Valcyte 450 mg Film-coated Tablets *

Pharmacy Only: Prescription

NL/H/0323/001-002/P/003 - Valcyte FCT and POS. The changes  in this notification were:
1. Roche no longer holds a Marketing Authorisation for Valcyte film-coated tablets (FCT) in Malta, Romania and Slovak Republic therefore references to these countries were removed from the FCT patient information leaflet.2. Roche no longer holds a Marketing Authorisation for Valcyte powder for oral solution (POS) in Bulgaria, Malta, Romania and Slovak Republic therefore  references to these countries were removed from the POS patient information leaflet. 

MAH Transfer from RPL to Roche Products (Ireland) Limited issue of new PA licence number(s).

Updated safety information

4.2     Posology and method of administration

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Maintenance treatment of CMV retinitis:

Following induction treatment, or in patients with inactive CMV retinitis, the recommended dose is 900mg valganciclovir (two Valcyte 450 mg tablets) once daily and, whenever possible, taken with food. 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.

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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). (See section 5.2)

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).

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Patients undergoing haemodialysis:

For patients on haemodialysis (ClcrCrCl < 10 ml/min) a dose recommendation cannot be given.  Thus Valcyte film-coated tablets should not be used in these patients (see sections 4.4 and 5.2).

Patients with hepatic impairment:

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

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

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4.3     Contraindications

Valcyte is contra-indicated 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 cross-hypersensitivity reaction between these drugs is possible. Therefore, Valcyte is contra-indicated in patients with hypersensitivity to aciclovir and valaciclovir.

Valcyte is contra-indicated 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).  

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, 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 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).

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Myelosuppression

Severe leucopenialeukopenia, neutropenia, anaemia, thrombocytopenia, pancytopenia, bone marrow failuredepression 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/ml, or the platelet count is less than 25000/ml, or the haemoglobin level is less than 8 g/dl (see sections 4.2 and 4.8).

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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 leucopenialeukopenia, neutropenia, anaemia and/or thrombocytopenia, it is recommended that treatment with haematopoietic growth factors and/or dose interruption be considered (see section 4.2).

Difference in bioavailability with oral ganciclovir

The bioavailability of ganciclovir after a single dose of 900 mg valganciclovir is approximately 60 %, compared with approximately 6 % after administration of 1000 mg oral ganciclovir (as capsules). Excessive exposure to ganciclovir may be associated with life-threatening adverse reactions.  Therefore, careful adherence to the dose recommendations is advised when instituting therapy, when switching from induction to maintenance therapy and in patients who may switch from oral ganciclovir to valganciclovir as Valcyte cannot be substituted for ganciclovir capsules on a one-to-one basis.  Patients switching from ganciclovir capsules should be advised of the risk of overdosage if they take more than the prescribed number of Valcyte tablets (see sections 4.2 and 4.9).

Renal impairment

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

Valcyte film-coated tablets should not be used in patients on haemodialysis (see sections 4.2 and 5.2).

Use with other medicines

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).

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4.5     Interaction with other medicinal products and other forms of interaction

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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

Convulsions 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).

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 6 g/day, an increase in the AUC of didanosine ranging from 84 to 124 % has been observed, and likewise 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. 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 analog 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 least 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). 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 There are no data from the use of Valcyte 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 foetuschild.

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).

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4.7     Effects on ability to drive and use machines

No studies on the effects on 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 tasks requiring alertness, including 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 reactionsundesirable effects observed with 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 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/ml) 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 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.

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 drug reactions

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

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.

*The frequencies of these adverse reactions are derived from post-marketing experience

**Retinal detachment has only been reported in AIDS 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 /mL) 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

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The most frequently reported adverse reactions on treatment in paediatric clinical trials were diarrhoea, nausea, neutropenia, leucopenialeukopenia 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.

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4.9     Overdose

Overdose experience with vValganciclovir and intravenous ganciclovir

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 sections 4.2 and 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, 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 depression, medullary aplasia, leucopenialeukopenia, 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.

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

5.2     Pharmacokinetic properties

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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.

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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 51 mg/ml. The steady state volume of distribution (V_d) of ganciclovir after intravenous administration was 0.680 ± 0.161 l/kg (n=114). For IV ganciclovir, the volume of distribution is correlated with body weight with values for the steady state volume of distribution ranging from 0.54-0.87 L/kg.   Ganciclovir penetrates the cerebrospinal fluid. Binding to plasma proteins was 1%-2% over ganciclovir concentrations of 0.5 and 51 µg/mL.

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.Ganciclovir itself is not metabolised to a significant extent.

Elimination

Following dosing with oral valganciclovir, the drug is rapidly hydrolysed to ganciclovir. Ganciclovir is eliminated from the systemic circulationValcyte, 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. In patients with normal renal function greater than 90% of IV administered ganciclovir was recovered un-metabolized in the urine within 24 hours. In patients with normal renal function the post-peak plasma concentrations of ganciclovir after administration of valganciclovir decline with a half-life ranging from 0.4 h to 2.0 h.

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 sections 4.2 and 4.4).

Patients undergoing haemodialysis

For patients receiving haemodialysis dose recommendations for Valcyte 450 mg film-coated tablets cannot be given.  This is because an individual dose of Valcyte required for these patients is less than the 450 mg tablet strength. Thus, Valcyte film-coated tablets should not be used in these patients (see sections 4.2 and 4.4).

Patients with hepatic impairment

The safety and efficacy of Valcyte film-coated tablets have not been studied in patients with hepatic impairment. Hepatic impairment should not 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.

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Elderly

No investigations on valganciclovir or ganciclovir pharmacokinetics in adults older than 65 years of age have been undertaken (see section 4.2).

Patients with renal impairment

The pharmacokinetics of ganciclovir from a single oral dose of 900 mg valganciclovir was evaluated in 24 otherwise healthy individuals with renal impairment.

Pharmacokinetic parameters of ganciclovir from a single oral dose of 900 mg Valcyte tablets in patients with various degrees of 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 sections 4.2 and 4.4).

Patients undergoing haemodialysis

For patients receiving haemodialysis dose recommendations for Valcyte 450 mg film-coated tablets cannot be given.  This is because an individual dose of Valcyte required for these patients is less than the 450 mg tablet strength. Thus, Valcyte film-coated tablets should not be used in these patients (see sections 4.2 and 4.4).

Stable liver transplant patients

The pharmacokinetics of ganciclovir from valganciclovir in stable liver transplant patients were investigated in one open label 4-part crossover study (N=28). The bioavailability of ganciclovir from valganciclovir, following a single dose of 900 mg valganciclovir under fed conditions, was approximately 60%. Ganciclovir AUC_0-24h was comparable to that achieved by 5 mg/kg intravenous ganciclovir in liver transplant patients.

Patients with hepatic impairment

The safety and efficacy of Valcyte film-coated tablets have not been studied in patients with hepatic impairment. Hepatic impairment should not 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.

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 pre-clinical 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.Ganciclovir was mutagenic in mouse lymphoma cells and clastogenic in mammalian cells. Such results are consistent with the positive mouse carcinogenicity study with ganciclovir. Ganciclovir is a potential carcinogen.

Ganciclovir causes impaired fertility and teratogenicity in animals. Based upon animal studies where aspermatogenesis was induced at ganciclovir systemic exposures below therapeutic levels, it is considered likely that ganciclovir causes inhibition of human spermatogenesis.

Animal data indicate that ganciclovir is excreted in the milk of lactating rats.

9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 13 September 2002/

Date of latest renewal: 20 September 2006

10.     DATE OF REVISION OF THE TEXT

09 October 2017

Detailed information on this medicinal product is available on the Health Products Regulatory Agency (HPRA) website: http://www.hpra.ie.

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 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).

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).

5.1     Pharmacodynamic properties

[…]

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.

[…]

5.2     Pharmacokinetic properties

[…]

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 absolute 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). For comparison, the bioavailability of ganciclovir after administration of 1000 mg oral ganciclovir (as capsules) is 6 ‑ 8 %. 

[…]

10.     DATE OF REVISION OF THE TEXT

20 June 201411 March 2015

Underlined text = new text

Strike through text = deleted text

2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 496.3 mg of valganciclovir hydrochloride equivalent to 450 mg of valganciclovir (as free base).

For the full list of excipients, see section 6.1.

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 patients 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 b.i.d. is therapeutically equivalent to intravenous ganciclovir 5 mg/kg b.i.d.

Treatment of cytomegalovirus (CMV) retinitisStandard dosage in adults

Adult patients

Induction treatment of CMV retinitis:

For patients with active CMV retinitis, the recommended dose is 900 mg valganciclovir (two Valcyte 450 mg tablets) twice a day for 21 days and, whenever possible, taken with food.  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 (two Valcyte 450 mg tablets) once daily and, whenever possible, taken with food. 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 900 mg (two Valcyte 450 mg tablets) once daily, starting within 10 days of 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 (two Valcyte 450 mg tablets) once daily, starting within 10 days of post-transplantation and continuing until 100 days post‑transplantation.

Whenever possible, the tablets should be taken with food.

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/1.73m², 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 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 25 mg increment for the actual deliverable dose. If the calculated dose exceeds 900 mg, a maximum dose of 900 mg 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.

[ … ]

Paediatric population:

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

The safety and efficacy of Valcyte in paediatric patients have not been established in adequate and well-controlled clinical studies. Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendation on a posology can be made.

[ … ]

Method of administration

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

For paediatric patients who are unable to swallow Valcyte film-coated tablets, Valcyte powder for oral solution can be administered.

[ … ]

4.3     Contraindications

Valcyte is contra-indicated 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 cross-hypersensitivity reaction between these drugs is possible. Therefore, Valcyte is contra-indicated in patients with hypersensitivity to aciclovir and valaciclovir.

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

4.4     Special warnings and precautions for use

[ … ]

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 section 4.2).

[ … ]

4.5     Interaction with other medicinal products and other forms of interaction

[ … ]

Effects of other medicinal products onDrug 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).

[ … ]

.

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.

Effects of ganciclovir on other medicinal products

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 6 g/day, an increase in the AUC of didanosine ranging from 84 to 124 % has been observed, and likewise 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. There was no clinically significant effect on ganciclovir concentrations. Patients should be closely monitored for didanosine toxicity (see section 4.4).

Mycophenolate Mofetil

Based on the results of a single dose administration study of recommended doses of oral mycophenolate mofetil (MMF) and intravenous ganciclovir and the known effects of renal impairment on the pharmacokinetics of MMF and ganciclovir, it is anticipated that co-administration of these agents (which have the potential to compete for renal tubular secretion) will result in increases in phenolic glucuronide of mycophenolic acid (MPAG) and ganciclovir concentration. No substantial alteration of mycophenolic acid (MPA) pharmacokinetics is anticipated and MMF dose adjustment is not required. In patients with renal impairment to whom MMF and ganciclovir are co-administered, the dose recommendation of ganciclovir should be observed and the patients monitored carefully.  Since both mycophenolate mofetil (MMF) and ganciclovir have the potential to cause neutropenia and leucopenia, patients should be monitored for additive toxicity.

Zalcitabine

No clinically significant pharmacokinetic changes were observed after concomitant administration of ganciclovir and zalcitabine.  Both valganciclovir and zalcitabine have the potential to cause peripheral neuropathy and patients should be monitored for such events.

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 6 g/day, an increase in the AUC of didanosine ranging from 84 to 124 % has been observed, and likewise 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. There was no clinically significant effect on ganciclovir concentrations. Patients should be closely monitored for didanosine toxicity (see section 4.4).

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.

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

At clinically relevant plasma concentrations of ganciclovir and other antivirals for, there is unlikely to be either a synergistic or antagonistic effect on the inhibition of either human immunodeficiency virus  (HIV) or HBV/HCV, there is unlikely to be a synergistic or antagonistic effect on the activity of either in the presence of ganciclovir or the other antiviralsCMV in the presence of a variety of antiretroviral drugs. The Mmetabolic interactions potential of valganciclovir or ganciclovir is low with, for example, protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are unlikely 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 analog 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, and hydroxyurea  and pegylated interferons/ ribavirin (with or without boceprevir or telaprevir).

Since ganciclovir is excreted through the kidney (section 5.2), toxicity may also be enhanced during co-administration of valganciclovir with drugs that might reduce the renal clearance of ganciclovir and hence increase its exposure.  The renal clearance of ganciclovir might be inhibited by two mechanisms: (a) nephrotoxicity, caused by drugs such as cidofovir and foscarnet, and (b) competitive inhibition of active tubular secretion in the kidney by, for example, other nucleoside analogues.

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

4.8     Undesirable effects

a    Summary of the safety profile

[ … ]

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

[ … ]

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.

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.