CYMEVENE

Posology Treatment of CMV disease Adults and paediatric population ≥ 12 years of age with normal renal function: - Induction treatment: 5 mg/kg given as an intravenous infusion over one hour, every 12 hours for 14 - 21 days. - Maintenance treatment: For immunocompromised patients at risk of relapse maintenance therapy may be given.

5 mg/kg given as an intravenous infusion over one hour, once daily on 7 days per week or 6 mg/kg once daily on 5 days per week. The duration of maintenance treatment should be determined on an individual basis, local treatment guidelines should be consulted.

- Treatment of disease progression: Any patient, in whom CMV disease progresses, either while on maintenance treatment or because treatment with ganciclovir has been withdrawn, may be re-treated using the induction treatment regimen.

2 but no recommendation on a posology can be made. Prevention of CMV disease using pre-emptive therapy Adults and paediatric population ≥ 12 years of age with normal renal function: Induction therapy: 5 mg/kg given as an intravenous infusion over one hour, every 12 hours for 7 – 14 days.

Maintenance therapy: 5 mg/kg given as an intravenous infusion over one hour, once daily on 7 days per week or 6 mg/kg once daily on 5 days per week. The duration of maintenance therapy is based on the risk of CMV disease, local treatment guidelines should be consulted.

2 but no recommendation on a posology can be made. Prevention of CMV disease using universal prophylaxis Adults and paediatric population > 16 years of age: 5 mg/kg given as an intravenous infusion over one hour, once daily on 7 days per week or 6 mg/kg once daily on 5 days per week.

The duration is based on the risk of CMV disease, local treatment guidelines should be consulted.

Paediatric population from birth to ≤ 16 years of age:

The recommended once daily dose of ganciclovir given as an intravenous infusion over one hour is based on Body Surface Area (BSA) using the Mosteller BSA formula and creatinine clearance derived from Schwartz formula (CrCLS) and is calculated using the equations below.

The duration of universal prophylaxis is based on the risk of CMV disease and should be determined on an individual basis. Paediatric dose (mg) = 3 x BSA x CrCLS (see Mosteller BSA formula and Schwartz Creatinine Clearance formula below).

Summary of the safety profile Valganciclovir is a pro-drug of ganciclovir, and adverse reactions associated with valganciclovir can be expected to occur with ganciclovir. Oral ganciclovir is no longer available but adverse reactions reported with its use can also be expected to occur in patients receiving intravenous ganciclovir.

Therefore, adverse drug reactions reported with intravenous or oral ganciclovir or with valganciclovir are included in the table of adverse reactions. 4). Other adverse drug reactions are presented in the table below. The frequencies presented in the table of adverse reactions are derived from a pooled population of HIV-infected patients (n = 1,704) receiving maintenance therapy with ganciclovir or valganciclovir.

Exception is made for agranulocytosis, granulocytopenia and anaphylactic reaction; 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).

The overall safety profile of ganciclovir/valganciclovir is consistent in HIV and transplant populations except that retinal detachment has only been reported in HIV patients with CMV retinitis. However, there are some differences in the frequency of certain reactions.

Intravenous ganciclovir is associated with a lower risk of diarrhoea compared to oral valganciclovir. 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. Tabulated list of adverse reactions ADR (MedDRA) System Organ Class Frequency Category Infections and infestations: Candida infections including oral candidiasis Upper respiratory tract infection Very common Sepsis Influenza Urinary tract infection Common ADR (MedDRA) System Organ Class Frequency Category Cellulitis Blood and lymphatic disorders: Neutropenia Anaemia Very common Thrombocytopenia Leukopenia Pancytopenia Common Bone marrow failure Uncommon Aplastic anaemia Agranulocytosis* Granulocytopenia* Rare Immune system disorders: Hypersensitivity Common Anaphylactic reaction* Rare Metabolic and nutrition disorders: Decreased appetite Very common Weight decreased Common Psychiatric disorders: Depression Confusional state Anxiety Common Agitation Psychotic disorder Thinking abnormal Hallucinations Uncommon Nervous system disorders: Headache Very common Insomnia Neuropathy peripheral Dizziness Paraesthesia Hypoaesthesia Seizure Dysgeusia (taste disturbance) Common Tremor Uncommon Eye disorders: Visual impairment Retinal detachment Vitreous floaters Eye pain Conjunctivitis Macular oedema Common Ear and labyrinth disorders: Ear pain Common ADR (MedDRA) System Organ Class Frequency Category Deafness Uncommon Cardiac disorders: Arrhythmia Uncommon Vascular disorders: Hypotension Common Respiratory, thoracic and mediastinal disorders: Cough Dyspnoea Very common Gastrointestinal disorders: Diarrhoea Nausea Vomiting Abdominal pain Very common Dyspepsia Flatulence Abdominal pain upper Constipation Mouth ulceration Dysphagia Abdominal distention Pancreatitis Common Hepato-biliary disorders: Blood alkaline phosphatase increased Hepatic function abnormal Aspartate aminotransferase increased Alanine aminotransferase increased Common Skin and subcutaneous tissue disorders: Dermatitis Very common Night sweats Pruritus Rash Alopecia Common Dry skin Urticaria Uncommon Musculoskeletal and connective tissue disorders: Back pain Myalgia Arthralgia Muscle spasms Common Renal and urinary disorders: Renal impairment Creatinine clearance renal decreased Blood creatinine increased Common ADR (MedDRA) System Organ Class Frequency Category Renal failure Haematuria Uncommon Reproductive system and breast disorders: Infertility male Uncommon General disorders and administration site conditions: Pyrexia Fatigue Very common Injection site reaction Pain Chills Malaise Asthenia Common Chest pain Uncommon * The frequencies of these adverse reactions are derived from post-marketing experience; all other frequency categories are based on the frequency recorded in clinical trials.

Cross-hypersensitivity Due to the similarity of the chemical structure of ganciclovir and that of aciclovir and penciclovir, a cross-hypersensitivity reaction between these drugs is possible. Caution should therefore be used when prescribing Cymevene to patients with known hypersensitivity to aciclovir or penciclovir (or to their prodrugs, valaciclovir or famciclovir respectively).

Mutagenicity, teratogenicity, carcinogenicity, fertility and contraception Prior to initiation of ganciclovir treatment, patients should be advised of the potential risks to the foetus. In animal studies ganciclovir was found to be mutagenic, teratogenic, carcinogenic and to impair fertility.

3). Ganciclovir should therefore be considered a potential teratogen and carcinogen in humans with the potential to cause birth defects and cancers. Therefore, women of childbearing potential must be advised to use effective contraception during treatment and for at least 30 days thereafter.

3). The use of ganciclovir warrants extreme caution, especially in the paediatric population due to the potential for long-term carcinogenicity and reproductive toxicity. 2). Refer to treatment guidelines. Myelosuppression Cymevene should be used with caution in patients with pre-existing haematological cytopenia or a history of drug-related haematological cytopenia and in patients receiving radiotherapy.

Severe leukopenia, neutropenia, anaemia, thrombocytopenia, pancytopenia and bone marrow failure have been observed in patients treated with ganciclovir. 8). It is recommended that complete blood counts including platelet counts be monitored during therapy.

8). During the first 14 days of administration it is recommended that white blood cell count (preferably as a differential test) is conducted every second day; in patients with low baseline neutrophil levels (< 1,000 neutrophils/μl), those who developed leukopenia during previous therapy with other myelotoxic substances, and those with renal impairment, this monitoring should be performed daily.

1. 6).