Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Zentiva Pharma UK Limited, 12 New Fetter Lane, London, EC4A 1JP, United Kingdom Trading as: Zentiva, 12 New Fetter Lane, London EC4A 1JP, UK
Valganciclovir is contra-indicated in patients with hypersensitivity to valganciclovir, ganciclovir or to any of the excipients listed in section 6.1.
Valganciclovir is contra-indicated during breast-feeding (see section 4.6).
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 valganciclovir to patients with known hypersensitivity to aciclovir or penciclovir, (or to their prodrugs valaciclovir or famciclovir respectively).
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. Valganciclovir 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 valganciclovir 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.
Severe leukopenia, neutropenia, anaemia, thrombocytopenia, pancytopenia, bone marrow failure and aplastic anaemia have been observed in patients treated with valganciclovir (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 8 g/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).
Valganciclovir 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 section 4.2).
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 valganciclovir 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 valganciclovir tablets (see sections 4.2 and 4.9).
In patients with impaired renal function, dosage adjustments based on creatinine clearance are required (see sections 4.2 and 5.2).
Valganciclovir film-coated tablets should not be used in patients on haemodialysis (see sections 4.2 and 5.2).
Seizures have been reported in patients taking imipenem-cilastatin and ganciclovir. Valganciclovir should not be used concomitantly with imipenem-cilastatin unless the potential benefits outweigh the potential risks (see section 4.5).
Patients treated with valganciclovir and (a) didanosine, (b) drugs that are known to be myelosuppressive (e.g. zidovudine), or © 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.
In-vivo drug interaction studies with valganciclovir have not been performed. Since valganciclovir is extensively and rapidly metabolised to ganciclovir; drug interactions associated with ganciclovir will be expected for valganciclovir.
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 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).
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.
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).
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).
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).
As a result of the potential for reproductive toxicity and teratogenicity women of child-bearing 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).
The safety of valganciclovir 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.
Valganciclovir should not be used in pregnancy unless the therapeutic benefit for the mother outweighs the potential risk of teratogenic damage to the foetus.
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).
A small clinical study with renal transplant patients receiving valganciclovir 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 valganciclovir 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).
No studies on the effects on ability to drive and use machines have been performed.
Adverse reactions such as seizures, dizziness and confusion have been reported with the use of valganciclovir and/or ganciclovir. If they occur, such effects may affect tasks requiring alertness, including the patient’s ability to drive and operate machinery.
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.
Tabulated list of adverse drug reactions:
Very common: Candida infections including oral candidiasis, upper respiratory tract infection
Common: Sepsis, influenza, urinary tract infection, cellulitis
Very common: Neutropenia, anaemia
Common: Thrombocytopenia, leukopenia, pancytopenia
Uncommon: Bone marrow failure
Rare: Aplastic anaemia, agranulocytosis*, granulocytopenia*
Common: Hypersensitivity
Rare: Anaphylactic reaction*
Very common: Decreased appetite
Common: Weight decreased
Common: Depression, anxiety, confusional state
Uncommon: Agitation, psychotic disorder, hallucinations, abnormal thinking
Very common: Headache
Common: Insomnia, dysgeusia (taste disturbance), hypoaesthesia, paraesthesia, peripheral neuropathy, dizziness, seizure
Uncommon: Tremor
Common: Macular oedema, retinal detachment**, vitreous floaters, eye pain, visual impairment, conjunctivitis
Common: Ear pain
Uncommon: Deafness
Uncommon: Arrhythmia
Common: Hypotension
Very common: Dyspnoea, cough
Very common: Diarrhoea, nausea, vomiting, abdominal pain
Common: Abdominal pain upper, dyspepsia, constipation, flatulence, dysphagia, mouth ulceration, pancreatitis, abdominal distension
Common: Hepatic function abnormal, blood alkaline phosphatase increased, aspartate aminotransferase increased, alanine aminotransferase increased
Very common: Dermatitis
Common: Night sweats, pruritus, rash, alopecia
Uncommon: Urticaria, dry skin
Common: Back pain, myalgia, arthralgia, muscle spasms
Common: Creatinine clearance renal decreased, blood creatine increased, renal impairment
Uncommon: Haematuria, renal failure
Uncommon: Male infertility
Very common: Pyrexia, fatigue
Common: Chills, pain, malaise, asthenia
Uncommon: Chest pain
* 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
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).
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.
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 valganciclovir 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.
Valganciclovir 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 valganciclovir, however the safety appears to be consistent with the known safety profile of valganciclovir/ganciclovir.
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 at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Not applicable.
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