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 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. 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 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. Prophylaxis may be continued until 200 days post-transplantation (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 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).

If the calculated Schwartz creatinine clearance exceeds 150 mL/min/1.73m2, then a maximum value of 150 mL/min/1.73m2 should be used in the equation:

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 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. A 50 mg dose is equivalent to 1 ml:

valganciclovir dose

Valcyte for Oral Solution to be administered

50 mg

1 ml

75 mg

1.5 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 solid organ transplant 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. 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 females = 0.85 × 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

Dosage for patients with renal impairment:

valganciclovir dose

Valcyte for Oral Solution to be administered

125 mg

2.5 ml

225 mg

4.5 ml

450 mg

9 ml

Patients undergoing haemodialysis:

Dosage adjustment is necessary for patients on haemodialysis (Clcr <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 established in patients with hepatic impairment (see section 5.2).

Patients with severe leukopenia, 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 that are graduated to 10 ml (500 mg), with 0.5 ml (25 mg) graduations are provided. It is recommended that patients use the dispenser. The maximum duration of use for one dispenser is specified for 20 applications. 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.

Valcyte is contraindicated during breast-feeding (see section 4.6).

4.4. Special warnings and precautions for use

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. If the solution gets into the eye, the eye should be thoroughly washed with water immediately (see section 6.6).

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. 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). 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. 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.

Myelosuppression

Severe leukopenia, neutropenia, anaemia, thrombocytopenia, pancytopenia, bone marrow failure 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/μl, or the platelet count is less than 25000/μl, 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 leukopenia 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 leukopenia, 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).

Renal impairment

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

Use with other medicines

Seizures 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.

Controlled diet

For patients on a sodium-controlled diet, this medicinal product contains a total of 0.188 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. Benzoate salt may increase jaundice (yellowing of the skin and eyes) in newborn babies (up to 4 weeks old). 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).

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

Pharmacokinetic interactions

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 valganciclovir should be closely monitored for ganciclovir toxicity.

Didanosine

Didanosine plasma concentrations were found to be consistently raised when given with IV ganciclovir. At intravenous doses of 5 and 10 mg/kg/day, an increase in the AUC of didanosine ranging from 38 to 67% has been observed, confirming a pharmacokinetic interaction during the concomitant administration of these drugs. There was no significant effect on ganciclovir concentrations. Patients should be closely monitored for didanosine toxicity e.g pancreatitis (see section 4.4)

Other antiretrovirals

Cytochrome P450 isoenzymes play no role in ganciclovir pharmacokinetics. As a consequence, pharmacokinetic interactions with protease inhibitors and non‑nucleoside reverse transcriptase inhibitors are not anticipated.

Pharmacodynamic interactions

Imipenem-cilastatin

Seizures have been reported in patients taking ganciclovir and imipenem-cilastatin concomitantly and a pharmacodynamic interaction between these two drugs cannot be discounted. These drugs should not be used concomitantly unless the potential benefits outweigh the potential risks (see section 4.4).

Zidovudine

Both zidovudine and ganciclovir have the potential to cause neutropenia and anaemia. A pharmacodynamic interaction may occur during concomitant administration of these drugs. Some patients may not tolerate concomitant therapy at full dosage (see section 4.4).

Potential drug interactions

Toxicity may be enhanced when ganciclovir/valganciclovir is co-administered with other drugs known to be myelosuppressive or associated with renal impairment. This includes nucleoside (e.g. zidovudine, didanosine, stavudine) and nucleotide analogues (e.g. tenofovir, adefovir), immunosuppressants (e.g. ciclosporin, tacrolimus, mycophenolate mofetil), antineoplastic agents (e.g. doxorubicin, vinblastine, vincristine, hydroxyurea) and anti-infective agents (trimethoprim/sulphonamides, dapsone, amphotericin B, flucytosine, pentamidine). Therefore, these drugs should only be considered for concomitant use with valganciclovir if the potential benefits outweigh the potential risks (see section 4.4).

4.6. Fertility, pregnancy and lactation

Contraception in males and females

As a result of the potential for reproductive toxicity and teratogenicity, women of childbearing potential must be advised to use effective contraception during and for at least 30 days after treatment. Male patients must be advised to practice barrier contraception during and for at least 90 days following treatment with valganciclovir unless it is certain that the female partner is not at risk of pregnancy (see sections 4.4 and 5.3).

Pregnancy

The safety of Valcyte for use in pregnant women has not been established. 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 foetus.

Breast-feeding

It is unknown if ganciclovir is excreted in human 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. Animal data indicate that ganciclovir is excreted in the milk of lactating rats Therefore, breast-feeding must be discontinued during treatment with valganciclovir (see sections 4.3 and 5.3).

Fertility

A small clinical study with renal transplant patients receiving Valcyte for CMV prophylaxis for up to 200 days demonstrated an impact of valganciclovir on spermatogenesis, with decreased sperm density and motility measured after treatment completion. This effect appears to be reversible and approximately six months after Valcyte discontinuation, mean sperm density and motility recovered to levels comparable to those observed in the untreated controls.

In animal studies, ganciclovir impaired fertility in male and female mice and has shown to inhibit spermatogenesis and induce testicular atrophy in mice, rats and dogs at doses considered clinically relevant.

Based on clinical and nonclinical studies, it is considered likely that ganciclovir (and valganciclovir) may cause temporary or permanent inhibition of human spermatogenesis (see sections 4.4 and 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.

Adverse reactions such as seizures, dizziness and 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 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).

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.

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

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

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 /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 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% 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. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Overdose experience with valganciclovir and intravenous ganciclovir

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

Reports of overdoses with intravenous ganciclovir, some with fatal outcomes, 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: myelosuppression including pancytopenia, bone marrow failure, leukopenia, neutropenia, granulocytopenia.

– Hepatotoxicity: hepatitis, liver function disorder

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

– Gastrointestinal toxicity: abdominal pain, diarrhoea, vomiting

– Neurotoxicity: generalised tremor, seizure

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