conjunctivitis
Macular oedema
Ear and labyrinth disorders:
Ear pain                                                   Common
Deafness                                                   Uncommon
Cardiac disorders:
Arrhythmias                                                Uncommon
Vascular disorders:
Hypotension                                                Common
Respiratory, thoracic and mediastinal disorders:
Cough                                                      Very common Dyspnoea
Gastrointestinal disorders:
Diarrhoea                                                  Very common Nausea
Vomiting
Abdominal pain
Dyspepsia                                                  Common
Flatulence
Abdominal pain upper
Constipation
Mouth ulceration
Dysphagia
Abdominal distention
Pancreatitis
Hepato-biliary disorders:
Blood alkaline phosphatase increased                       Common
Hepatic function abnormal
Aspartate aminotransferase increased
Alanine aminotransferase increased
Skin and subcutaneous tissues disorders:
Dermatitis                                                 Very common Night sweats                                               Common
Pruritus
Rash

VALCYTE®                                                                             Valcyte PI version 3 ADR                                                                          Frequency (MedDRA)                                                                     Category System Organ Class
Alopecia
Dry skin                                                                     Uncommon Urticaria
Musculo-skeletal and connective tissue disorders:
Back pain                                                                    Common Myalgia
Arthralgia
Muscle spasms
Renal and urinary disorders:
Renal impairment                                                             Common Creatinine clearance renal decreased
Blood creatinine increased
Renal failure                                                                Uncommon Haematuria
Reproductive system and breast disorders:
Infertility male                                                             Uncommon General disorders and administration site conditions:
Pyrexia                                                                      Very common Fatigue
Pain                                                                         Common Chills
Malaise
Asthenia
Chest pain                                                                   Uncommon 
*The frequencies of these adverse reactions are derived from post-marketing experience **Retinal detachment has only been reported in HIV patients treated for CMV retinitis 
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 normalises within 2 to 5 days after discontinuation of the drug or dose reduction (see section 4.4).

Thrombocytopenia
Patients with low baseline platelet counts (< 100,000 /L) 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 AIDS (see section 4.4). 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 (14%) undergoing treatment with valganciclovir, intravenous or oral ganciclovir 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% 
VALCYTE®                                                                             Valcyte PI version 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 common 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, anaemia and thrombocytopenia were similar in both arms.
 c     Paediatric population
Valcyte has been studied in 179 paediatric solid organ transplant patients who were 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.

The most frequently reported adverse reactions on treatment in paediatric clinical trials were diarrhoea, nausea, neutropenia, leukopenia and anaemia.
In solid organ transplant patients, the overall safety profile was similar in paediatric patients as compared to adults. Neutropenia was reported with slightly higher incidence in the two studies conducted in paediatric solid organ transplant patients as compared to adults, but there was no correlation between neutropenia and infectious adverse events in the paediatric population. A higher risk of cytopenias in neonates and infants warrants careful monitoring of blood counts in these age groups (see section 4.4).

In kidney transplant paediatric patients, prolongation of valganciclovir exposure up to 200 days was not associated with an overall increase in the incidence of adverse events. The incidence of severe neutropenia (ANC < 500/µL) was higher in paediatric kidney patients treated until Day 200 as compared to paediatric patients treated until Day 100 and as compared to adult kidney transplant patients treated until Day 100 or Day 200 (see section 4.4).
Only limited data are available in neonates or infants with symptomatic congenital CMV infection treated with Valcyte, however the safety appears to be consistent with the known safety profile of valganciclovir/ganciclovir.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.go v.il