4.1. Therapeutic indications

Cymevene is indicated in adults and adolescents ≥ 12 years of age for the:

- treatment of cytomegalovirus (CMV) disease in immunocompromised patients;

- prevention of CMV disease using pre-emptive therapy in patients with drug-induced immunosuppression (for example following organ transplantation or cancer chemotherapy).

Cymevene is also indicated from birth for the:

- prevention of CMV disease using universal prophylaxis in patients with drug-induced immunosuppression (for example following organ transplantation or cancer chemotherapy).

Consideration should be given to official guidance on the appropriate use of antiviral agents.

4.2. Posology and method of administration

Posology

Treatment of CMV disease

Adults and paediatric population ≥ 12 years of age with normal renal function:

- Induction treatment: 5 mg/kg given as an intravenous infusion over one hour, every 12 hours for 14 - 21 days.

- Maintenance treatment: For immunocompromised patients at risk of relapse maintenance therapy may be given. 5 mg/kg given as an intravenous infusion over one hour, once daily on 7 days per week or 6 mg/kg once daily on 5 days per week. The duration of maintenance treatment should be determined on an individual basis, local treatment guidelines should be consulted.

- Treatment of disease progression: Any patient, in whom CMV disease progresses, either while on maintenance treatment or because treatment with ganciclovir has been withdrawn, may be re-treated using the induction treatment regimen.

Paediatric population from birth to < 12 years of age:

Currently available paediatric data are described in sections 5.1 and 5.2 but no recommendation on a posology can be made.

Prevention of CMV disease using pre-emptive therapy

Adults and paediatric population ≥ 12 years of age with normal renal function:

Induction therapy: 5 mg/kg given as an intravenous infusion over one hour, every 12 hours for 7 – 14 days.

Maintenance therapy: 5 mg/kg given as an intravenous infusion over one hour, once daily on 7 days per week or 6 mg/kg once daily on 5 days per week. The duration of maintenance therapy is based on the risk of CMV disease, local treatment guidelines should be consulted.

Paediatric population from birth to < 12 years of age:

Currently available data are described in sections 5.1 and 5.2 but no recommendation on a posology can be made.

Prevention of CMV disease using universal prophylaxis

Adults and paediatric population > 16 years of age:

5 mg/kg given as an intravenous infusion over one hour, once daily on 7 days per week or 6 mg/kg once daily on 5 days per week. The duration is based on the risk of CMV disease, local treatment guidelines should be consulted.

Paediatric population from birth to ≤ 16 years of age:

The recommended once daily dose of ganciclovir given as an intravenous infusion over one hour is based on Body Surface Area (BSA) using the Mosteller BSA formula and creatinine clearance derived from Schwartz formula (CrCLS) and is calculated using the equations below. The duration of universal prophylaxis is based on the risk of CMV disease and should be determined on an individual basis.

Paediatric dose (mg) = 3 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 = 0.33 for patients < 1 year of age with low birth weight, 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.

It is recommended that serum creatinine levels, height and weight are reviewed regularly, and the dose amended as appropriate.

Special dosage instructions

Renal impairment

Paediatric patients (from birth to ≤ 16 years of age) with renal impairment receiving a prophylactic dose of ganciclovir calculated using the 3 x BSA x CrCLS dosing algorithm do not require further dose modification because this dose is already adjusted for creatinine clearance.

For patients 12 years and older with renal impairment, treated on a mg/kg bodyweight basis for pre-emptive therapy and treatment of CMV disease, the mg/kg dose of ganciclovir should be modified according to creatinine clearance as shown in the table below (see sections 4.4 and 5.2).

Dose modifications for patients with renal impairment receiving mg/kg dosing:

CrCl

Induction dose

Maintenance dose

> 70 mL/min

5.0 mg/kg q12h

5.0 mg/kg/day

50-69 mL/min

2.5 mg/kg q12h

2.5 mg/kg/day

25-49 mL/min

2.5 mg/kg/day

1.25 mg/kg/day

10-24 mL/min

1.25 mg/kg/day

0.625 mg/kg/day

< 10 mL/min

1.25 mg/kg 3x/wk after haemodialysis

0.625 mg/kg 3x/wk after haemodialysis

Estimated creatinine clearance can be calculated from serum creatinine using the following formulae:

For females: 0.85 x male value

As dosage modifications are recommended in patients with renal impairment, serum creatinine or estimated creatinine-clearance levels should be monitored.

Hepatic impairment

The safety and efficacy of Cymevene have not been studied in patients with hepatic impairment (see section 5.2).

Severe leukopenia, neutropenia, anaemia, thrombocytopenia and pancytopenia

See section 4.4 before initiation of treatment.

If the blood cell counts are significantly reduced during therapy with ganciclovir, treatment with haematopoietic growth factors and/or discontinuation of treatment should be considered (see sections 4.4 and 4.8).

Elderly

No studies on the efficacy or safety of ganciclovir in the elderly have been conducted. Since renal function decreases with age, ganciclovir should be administered to the elderly with special consideration for their renal status (see section 5.2).

Method of administration

Caution:

Ganciclovir must be administered by intravenous infusion over 1 hour at a concentration not exceeding 10 mg/mL. Do not administer by rapid or bolus intravenous injection because the resulting excessive plasma levels may increase the toxicity of ganciclovir.

Do not administer by intramuscular or subcutaneous injection because this may result in severe tissue irritation due to the high pH (~11) of ganciclovir solutions (see section 4.8).

The recommended dosage, frequency and infusion rates should not be exceeded.

Cymevene is a powder for solution for infusion. After reconstitution Cymevene is a colourless to slightly yellowish solution, practically free from visible particles.

The infusion should be given into a vein with adequate blood flow, preferably via a plastic cannula.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

Precautions to be taken before handling or administering the medicinal product:

Since ganciclovir is considered a potential teratogen and carcinogen in humans, caution should be taken in its handling (see section 6.6).

4.3. Contraindications

Hypersensitivity to the active substance or valganciclovir or to any of the excipients listed in section 6.1.

Breastfeeding (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 Cymevene 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 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 childbearing 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.

Myelosuppression

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 (< 1,000 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).

Renal impairment

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).

Use with other medicines

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).

Excipients

This medicinal product contains 45 mg sodium per 500 mg vial, equivalent to 2% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

4.5. Interaction with other medicinal products and other forms of interaction

Pharmacokinetic interactions

Probenecid

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

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).

Other antiretrovirals

Cytochrome P450 isoenzymes play no role in ganciclovir pharmacokinetics. Consequently, 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. 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).

Other potential drug interactions

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/sulfamethoxazole), 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).

Paediatric population

Interaction studies have only been performed in adults.

4.6. Fertility, pregnancy and lactation

Fertility

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).

Pregnancy

The safety of ganciclovir for use in pregnant women has not been established. However, ganciclovir readily diffuses across the human placenta. In animal 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.

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 ganciclovir unless it is certain that the female partner is not at risk of pregnancy (see sections 4.4 and 5.3).

Breastfeeding

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).

4.7. Effects on ability to drive and use machines

Ganciclovir may have a major influence on the ability to drive and use machines (see section 4.8).

4.8. Undesirable effects

Summary of the safety profile

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 drug 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 = 1,704) 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.

Tabulated list of adverse 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:

Arrhythmia

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 tissue disorders:

Dermatitis

Very common

Night sweats

Common

Pruritus

Rash

Alopecia

Dry skin

Uncommon

Urticaria

Musculoskeletal 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

Injection site reaction

Common

Pain

Chills

Malaise

Asthenia

Chest pain

Uncommon

* 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.

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 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

Severe neutropenia was reported more frequently in HIV patients (14%) receiving maintenance therapy with valganciclovir, oral or intravenous ganciclovir (n = 1,704) 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%.

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.

Seizures

Seizures have been reported in patients taking imipenem-cilastatin and ganciclovir (see sections 4.4 and 4.5).

Retinal detachment

This adverse reaction has only been reported in studies in HIV patients treated with Cymevene for CMV retinitis.

Injection site reactions

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.

Paediatric population

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 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

Symptoms

Reports of overdoses with i.v. ganciclovir, some with fatal outcomes, have been received from clinical trials and during post-marketing experience. The majority of the reports were either not associated with any adverse reactions, or included one or more of the adverse reactions listed below:

– 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

Management

Ganciclovir is removed by haemodialysis, therefore haemodialysis may be of benefit in reducing drug exposure in patients who receive an overdose of ganciclovir (see section 5.2).

Additional information on special populations

Renal impairment: It is expected that an overdose of ganciclovir could result in increased renal toxicity in patients with renal impairment (see section 4.4).

Paediatric population

No specific information available