SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Valcyte 50 mg/ml powder for oral solution.

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each bottle contains 5.5 g valganciclovir hydrochloride per 12 g powder for oral solution.

Each ml of the reconstituted solution contains 50 mg valganciclovir (as hydrochloride).

Excipients with known effect:

This medicinal product contains a total of 0.188 mg/ml sodium.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Powder for oral solution.

The powder is a granulate with a white to slightly yellow colour.

When the powder is dissolved, it forms a clear, colourless to brown solution.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Valcyte is indicated for the induction and maintenance treatment of cytomegalovirus (CMV) retinitis in adult patients with acquired immunodeficiency syndrome (AIDS).

Valcyte is indicated for the prevention of CMV disease in CMV-negative adults and children (aged from birth to 18 years) who have received a solid organ transplant from a CMV-positive donor.

4.2    Posology and method of administration

Posology

Caution - Strict adherence to dosage recommendations is essential to avoid overdose (see sections 4.4 and 4.9).

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

Treatment of cytomegalovirus (CMV) retinitis Adult patients

Induction treatment of CMV retinitis:

For patients with active CMV retinitis, the recommended dose is 900mg valganciclovir twice a day for 21 days. Prolonged induction treatment may increase the risk of bone marrow toxicity (see section 4.4).

Maintenance treatment of CMV retinitis:

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

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 900mg once daily, starting within 10 days post-transplantation and continuing until 100 days post transplantation. Prophylaxis may be continued until 200 days posttransplantation (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 900mg once daily, starting within 10 days posttransplantation 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 (CrCl) derived from Schwartz formula (CrCLS), and is calculated using the equation below:

Paediatric Dose (mg) = 7 x BSA x CrCLS (see Mosteller BSA formula and Schwartz Creatinine Clearance formula below).

If the calculated Schwartz creatinine clearance exceeds 150 mL/min/1.73m , then a maximum value of 150 mL/min/1.73m should be used in the equation:

Mosteller BSA (m2) =\^Heigh‘ ^(cm) xWeighM

V    3600

Schwartz Creatinine Clearance (ml /min/1.73m² )

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. 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.

*For appropriate sub-populations a lowering of k value may also be necessary (e.g. in paediatric patients with low birth weight).

For paediatric kidney transplant patients, the recommended once daily mg dose (7 x BSA x CrCLS) 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 CrCLS) should start within 10 days post-transplantation and continue until 100 days post-transplantation.

All calculated doses should be rounded to the nearest 25mg increment for the actual deliverable dose. If the calculated dose exceeds 900mg, a maximum dose of 900mg 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 405mg and 495mg, one 450mg 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 Patients with renal impairment

Serum creatinine levels or creatinine clearance should be monitored carefully. Dosage adjustment is required according to creatinine clearance, as shown in the Table below (see sections 4.4 and 5.2).

An estimated creatinine clearance (ml/min) can be related to serum creatinine by the following formulae:

For males =    (140 - age [years]) x (body weight [kg])

(72) x (0.011 x serum creatinine [micromol/l])

For females = 0.85 x male value

CrCl (ml/min)	Induction dose of valganciclovir	Maintenance/Prevention dose of valganciclovir
>60	900mg twice daily	900mg once daily
40 - 59	450mg twice daily	450mg once daily
25 - 39	450mg once daily	225mg once daily
10 - 24	225mg once daily	125mg once daily
<10	200mg three times a week after dialysis	100mg three times a week after dialysis

Patients undergoing haemodialysis:

Dosage adjustment is necessary for patients on haemodialysis (CrCl <10ml/min) (see sections 4.4 and 5.2) and a dosing recommendation is given in the Table above.

Patients with hepatic impairment

Safety and efficacy of Valcyte have not been studied in patients with hepatic impairment (see section 5.2).

Paediatric population

Dosing of paediatric SOT patients is individualised based on a patient’s renal function, together with body length and weight.

Elderly patients:

Safety and efficacy of Valcyte have not been established in this patient population.

Patients with severe leucopenia, neutropenia, anaemia, thrombocytopenia and pancytopenia:

See section 4.4 before initiation of therapy.

If there is a significant deterioration of blood cell counts during therapy with Valcyte, treatment with haematopoietic growth factors and/or dose interruption should be considered (see section 4.4).

Method of administration

Valcyte is administered orally, and whenever possible, should be taken with food (see section 5.2).

Precautions to be taken before handling or administering the medicinal product

Valcyte powder for oral solution requires reconstitution prior to oral administration. Two oral dosing dispensers with graduations in 25mg up to 500mg are provided. It is recommended that patients use the dispenser. For instructions on reconstitution of the medicinal product before administration, see sections 4.4 and 6.6.

4.3    Contraindications

Valcyte is contraindicated in patients with hypersensitivity to valganciclovir, ganciclovir or to any of the excipients listed in section 6.1.

Due to the similarity of the chemical structure of valganciclovir (the active substance of Valcyte) and that of aciclovir and valaciclovir, a crosshypersensitivity reaction between these drugs is possible. Therefore, Valcyte is contraindicated in patients with hypersensitivity to aciclovir and valaciclovir. Valcyte is contraindicated during breast-feeding (see section 4.6).

4.4    Special warnings and precautions for use

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. If the solution gets into the eye, the eye should be thoroughly washed with water immediately.

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, aspermatogenic and carcinogenic, and a suppressor of female fertility. Valcyte should, therefore, be considered a potential teratogen and carcinogen in humans with the potential to cause birth defects and cancers (see section 5.3). 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 treatment. Men must be advised to practise barrier contraception during treatment, and for at least 90 days thereafter, unless it is certain that the female partner is not at risk of pregnancy (see sections 4.6, 4.8 and 5.3).

Valganciclovir has the potential to cause carcinogenicity and reproductive toxicity in the long term.

Severe leucopenia, neutropenia, anaemia, thrombocytopenia, pancytopenia, bone marrow depression and aplastic anaemia have been observed in patients treated with Valcyte (and ganciclovir). Therapy should not be initiated if the absolute neutrophil count is less than 500 cells/pl, or the platelet count is less than 25000/pl, or the haemoglobin level is less than 8g/dl (see sections 4.2 and 4.8).

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).

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. In patients developing severe leucopenia, neutropenia, anaemia and/or thrombocytopenia, it is recommended that treatment with haematopoietic growth factors and/or dose interruption be considered (see sections 4.2 and 4.8).

In patients with impaired renal function, dosage adjustments based on creatinine clearance are required (see sections 4.2 and 5.2).

Convulsions have been reported in patients taking imipenem-cilastatin and ganciclovir. Valcyte should not be used concomitantly with imipenem-cilastatin unless the potential benefits outweigh the potential risks (see section

4.5) .

Patients treated with Valcyte and (a) didanosine, (b) drugs that are known to be myelosuppressive (e.g. zidovudine), or (c) substances affecting renal function, should be closely monitored for signs of added toxicity (see section

4.5) .

The controlled clinical study using valganciclovir for the prophylactic treatment of CMV disease in transplantation, as detailed in section 5.1, did not include lung and intestinal transplant patients. Therefore, experience in these transplant patients is limited.

For patients on a sodium-controlled diet, this medicinal product contains a total of 0.188mg/ml sodium.

4.5 Interaction with other medicinal products and other forms of interaction

Drug interactions with valganciclovir

In-vivo drug interaction studies with Valcyte have not been performed. Since valganciclovir is extensively and rapidly metabolised to ganciclovir; drug interactions associated with ganciclovir will be expected for valganciclovir.

Drug interactions with ganciclovir Imipenem-cilastatin

Convulsions have been reported in patients taking ganciclovir and imipenem-cilastatin concomitantly. These drugs should not be used concomitantly unless the potential benefits outweigh the potential risks (see section 4.4).

Probenecid

Probenecid given with oral ganciclovir resulted in statistically significantly decreased renal clearance of ganciclovir (20%) leading to statistically significantly increased exposure (40%). These changes were consistent with a mechanism of interaction involving competition for renal tubular secretion. Therefore, patients taking probenecid and Valcyte should be closely monitored for ganciclovir toxicity.

Trimethoprim

No clinically significant pharmacokinetic interaction was observed when trimethoprim and oral ganciclovir were given in combination. However, there is a potential for toxicity to be enhanced since both drugs are known to be myelosuppressive and therefore both drugs should be used concomitantly only if the potential benefits outweigh the risks.

Mycophenolate Mofetil

Since both mycophenolate mofetil (MMF) and ganciclovir have the potential to cause neutropenia and leucopenia, patients should be monitored for additive toxicity.

Stavudine

No clinically significant interactions were observed when stavudine and oral ganciclovir were given in combination.

Zidovudine

When zidovudine was given in the presence of oral ganciclovir there was a small (17%), but statistically significant increase in the AUC of zidovudine. There was also a trend towards lower ganciclovir concentrations when administered with zidovudine, although this was not statistically significant. However, since both zidovudine and ganciclovir have the potential to cause neutropenia and anaemia, some patients may not tolerate concomitant therapy at full dosage (see section 4.4).

Didanosine

Didanosine plasma concentrations were found to be consistently raised when given with ganciclovir (both intravenous and oral). At ganciclovir oral doses of 3 and 6g/day, an increase in the AUC of didanosine ranging from 84 to 124% has been observed, and likewise at intravenous doses of 5 and 10mg/kg/day, an increase in the AUC of didanosine ranging from 38 to 67% has been observed. There was no clinically significant effect on ganciclovir concentrations. Patients should be closely monitored for didanosine toxicity (see section 4.4).

Other antiretrovirals (including therapy for HIV, HBV/HCV)

At clinically relevant plasma concentrations of ganciclovir and other antivirals for the inhibition of human immunodeficiency virus (HIV) or HBV/HCV, there is unlikely to be a synergistic or antagonistic effect on the activity of either ganciclovir or the other antivirals.

The metabolic interaction potential of valganciclovir or ganciclovir is low due to the lack of cytochrome P450 involvement in the metabolism of either valganciclovir or ganciclovir. In addition, ganciclovir is not a substrate to P-glycoprotein, nor does it affect the UDP-glucuronosyltransferase (UGT enzyme). Therefore metabolic and drug transport interactions of valganciclovir or ganciclovir with the following classes of antivirals are considered unlikely:

•    Non-nucleoside reverse transcriptase inhibitors (NNRTIs), e.g. rilpivirine, etravirine, efavirenz

•    Protease inhibitors (PIs), e.g. darunavir, boceprevir and telaprevir

•    Entry inhibitors (fusion inhibitor and CCR5 co-receptor antagonist), e.g. enfuvirtide and maraviroc

•    HIV integrase strand transfer inhibitor (INSTI), e.g. raltegravir

Since ganciclovir is excreted through the kidney via glomerular filtration and active tubular secretion (section 5.2), coadministration of valganciclovir with antiviral drugs that share the tubular secretion pathway may change the plasma concentrations of valganciclovir and/or the coadministered drug. Some examples include nucleos(t)ide analogue reverse-transcriptase inhibitors (NRTIs) (including those used for HBV therapy), e.g. lamivudine, emtricitabine, tenofovir, adefovir and entecavir. The renal clearance of ganciclovir may also be inhibited due to nephrotoxicity caused by drugs such as cidofovir, foscarnet, NRTIs (e.g. tenofovir, adefovir). Concomitant use of valganciclovir with any of these drugs should be considered only if the potential benefits outweigh the potential risks (see section 4.4).

Other potential drug interactions

Toxicity may be enhanced when valganciclovir is co-administered with, or is given immediately before or after, other drugs that inhibit replication of rapidly dividing cell populations such as occur in the bone marrow, testes and germinal layers of the skin and gastrointestinal mucosa. Examples of these types of drugs are dapsone, pentamidine, flucytosine, vincristine, vinblastine, adriamycin, amphotericin B, trimethoprim/sulpha combinations, nucleoside analogues, hydroxyurea and pegylated interferons/ribavirin (with or without boceprevir or telaprevir).

Concomitant use of valganciclovir with all of these drugs should be considered only if the potential benefits outweigh the potential risks (see section 4.4).

4.6 Fertility, pregnancy and lactation

Contraception in males and females

Women of child-bearing potential must be advised to use effective contraception during treatment. Male patients must be advised to practice barrier contraception during, and for at least 90 days following treatment with Valcyte unless it is certain that the female partner is not at risk of pregnancy (see section 5.3).

Pregnancy

There are no adequate data from the use of Valcyte in pregnant women. Its active metabolite, ganciclovir, readily diffuses across the human placenta. Based on its pharmacological mechanism of action and reproductive toxicity observed in animal studies with ganciclovir (see section 5.3) there is a theoretical risk of teratogenicity in humans.

Valcyte should not be used in pregnancy unless the therapeutic benefit for the mother outweighs the potential risk of teratogenic damage to the child.

Breast-feeding

It is unknown if ganciclovir is excreted in breast milk, but the possibility of ganciclovir being excreted in the breast milk and causing serious adverse reactions in the nursing infant cannot be discounted. Therefore, breast-feeding must be discontinued (see section 4.3).

Fertility

No human data on the effect of valganciclovir on fertility are available. Fertility studies have not been repeated with valganciclovir because of the rapid and extensive conversion of valganciclovir to ganciclovir in the body. Ganciclovir is associated with impaired fertility in animal studies (see section 5.3).

4.7    Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

Convulsions, sedation, dizziness, ataxia, and/or confusion have been reported with the use of Valcyte and/or ganciclovir. If they occur, such effects may affect the patient’s ability to drive and operate machinery.

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 undesirable effects observed with valganciclovir clinical studies have been previously observed with ganciclovir. The most commonly reported adverse drug reactions following administration of valganciclovir in adults are neutropenia, anaemia and diarrhoea.

Valganciclovir is associated with a higher risk of diarrhoea compared to intravenous ganciclovir. In addition, valganciclovir is associated with a higher risk of neutropenia and leucopenia compared to oral ganciclovir.

Severe neutropenia (ANC <500 cells/pl) is seen more frequently in AIDS patients with CMV retinitis undergoing treatment with valganciclovir than in solid organ transplant patients receiving valganciclovir (see section 4.4).

The frequency of adverse reactions reported in clinical trials with either valganciclovir, oral ganciclovir, or intravenous ganciclovir is presented in the Table below. The adverse reactions listed were reported in clinical trials in patients with AIDS for the induction or maintenance treatment of CMV retinitis, or in liver, kidney or heart transplant patients for the prophylaxis of CMV disease. The term (severe) in parenthesis in the Table indicates that the adverse reaction has been reported in patients at both mild/moderate intensity and severe/life-threatening intensity at that specific frequency.

The overall safety profile of Valcyte did not change with the extension of prophylaxis up to 200 days in adult kidney transplant patients at high risk of CMV disease (D+/R-). Leucopenia 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.

b Tabulated list of adverse reactions

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Body System	Very Common (> 1/10)	Common (> 1/100 to < 1/10)	Uncommon (> 1/1000 to < 1/100)	Rare (> 1/10,000 to < 1/1000)
Infections and infestations		Oral candidiasis, sepsis (bacteraemia, viraemia), cellulitis, urinary tract infection
Blood and lymphatic system disorders	(Severe) neutropenia, anaemia	(Severe) anaemia, (severe) thrombocytopeni a, (severe) leucopenia, (severe) pancytopenia	Bone marrow failure	Aplastic anaemia
Immune system disorders			Anaphylactic reaction
Metabolism and nutrition disorders		Decreased appetite, anorexia
Psychiatric disorders		Depression, anxiety, confusion, abnormal thinking	Agitation, psychotic disorder, hallucination
Nervous system disorders		Headache, insomnia, dysgeusia (taste disturbance), hypoaesthesia, paraesthesia, peripheral neuropathy,	Tremor

Body System	Very Common (> 1/10)	Common (> 1/100 to < 1/10)	Uncommon (> 1/1000 to < 1/100)	Rare (> 1/10,000 to < 1/1000)
		dizziness, convulsion
Eye disorders		Macular oedema, retinal detachment, vitreous floaters, eye pain	Visual disturbance, conjunctivitis
Ear and labyrinth disorders		Ear pain	Deafness
Cardiac disorders			Arrhythmia
Vascular disorders			Hypotension
Respiratory, thoracic and mediastinal disorders	Dyspnoea	Cough
Gastrointestinal disorders	Diarrhoea	Nausea, vomiting, abdominal pain, abdominal pain upper, dyspepsia, constipation, flatulence, dysphagia	Abdominal distension, mouth ulceration, pancreatitis
Hepatobiliary disorders		(Severe) hepatic function abnormal, blood alkaline phosphatase increased, aspartate aminotransferase increased	Alanine aminotrans ferase increased
Skin and subcutaneous tissue disorders		Dermatitis, night sweats, pruritus	Alopecia, urticaria, dry skin
Musculoskeletal and connective tissue disorders		Back pain, myalgia, arthralgia, muscle spasms
Renal and urinary disorders		Creatinine renal clearance decreased, renal impairment	Haematuria, renal failure
Reproductive system and breast disorders			Male infertility
General disorders and administration site conditions		Fatigue, pyrexia, chills, pain, chest pain, malaise, asthenia
Investigations		Weight decreased,

Body System	Very Common (> 1/10)	Common (> 1/100 to < 1/10)	Uncommon (> 1/1000 to < 1/100)	Rare (> 1/10,000 to < 1/1000)
		blood creatinine increased

Severe thrombocytopenia may be associated with potentially life-threatening bleeding.

Retinal detachment has only been reported in AIDS patients treated with Valcyte for CMV retinitis.

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, leucopenia and anaemia.

In solid organ transplant patients, the overall safety profile was similar in paediatric patients as compared to adults. However, the rates of certain adverse events, such as upper respiratory tract infection, pyrexia, abdominal pain and dysuria, which may be characteristic of the paediatric population, were reported in higher incidence in paediatrics than in adults. Neutropenia was also 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.

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/pL) 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. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme website: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Overdose experience with valganciclovir

One adult developed fatal bone marrow depression (medullary aplasia) after several days of dosing that was at least 10-fold greater than recommended for the patient's degree of renal impairment (decreased creatinine clearance).

It is expected that an overdose of valganciclovir could also possibly result in increased renal toxicity (see section 4.2 and section 4.4).

Haemodialysis and hydration may be of benefit in reducing blood plasma levels in patients who receive an overdose of valganciclovir (see section 5.2)

Overdose experience with intravenous ganciclovir

Reports of overdoses with intravenous ganciclovir have been received from clinical trials and during post-marketing experience. In some of these cases no adverse events were reported. The majority of patients experienced one or more of the following adverse events:

Haematological toxicity: pancytopenia, bone marrow depression, medullary aplasia, leucopenia, neutropenia, granulocytopenia

-    Hepatotoxicity: hepatitis, liver function disorder

Renal toxicity: worsening of haematuria in a patient with pre-existing renal impairment, acute renal failure, elevated creatinine

-    Gastrointestinal toxicity : abdominal pain, diarrhoea, vomiting

-    Neurotoxicity: generalised tremor, convulsion

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antivirals for systemic use, nucleosides and nucleotides excl. reverse transcriptase inhibitors, ATC code: J05A B14

Mechanism of action

Valganciclovir is an L-valyl ester (prodrug) of ganciclovir. After oral administration, valganciclovir is rapidly and extensively metabolised to ganciclovir by intestinal and hepatic esterases. Ganciclovir is a synthetic analogue of 2’-deoxyguanosine and inhibits replication of herpes viruses in vitro and in vivo. Sensitive human viruses include human cytomegalovirus (HCMV), herpes simplex virus-1 and -2 (HSV-1 and HSV-2), human herpes virus -6, -7 and -8 (HHV-6, HHV-7, HHV-8), Epstein-Barr virus (EBV), varicella-zoster virus (VZV) and hepatitis B virus (HBV).

In CMV-infected cells, ganciclovir is initially phosphorylated to ganciclovir monophosphate by the viral protein kinase, pUL97. Further phosphorylation occurs by cellular kinases to produce ganciclovir triphosphate, which is then slowly metabolised intracellularly. Triphosphate metabolism has been shown to occur in HSV- and HCMV- infected cells with half-lives of 18 and between 6 and 24 hours respectively, after the removal of extracellular ganciclovir. As the phosphorylation is largely dependent on the viral kinase, phosphorylation of ganciclovir occurs preferentially in virus-infected cells.

The virustatic activity of ganciclovir is due to inhibition of viral DNA synthesis by: (a) competitive inhibition of incorporation of deoxyguanosine-triphosphate into DNA by viral DNA polymerase, and (b) incorporation of ganciclovir triphosphate into viral DNA causing termination of, or very limited, further viral DNA elongation.

Antiviral Activity

The in-vitro anti-viral activity, measured as IC₅₀ of ganciclovir against CMV, is in the range of 0.08^M (0.02^,g/ml) to 14^M (3.5^,g/ml).

The clinical antiviral effect of Valcyte has been demonstrated in the treatment of AIDS patients with newly diagnosed CMV retinitis. CMV shedding was decreased in urine from 46% (32/69) of patients at study entry to 7% (4/55) of patients following four weeks of Valcyte treatment.

Clinical efficacy and safety

Adult patients Treatment of CMV retinitis:

Patients with newly diagnosed CMV retinitis were randomised in one study to induction therapy with either Valcyte 900 mg (twice daily) or intravenous ganciclovir

5    mg/kg (twice daily). The proportion of patients with photographic progression of CMV retinitis at week 4 was comparable in both treatment groups, 7/70 and 7/71 patients progressing in the intravenous ganciclovir and valganciclovir arms respectively.

Following induction treatment dosing, all patients in this study received maintenance treatment with Valcyte given at the dose of 900 mg once daily. The mean (median) time from randomisation to progression of CMV retinitis in the group receiving induction and maintenance treatment with Valcyte was 226 (160) days and in the group receiving induction treatment with intravenous ganciclovir and maintenance treatment with Valcyte was 219 (125) days.

Prevention of CMV disease in transplantation

A double-blind, double-dummy clinical active comparator study has been conducted in heart, liver and kidney transplant patients (lung and gastro-intestinal transplant patients were not included in the study) at high-risk of CMV disease (D+/R-) who received either Valcyte (900 mg once daily) or oral ganciclovir (1000 mg three times daily) starting within 10 days of transplantation until Day 100 post-transplant. The incidence of CMV disease (CMV syndrome + tissue invasive disease) during the first

6    months post-transplant was 12.1% in the Valcyte arm (n=239) compared with 15.2% in the oral ganciclovir arm (n=125). The large majority of cases occurred following cessation of prophylaxis (post-Day 100) with cases in the valganciclovir arm occurring on average later than those in the oral ganciclovir arm. The incidence of acute rejection in the first 6 months was 29.7% in patients randomised to valganciclovir compared with 36.0% in the oral ganciclovir arm, with the incidence of graft loss being equivalent, occurring in 0.8% of patients, in each arm.

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____

	Valganciclovir 900 mg od 100 Days N = 163	Valganciclovir 900 mg od 200 Days N = 155	Between Treatment Group Difference
Patients with confirmed or assumed CMV disease2	71 (43.6%) [35.8% ; 51.5%]	36 (23.2%) [16.8% ; 30.7%]	20.3% [9.9% ; 30.8%]
Patients with confirmed CMV disease	60 (36.8%) [29.4% ; 44.7%]	25 (16.1%) [10.7% ; 22.9%]	20.7% [10.9% ; 30.4%]

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 no week 52 assessment and 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 98.2% (160/163) for the 100 day dosing regimen and 98.1% (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.

Viral Resistance

Virus resistant to ganciclovir can arise after chronic dosing with valganciclovir by selection of mutations in the viral kinase gene (UL97) responsible for ganciclovir monophosphorylation and/or the viral polymerase gene (UL54). In clinical isolates, seven canonical UL97 substitutions, M460V/I, H520Q, C592G, A594V, L595S, C603W are the most frequently reported ganciclovir resistance-associated substitutions. Viruses containing mutations in the UL97 gene are resistant to ganciclovir alone, whereas viruses with mutations in the UL54 gene are resistant to ganciclovir but may show cross-resistance to other antivirals that also target the viral polymerase.

Treatment of CMV retinitis:

Genotypic analysis of CMV in polymorphonuclear leucocytes (PMNL) isolates from 148 patients with CMV retinitis enrolled in one clinical study has shown that 2.2%, 6.5%, 12.8%, and 15.3% contain UL97 mutations after 3, 6, 12 and 18 months, respectively, of valganciclovir treatment.

Prevention of CMV disease in transplantation:

Active comparator study

Resistance was studied by genotypic analysis of CMV in PMNL samples collected i) on Day 100 (end of study drug prophylaxis) and ii) in cases of suspected CMV disease up to 6 months after transplantation. From the 245 patients randomised to receive valganciclovir, 198 Day 100 samples were available for testing and no ganciclovir resistance mutations were observed. This compares with 2 ganciclovir resistance mutations detected in the 103 samples tested (1.9%) for patients in the oral ganciclovir comparator arm.

Of the 245 patients randomised to receive valganciclovir, samples from 50 patients with suspected CMV disease were tested and no resistance mutations were observed. Of the 127 patients randomised on the ganciclovir comparator arm, samples from 29 patients with suspected CMV disease were tested, from which two resistance mutations were observed, giving an incidence of resistance of 6.9%.

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.

Paediatric population

Treatment of CMV retinitis:

The European Medicines Agency has waived the obligation to perform studies with Valcyte in all subsets of the paediatric population in the treatment of infection due to CMV in immuno-compromised patients (see section 4.2 for information on paediatric use).

Prevention of CMV disease in transplantation

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 the paediatric dosing algorithm (see section 4.2) 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 section 4.8).

A phase IV tolerability study in paediatric kidney transplant recipients (aged 1 to 16 years, n=57) receiving valganciclovir once daily for up to 200 days according to the dosing algorithm (see section 4.2) resulted in a low incidence of CMV. Follow up after treatment was 24 weeks. CMV D/R serology status at baseline was D+/R+ in 45%, D+/R- in 39%,

D-/R+ in 7%, D-/R- in 7% and ND/R+ in 2% of the cases. CMV viremia was reported in 3 patients and a case of CMV syndrome was suspected in one patient but not confirmed by CMV PCR by the central laboratory. The observed adverse drug reactions were of similar nature to those in adults (see section 4.8).

These data support the extrapolation of efficacy data from adults to children and provide posology recommendations for paediatric patients.

A phase I pharmacokinetic and safety study in heart transplant patients (aged 3 weeks to 125 days, n=14) who received a single daily dose of valganciclovir according to the paediatric dosing algorithm (see section 4.2) on 2 consecutive days produced exposures similar to those in adults (see section 5.2). Follow up after treatment was 7 days. The safety profile was consistent with other paediatric and adult studies, although patient numbers and valganciclovir exposure were limited in this study.

Congenital CMV

The efficacy and safety of ganciclovir and/or valganciclovir was studied in neonates and infants with congenital symptomatic CMV infection in two studies.

In the first study, the pharmacokinetics and safety of a single dose of valganciclovir (dose range 14-16-20 mg/kg/dose) was studied in 24 neonates (aged 8 to 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 most of the study period. In the second study the efficacy and safety of six weeks versus six months of valganciclovir treatment was studied in 109 infants aged 2- to 30 days with symptomatic congenital CMV disease. All infants received oral valganciclovir at a dose of 16 mg/kg b.i.d. for 6 weeks. After 6 weeks of treatment the infants were randomized 1:1 to continue treatment with valganciclovir at the same dose or receive a matched placebo to complete 6 months of treatment.

This treatment indication is not currently recommended for valganciclovir. The design of the studies and results obtained are too limited to allow appropriate efficacy and safety conclusions on valganciclovir.

5.2 Pharmacokinetic properties

The pharmacokinetic properties of valganciclovir have been evaluated in HIV- and CMV-seropositive patients, patients with AIDS and CMV retinitis and in solid organ transplant patients.

Absorption

Valganciclovir is a prodrug of ganciclovir. It is well absorbed from the gastrointestinal tract and rapidly and extensively metabolised in the intestinal wall and liver to ganciclovir. Systemic exposure to valganciclovir is transient and low. The bioavailability of ganciclovir from oral dosing of valganciclovir is approximately 60% across all the patient populations studied and the resultant exposure to ganciclovir is similar to that after its intravenous administration (please see below).

Valganciclovir in HIV positive, CMV positive patients:

Systemic exposure of HIV positive, CMV positive patients after twice daily administration of ganciclovir and valganciclovir for one week is:

Parameter	Ganciclovir (5 mg/kg, IV) n = 18	Valganciclovir (900 mg, p.o.) n = 25
		Ganciclovir	Valganciclovir
AUC(0 - 12 h) (gg.h/ml)	28.6 ± 9.0	32.8 ± 10.1	0.37 ± 0.22
Cmax (M-g/ml)	10.4 ± 4.9	6.7 ± 2.1	0.18 ± 0.06

The efficacy of ganciclovir in increasing the time-to-progression of CMV retinitis has been shown to correlate with systemic exposure (AUC).

Valganciclovir in solid organ transplant patients:

Steady state systemic exposure of solid organ transplant patients to ganciclovir after daily oral administration of ganciclovir and valganciclovir is:

Parameter	Ganciclovir	Valganciclovir (900 mg, once daily)
	(1000 mg three times	n = 161
	daily) n = 82	Ganciclovir
AUC(0 - 24 h) (Mg.h/ml)	28.0 ± 10.9	46.3 ± 15.2
Cmax (Mg/ml)	1.4 ± 0.5	5.3 ± 1.5

The systemic exposure of ganciclovir to heart, kidney and liver transplant recipients was similar after oral administration of valganciclovir according to the renal function dosing algorithm.

Following the administration of valganciclovir as an oral solution, equivalent systemic ganciclovir exposures were obtained compared to the tablet formulation.

Food effect:

Dose proportionality with respect to ganciclovir AUC following administration of valganciclovir in the dose range 450 to 2625 mg was demonstrated only under fed conditions. When valganciclovir was given with food at the recommended dose of 900 mg, higher values were seen in both mean ganciclovir AUC (approximately 30%) and mean ganciclovir C_max values (approximately 14%) than in the fasting state.

Also, the inter-individual variation in exposure of ganciclovir decreases when taking Valcyte with food. Valcyte has only been administered with food in clinical studies. Therefore, it is recommended that Valcyte be administered with food (see section 4.2).

Distribution:

Because of rapid conversion of valganciclovir to ganciclovir, protein binding of valganciclovir was not determined. Plasma protein binding of ganciclovir was 1 - 2% over concentrations of 0.5 and 51p,g/ml. The steady state volume of distribution (V_d) of ganciclovir after intravenous administration was 0.680 ± 0.161 l/kg (n=114).

Biotransformation

Valganciclovir is rapidly and extensively metabolised to ganciclovir; no other metabolites have been detected. No metabolite of orally administered radiolabelled ganciclovir (1000 mg single dose) accounted for more than 1 - 2% of the radioactivity recovered in the faeces or urine.

Elimination

Following dosing with Valcyte, renal excretion, as ganciclovir, by glomerular filtration and active tubular secretion is the major route of elimination of valganciclovir. Renal clearance accounts for 81.5% ± 22% (n=70) of the systemic clearance of ganciclovir. Post-hoc Bayesian estimates for population mean apparent clearance of ganciclovir in patients with CrCl > 60 ml/min is 14.05 ± 4.13 l/h. In patients with renal impairment, the mean apparent clearance of ganciclovir is 8.46 ± 1.67 l/h (CrCl between 40 and 60 ml/min) and 7.00 ± 1.08 l/h (CrCl between 25 and 40 ml/min).

The half-life of ganciclovir from valganciclovir is 4.1 ± 0.9 hours in HIV- and CMV-seropositive patients.

Pharmacokinetics in special clinical situations Patients with renal impairment

Decreasing renal function resulted in decreased clearance of ganciclovir from valganciclovir with a corresponding increase in terminal half-life. Therefore, dosage adjustment is required for renally impaired patients (see section 4.2 and 4.4).

Patients undergoing haemodialysis

For patients receiving haemodialysis Valcyte powder for oral solution is recommended to provide an individualised dose (see sections 4.2 and 4.4).

Patients with hepatic impairment

The safety and efficacy of Valcyte have not been studied in patients with hepatic impairment. Hepatic impairment should not significantly affect the pharmacokinetics of ganciclovir since it is excreted renally and, therefore, no specific dose recommendation is made.

Patients with cystic fibrosis

In a phase I pharmacokinetic study in lung transplant recipients with or without cystic fibrosis (CF), 31 patients (16 CF/15 non-CF) received post-transplant prophylaxis with 900 mg/day Valcyte. The study indicated that cystic fibrosis had no statistically

significant influence on the overall average systemic exposure to ganciclovir in lung transplant recipients. Ganciclovir exposure in lung transplant recipients was comparable to that shown to be efficacious in the prevention of CMV disease in other solid organ transplant recipients.

Paediatric population

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. Pharmacokinetic 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.

In a phase I pharmacokinetic and safety study in paediatric heart transplant recipients (aged 3 weeks to 125 days, n = 14), valganciclovir was given once daily for two study days. Population pharmacokinetics estimated that mean bioavailability was 64%.

A comparison of the results from these two studies and the pharmacokinetic results from the adult population shows that ranges of AUC _0-24h were very similar across all age groups, including adults. Mean values for AUC_0-24h and C_max were also similar across the paediatric age groups < 12 years old, although there was a trend of decreasing mean values for AUC_0-24h and C_max across the entire pediatric age range, which appeared to correlate with increasing age. This trend was more apparent for mean values of clearance and half-life (t_1/2); however this is to be expected as clearance is influenced by changes in weight, height and renal function associated with patient growth, as indicated by population pharmacokinetic modelling.

The following table summarizes the model-estimated AUC_0-24h ranges for ganciclovir from these two studies, as well as mean and standard deviation values for AUC_0-24h, C_max, CL and t ^ for the relevant paediatric age groups compared to adult data:

PK Parameter	Adults*	Paediatrics
	> 18 years	< 4 months	4 months - < 2 years	> 2 - < 12 years	> 12 years - 16 years
	(n=160)	(n = 14)	(n=17)	(n=21)	(n=25)
AUCo_24h (Pg'h/ml)	46.3 ± 15.2	68.1 ± 19.8	64.3 ± 29.2	59.2 ± 15.1	50.3 ± 15.0
Range of AUCo_24h	15.4 -116.1	34 - 124	34 - 152	36 - 108	22 - 93
Cmax (P-g/ml)	5.3 ± 1.5	10.5 ± 3.36	10.3 ± 3.3	9.4 ± 2.7	8.0 ± 2.4
Clearance (l/h)	12.7 ± 4.5	1.25 ± 0.473	2.5 ± 2.4	4.5 ± 2.9	6.4 ± 2.9
t1/2 (h)	6.5 ± 1.4	1.97 ± 0.185	3.1 ±1.4	4.1 ± 1.3	5.5 ± 1.1

* Extracted from study report PV 16000

The once daily dose of Valcyte in both of the studies described above was based on body surface area (BSA) and creatinine clearance (CrCl) derived from a modified Schwartz formula, and was calculated using the dosing algorithm presented in section 4.2.

Ganciclovir pharmacokinetics following valganciclovir administration were also evaluated in two studies in neonates and infants with symptomatic congenital CMV disease. In the first study 24 neonates aged 8 to 34 days 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; total treatment duration was 6 weeks. 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.

In the second study, 109 neonates aged 2 to 30 days received 16 mg/kg valganciclovir powder for oral solution twice daily for 6 weeks and subsequently 96 out of 109 enrolled patients were randomized to continue receiving valganciclovir or placebo for 6 months. However, the mean AUC_0-12h was lower compared to the mean AUC_0-12h values from the first study. The following table shows the mean values of AUC, C_max, and t/₂ including standard deviations compared with adult data:

PK Parameter	Adults	Paediatrics (neonates and infants)
	5 mg/kg GAN Single dose (n=8)	6 mg/kg GAN Twice daily (n=19)	16 mg/kg VAL Twice daily (n=19)	16 mg/kg VAL Twice daily (n = 100)
AUCo-cc C^gh/mL)	25.4 ± 4.32	-	-	-
AUCo_i2h (^gh/mL)	-	38.2 ± 42.7	30.1 ± 15.1	20.85 ± 5.40
Cmax (P-g/ml)	9.03 ± 1.26	12.9 ± 21.5	5.44 ± 4. 04	-
t1/2 (h)	3.32 ± 0.47	2.52 ± 0. 55	2.98 ± 1. 26	2.98 ± 1.12

GAN = Ganciclovir, i.v.

VAL = Valganciclovir, oral

These data are too limited to allow conclusions regarding efficacy or posology recommendations for paediatric patients with congenital CMV infection.

5.3 Preclinical safety data

Valganciclovir is a pro-drug of ganciclovir and therefore effects observed with ganciclovir apply equally to valganciclovir. Toxicity of valganciclovir in preclinical safety studies was the same as that seen with ganciclovir and was induced at ganciclovir exposure levels comparable to, or lower than, those in humans given the induction dose.

These findings were gonadotoxicity (testicular cell loss) and nephrotoxicity (uraemia, cell degeneration), which were irreversible; myelotoxicity (anaemia, neutropenia, lymphocytopenia) and gastrointestinal toxicity (mucosal cell necrosis), which were reversible.

Further studies have shown ganciclovir to be mutagenic, carcinogenic, teratogenic, embryotoxic, aspermatogenic (i.e. impairs male fertility) and to suppress female fertility.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

povidone

fumaric acid

sodium benzoate (E211)

sodium saccharin

mannitol

Tutti-frutti flavour: maltodextrins (maize) propylene glycol

arabic gum E414 and natural flavouring substances mainly consisting of banana, pineapple and peach flavour

6.2    Incompatibilities

Not applicable

6.3    Shelf life

Powder for oral solution: 3 years.

Reconstituted solution: 49 days. Store in a refrigerator (2°C - 8°C).

6.4    Special precautions for storage

This medicinal product does not require any special storage condition.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

6.5    Nature and contents of container

Carton containing a 100ml amber glass bottle with a child-resistant polypropylene screw cap with a polyethylene liner, a low density polyethylene bottle adapter and a plastic bag containing 2 polypropylene oral dispensers graduated to 500mg with graduations of 25mg.

Each bottle contains 12g of powder for oral solution. When reconstituted, the volume of the solution is 100ml, providing a minimal usable volume of 88ml.

Pack size: one bottle containing 12g powder.

Special precautions for disposal

Since Valcyte is considered a potential teratogen and carcinogen in humans, caution should be observed in handling the powder and the reconstituted solution (see section 4.4). Avoid inhalation and direct contact of the powder and solution with skin and mucous membranes. If such contact occurs, wash thoroughly with soap and water. If the powder or solution gets into the eyes, rinse eyes thoroughly with water.

It is recommended that Valcyte powder for oral solution be reconstituted by the pharmacist prior to dispensing to the patient.

Preparation of oral solution

1.    Measure 91 ml of water in a graduated cylinder.

2.    Remove the child resistant cap, add the water to the bottle, then close the bottle with the child resistant cap. Shake the closed bottle until the powder is dissolved forming a clear, colourless to brown solution.

3.    Remove the child resistant cap and push the bottle adapter into the neck of the bottle.

4.    Close the bottle with the child resistant cap tightly. This will assure the proper seating of the bottle adapter in the bottle and child resistant status of the cap.

5.    Write the date of expiration of the reconstituted solution on the bottle label (see section 6.3).

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7    MARKETING AUTHORISATION HOLDER

Roche Products Limited 6 Falcon Way Shire Park

Welwyn Garden City AL7 1TW United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 00031/0829

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

09/09/2008 / 17/01/2013

11/03/2015