Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: CHEPLAPHARM Arzneimittel GmbH, Ziegelhof 24, 17489 Greifswald, Germany
Hypersensitivity to the active substance or valganciclovir or to any of the excipients listed in section 6.1.
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 Cymevene to patients with known hypersensitivity to aciclovir or penciclovir (or to their prodrugs, valaciclovir or famciclovir respectively).
Prior to initiation of ganciclovir treatment, patients should be advised of the potential risks to the foetus. In animal studies ganciclovir was found to be mutagenic, teratogenic, carcinogenic and to impair fertility. Based on clinical and nonclinical studies it is considered likely that ganciclovir causes temporary or permanent inhibition of spermatogenesis (see sections 4.6, 4.8 and 5.3).
Ganciclovir should therefore be considered a potential teratogen and carcinogen in humans with the potential to cause birth defects and cancers. Therefore, women of child bearing potential must be advised to use effective contraception during treatment and for at least 30 days thereafter. Men must be advised to practice 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).
The use of ganciclovir warrants extreme caution, especially in the paediatric population due to the potential for long-term carcinogenicity and reproductive toxicity. The benefits of treatment should be carefully considered in each case and should clearly outweigh the risks (see section 4.2). Refer to treatment guidelines.
Cymevene 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.
Severe leukopenia, neutropenia, anaemia, thrombocytopenia, pancytopenia and bone marrow failure have been observed in patients treated with ganciclovir. Therapy should not be initiated if the absolute neutrophil count is less than 500 cells/µL or the platelet count is less than 25,000 cells/µL or the haemoglobin is less than 8 g/dL (see sections 4.2 and 4.8).
It is recommended that complete blood counts including platelet counts be monitored during therapy. Increased haematological monitoring may be warranted in patients with renal impairment and in neonates and infants (see section 4.8). During the first 14 days of administration it is recommended that white blood cell count (preferably as a differential test) is conducted every second day; in patients with low baseline neutrophil levels (<1000 neutrophils/µl), those who developed leukopenia during previous therapy with other myelotoxic substances, and those with renal impairment, this monitoring should be performed daily.
For patients with severe leukopenia, neutropenia, anaemia and/or thrombocytopenia it is recommended to consider the use of treatment with haematopoietic growth factors and/or the interruption of ganciclovir therapy (see sections 4.2 and 4.8).
Patients with impaired renal function are at increased risk of toxicity (especially haematological toxicity). Dosage reduction is required (see sections 4.2 and 5.2).
Seizures have been reported in patients taking imipenem-cilastatin and ganciclovir. Ganciclovir should not be used concomitantly with imipenem-cilastatin unless the potential benefits outweigh the potential risks (see section 4.5).
Patients treated with ganciclovir and didanosine, medicines known to be myelosuppressive or affecting renal function, should be closely monitored for signs of added toxicity (see section 4.5).
This medicinal product contains 2 mmol (43mg) sodium per 500 mg dose. To be taken into consideration by patients on a controlled sodium diet.
Probenecid given with oral ganciclovir resulted in statistically decreased renal clearance of ganciclovir, and led to clinically significant increased exposure. Such an effect is also anticipated during concomitant administration of intravenous ganciclovir and probenecid. Therefore, patients taking probenecid and Cymevene should be closely monitored for ganciclovir toxicity.
Didanosine plasma concentrations were found to be consistently raised when given with 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. There was no clinically significant effect on ganciclovir concentrations. Patients should be closely monitored for didanosine toxicity (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. 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 is co-administered with other drugs known to be myelosuppressive or associated with renal impairment. This includes anti-infective agents (such as dapsone, pentamidine, flucytosine, amphotericin B, trimethoprim/sulphamethoxazole), immunosuppressants (e.g.ciclosporin, tacrolimus, mycophenolate mofetil) antineoplastic agents (e.g. vincristine, vinblastine, doxorubicin and hydroxyurea) as well as nucleoside (including zidovudine, stavudine and didanosine) and nucleotide analogues (including tenofovir, adefovir). Therefore, these drugs should be considered for concomitant use with ganciclovir only if the potential benefits outweigh the potential risks (see section 4.4).
Interaction studies have only been performed in adults.
A small clinical study with renal transplant patients receiving Valcyte for CMV prophylaxis for up to 200 days demonstrated an impact of valganciclovir/ganciclovir 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 may cause temporary or permanent inhibition of human spermatogenesis (see sections 4.4 and 5.3).
The safety of ganciclovir for use in pregnant women has not been established. However, ganciclovir readily diffuses across the human placenta. In animals studies ganciclovir was associated with reproductive toxicity and teratogenicity (see sections 4.4 and 5.3). Therefore, ganciclovir should not be used in pregnant women unless the clinical need for treatment of the woman outweighs the potential teratogenic risk to the foetus.
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 ganciclovir unless it is certain that the female partner is not at risk of pregnancy (see sections 4.4 and 5.3).
It is unknown if ganciclovir is excreted in human breast milk, but the possibility of ganciclovir being excreted in breast milk and causing serious adverse reactions in the breastfed infant cannot be excluded. Animal data indicate that ganciclovir is excreted in the milk of lactating rats. Therefore, breastfeeding must be discontinued during treatment with ganciclovir (see section 4.3).
Ganciclovir may have a major influence on the ability to drive and use machines (see section 4.8).
Valganciclovir is a pro-drug of ganciclovir, and adverse reactions associated with valganciclovir can be expected to occur with ganciclovir. Oral ganciclovir is no longer available but adverse reactions reported with its use can also be expected to occur in patients receiving intravenous ganciclovir. Therefore, adverse drug reactions reported with intravenous or oral ganciclovir or with valganciclovir are included in the table of adverse reactions.
In patients treated with ganciclovir/valganciclovir the most serious and frequent adverse drug reactions are haematological reactions and include neutropenia, anaemia and thrombocytopenia (see section 4.4). Other adverse drugs reactions are presented in the table below.
The frequencies presented in the table of adverse reactions are derived from a pooled population of HIV-infected patients (n=1704) receiving maintenance therapy with ganciclovir or valganciclovir. Exception is made for agranulocytosis, granulocytopenia and anaphylactic reaction; 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 HIV patients with CMV retinitis. However, there are some differences in the frequency of certain reactions. Intravenous ganciclovir is associated with a lower risk of diarrhoea compared to oral valganciclovir. 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.
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, Confusional state, Anxiety
Uncommon: Agitation, Psychotic disorder, Thinking abnormal, Hallucinations
Very common: Headache
Common: Insomnia, Neuropathy peripheral, Dizziness, Paraesthesia, Hypoaesthesia, Seizure, Dysgeusia (taste disturbance)
Uncommon: Tremor
Common: Visual impairment, Retinal detachment, Vitreous floaters, Eye pain, Conjunctivitis, Macular oedema
Common: Ear pain, Deafness
Uncommon: Arrhythmia
Common: Hypotension
Very common: Cough, Dyspnoea
Very common: Diarrhoea, Nausea, Vomiting, Abdominal pain
Common: Dyspepsia, Flatulence, Abdominal pain upper, Constipation, Mouth ulceration, Dysphagia, Abdominal distention, Pancreatitis
Common: Blood alkaline phosphatase increased, Hepatic function abnormal, Aspartate aminotransferase increased, Alanine aminotransferase increased
Very common: Dermatitis
Common: Night sweats, Pruritus, Rash, Alopecia
Uncommon: Dry skin, Urticaria
Common: Back pain, Myalgia, Arthralgia, Muscle spasms
Common: Renal impairment, Creatinine clearance renal decreased, Blood creatinine increased
Uncommon: Renal failure, Haematuria
Uncommon: Infertility male
Very common: Pyrexia, Fatigue
Common: Injection site reaction, Pain, Chills, Malaise, Asthenia
Uncommon: Chest pain
* The frequencies of these adverse reactions are derived from post-marketing experience, all other frequency categories are based on the frequency recorded in clinical trials.
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 and following administration of a cumulative dose of ≤200 mg/kg. The cell count usually normalises within 2 to 5 days after discontinuation of the drug or dose reduction (see section 4.4).
Severe neutropenia was reported more frequently in HIV patients (14%) receiving maintenance therapy with valganciclovir, oral or intravenous ganciclovir (n=1704) than in 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%.
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.
Seizures have been reported in patients taking imipenem-cilastatin and ganciclovir (see sections 4.4 and 4.5).
This adverse reaction has only been reported in studies in HIV patients treated with Cymevene for CMV retinitis.
Injection site reactions occur commonly in patients receiving ganciclovir. Cymevene should be administered as recommended in section 4.2 to reduce the risk of local tissue irritation.
Formal safety studies with ganciclovir have not been conducted in children <12 years of age but based on experience with valganciclovir, a pro-drug of ganciclovir, the overall safety profile of the active drug is similar in paediatric and adult patients. Neutropenia occurs more often in paediatric patients, but there is no correlation between neutropenia and infectious adverse reactions in the paediatric population. A higher risk of cytopenias in neonates and infants warrants the careful monitoring of blood counts in these age groups (see section 4.4).
Only limited data are available in neonates or infants with HIV/AIDS or symptomatic congenital CMV infection treated with valganciclovir or ganciclovir, however the safety profile 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, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6. Do not use bacteriostatic water for injections containing parabens (para-hydroxybenzoates) since these are incompatible with Cymevene and may cause precipitation.
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