VALCYTE

9). Valganciclovir is rapidly and extensively metabolised to ganciclovir after oral dosing. Oral valganciclovir 900 mg taken twice daily is therapeutically equivalent to intravenous ganciclovir 5 mg/kg taken twice daily. The ganciclovir systemic exposure following administration of 900 mg valganciclovir oral solution is equivalent to valganciclovir 900 mg tablets.

Treatment of cytomegalovirus (CMV) retinitis Adult patients Induction treatment of CMV retinitis For patients with active CMV retinitis, the recommended dose is 900 mg valganciclovir twice a day for 21 days. 4).

Maintenance treatment of CMV retinitis:

Following induction treatment, or in patients with inactive CMV retinitis, the recommended dose is 900 mg valganciclovir once daily. Patients whose retinitis worsens may repeat induction treatment; however, consideration should be given to the possibility of viral drug resistance.

The duration of maintenance treatment should be determined on an individual basis. Paediatric population The safety and efficacy of Valcyte in the treatment of CMV retinitis have not been established in adequate and well-controlled clinical studies in paediatric patients.

Prevention of CMV disease in solid organ transplantation Adult patients For kidney transplant patients, the recommended dose is 900 mg once daily, starting within 10 days post-transplantation and continuing until 100 days post transplantation.

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 post-transplantation and continuing until 100 days post-transplantation. Paediatric population In paediatric solid organ transplant patients, aged from birth, who are at risk of developing CMV disease, the recommended once daily dose of Valcyte is based on body surface area (BSA) and creatinine clearance (Clcr) derived from Schwartz formula (ClcrS), and is calculated using the equation below: Paediatric Dose (mg) = 7 x BSA x ClcrS (see Mosteller BSA formula and Schwartz Creatinine Clearance formula below).

7 for boys aged 13 to 16 years. Refer to adult dosing for patients older than 16 years of age. The k values provided are based on the Jaffe method of measuring serum creatinine and may require correction when enzymatic methods are used.

g. in paediatric patients with low birth weight). For paediatric kidney transplant patients, the recommended once daily mg dose (7 x BSA x ClcrS) should start within 10 days post-transplantation and continue until 200 days post-transplantation.

For paediatric patients who have received a solid organ transplant other than kidney, the recommended once daily mg dose (7x BSA x ClcrS) should start within 10 days post-transplantation and continue until 100 days post-transplantation.

All calculated doses should be rounded to the nearest 25 mg increment for the actual deliverable dose. The oral dispenser is graduated in ml. 5 ml 100 mg 2 ml 500 mg 10 ml If the calculated dose exceeds 900 mg (2 x 9 ml), a maximum dose of 900 mg (2 x 9 ml) should be administered.

The oral solution is the preferred formulation since it provides the ability to administer a dose calculated according to the formula above; however, Valcyte film-coated tablets may be used if the calculated doses are within 10% of available tablet doses, and the patient is able to swallow tablets.

For example, if the calculated dose is between 405 mg and 495 mg, one 450 mg tablet may be taken. It is recommended to monitor serum creatinine levels regularly and consider changes in height and body weight and adapt the dose as appropriate during the prophylaxis period.

Special dosage instructions Paediatric population Dosing of paediatric SOT patients is individualised based on a patient’s renal function, together with body surface area.

Elderly patients:

Safety and efficacy have not been established in this patient population. No studies have been conducted in adults older than 65 years of age. Since renal clearance decreases with age, Valcyte should be administered to elderly patients with special consideration of their renal status (see table below).

Patients with renal impairment Serum creatinine levels or estimated creatinine clearance should be monitored carefully. 2). 85 × male value Clcr (ml/min) Induction dose of valganciclovir Maintenance/Prevention dose of valganciclovir ≥ 60 900 mg twice daily 900 mg once daily 40 – 59 450 mg twice daily 450 mg once daily 25 – 39 450 mg once daily 225 mg once daily 10 – 24 225 mg once daily 125 mg once daily <10 200 mg three times a week after dialysis 100 mg three times a week after dialysis Patients undergoing haemodialysis: Dosage adjustment is necessary for patients on haemodialysis (Clcr <10ml/min) (see […]

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.

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).

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 (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 Cellulitis Common 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 Common ADR (MedDRA) System Organ Class Frequency Category Neuropathy peripheral Dizziness Paraesthesia Hypoaesthesia Seizure Dysgeusia (taste disturbance) Tremor Uncommon Eye disorders: Visual impairment Retinal detachment** Vitreous floaters Eye pain Conjunctivitis Macular oedema Common Ear and labyrinth disorders: Ear pain Common Deafness Uncommon Cardiac disorders: Arrhythmias 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 tissues disorders: Dermatitis Very common ADR (MedDRA) System Organ Class Frequency Category Night sweats Pruritus Rash Alopecia Common Dry skin Urticaria Uncommon Musculo-skeletal 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 Renal failure Haematuria Uncommon Reproductive system and breast disorders: Infertility male Uncommon General disorders and administration site conditions: Pyrexia Fatigue Very common Pain Chills Malaise Asthenia Common 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. 4). Thrombocytopenia Patients with low baseline platelet counts (< 100,000 /μL) have an increased risk of developing thrombocytopenia. 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% 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 […]

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 Valcyte to patients with known hypersensitivity to aciclovir or penciclovir, (or to their prodrugs, valaciclovir or famciclovir respectively).

Precautions to be taken before handling Owing to the teratogenic character, the Valcyte powder and reconstituted solution should be handled with caution. Inhalation should be avoided. If the powder or solution make direct contact with skin, the area should be washed thoroughly with soap and water.

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

3). Based on clinical and nonclinical studies it is also considered likely that Valcyte causes temporary or permanent inhibition of spermatogenesis. Women of child bearing potential must be advised to use effective contraception during and for at least 30 days after treatment.

3). Valganciclovir has the potential to cause carcinogenicity and reproductive toxicity in the long term. Myelosuppression Severe leukopenia, neutropenia, anaemia, thrombocytopenia, pancytopenia, bone marrow failure and aplastic anaemia have been observed in patients treated with Valcyte (and ganciclovir).

8). 1). Valcyte 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. It is recommended that complete blood counts and platelet counts should be monitored regularly during therapy.

Increased haematological monitoring may be warranted in patients with renal impairment and paediatrics, at a minimum each time the patient attends the transplant clinic. 8). 2). Use with other medicines Seizures have been reported in patients taking imipenem-cilastatin and ganciclovir.

5). g. 5). 1, did not include lung and intestinal transplant patients. Therefore, experience in these transplant patients is limited. 188 mg/ml sodium (essentially ‘sodium-free’). Benzoic acid and benzoates (sodium benzoate) This medicine contains 100mg of sodium benzoate in each 12g bottle, which is equivalent to 1mg/ml after reconstitution.

Increase in bilirubinaemia following its displacement from albumin may increase neonatal jaundice which may develop into kernicterus (non-conjugated bilirubin deposits in the brain tissue).

1. 6).