SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Cymevene powder for infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Ganciclovir 500mg (as ganciclovir sodium 543mg).

3. Pharmaceutical Form

Sterile, freeze-dried powder for reconstitution with water for injection.

4 CLINICAL PARTICULARS

4.1    Therapeutic indications

Cymevene is indicated for the treatment of life-threatening or sight-threatening cytomegalovirus (CMV) infections in immunocompromised individuals.

These states include acquired immunodeficiency syndrome (AIDS), iatrogenic immunosuppression associated with organ transplantation, or chemotherapy for neoplasia.

Cymevene may also be used for the prevention of CMV disease, specifically in those patients receiving immunosuppressive therapy secondary to organ transplantation.

4.2    Posology and Method of Administration

For intravenous infusion following reconstitution with 10ml water for injection BP. Based on patient weight and therapeutic indication the appropriate calculated dose volume should be removed from the vial (ganciclovir concentration 50mg/ml) and added to an acceptable infusion fluid (typically 100ml) for delivery over the course of 1 hour. Infusion concentrations greater than 10mg/ml are not recommended. (See section 6.6 Instructions for use/handling).

Adults

Treatment of CMV infection

Initial (induction) treatment: 5mg/kg infused at a constant rate over 1 hour every 12 hours (10mg/kg/day) for 14 to 21 days.

Long-term (maintenance) treatment: For immunocompromised patients at risk of relapse of CMV retinitis a course of maintenance therapy may be given. Intravenous infusion of 6mg/kg once daily 5 days per week, or 5mg/kg once daily 7 days per week is recommended.

Treatment of disease progression: Indefinite treatment may be required in patients with AIDS, but even with continued maintenance treatment, patients may have progression of retinitis. Any patient in whom the retinitis progresses, either while on maintenance treatment or because treatment with Cymevene has been withdrawn, may be re-treated using the induction treatment regimen.

Prevention of CMV disease

Induction regimen: 5mg/kg infused every 12 hours (10mg/kg/day) for 7 to 14 days.

Maintenance regimen: Intravenous infusion of 6mg/kg once daily 5 days per week, or 5mg/kg once daily 7 days per week is recommended.

Special dosage instructions

Patients with renal impairment:

Serum creatinine levels or creatinine clearance should be monitored carefully. Dosage adjustment is required according to creatinine clearance as shown in the table below (see section 4.4 Special warnings and precautions for use and section 5.2 Pharmacokinetic properties).

An estimated creatinine clearance (ml/min) can be related to serum creatinine by the following formulae:

For males =    (140 - age [years]) x (body weight [kg])

(72) x (0.011 x serum creatinine [micromol/L])

For females = 0.85 x male value

CrCl	Induction dose of ganciclovir
> 70ml/min	5.0mg/kg every 12 hours
50 - 69ml/min	2.5mg/kg every 12 hours
25 - 49ml/min	2.5mg/kg/day
10 - 24ml/min	1.25mg/kg/day

< 10ml/min	1.25mg/kg/day
	after haemodialysis

Elderly patients

No studies on the efficacy or safety of Cymevene in elderly patients have been conducted. Since elderly individuals often have reduced renal function, Cymevene should be administered to elderly patients with special consideration for their renal status (see above).

Paediatric patients

There has been limited clinical experience in treating patients under the age of 12 years (see section 4.4 Special warnings and precautions for use and 5.2 Pharmacokinetic properties). Reported adverse events were similar to those seen in adults. However, the use of Cymevene in children warrants extreme caution due to the potential for long-term carcinogenicity and reproductive toxicity. The benefits of treatment should outweigh the risks. Cymevene is not indicated for the treatment of congenital or neonatal CMV infections.

Dosage reductions

For less severe neutropenia or other cytopenias a reduction in the total daily dose should be considered. Cell counts usually normalise within 3 to 7 days after discontinuing the drug or decreasing the dose. As evidence of marrow recovery becomes apparent gradual increases in dose, with careful monitoring of white blood cell counts, may be appropriate.

Patients with severe leucopenia, neutropenia, anaemia, thrombocytopenia and pancytopenia

see section 4.4 Special warnings and precautions for use before initiation of therapy.

If there is a significant deterioration of blood cell counts during therapy with Cymevene, treatment with haematopoetic growth factors and/or dose interruption should be considered (see section 4.4 Special warnings and precautions for use and section 4.8 Undesirable effects).

Method of administration

Cymevene is a powder for solution for intravenous infusion. For directions on the preparation of the infusion solution, see section 6.6 Instructions for use and handling, and disposal.

Cymevene must only be given by intravenous infusion, preferably via a plastic cannula, into a vein with adequate blood flow.

Caution - do not administer by rapid or bolus i.v. injection! The toxicity of Cymevene may be increased as a result of excessive plasma levels.

Caution - i.m. or s.c. injection may result in severe tissue irritation due to the high pH (~11) of ganciclovir solutions.

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

Caution should be exercised in the handling of Cymevene, see section 6.6 Instructions for use and handling, and disposal.

4.3 Contra-indications

Cymevene is contra-indicated in patients with hypersensitivity to ganciclovir, valganciclovir or to any of the excipients.

Due to the similarity of the chemical structure of Cymevene and that of aciclovir and valaciclovir, a cross-hypersensitivity reaction between these drugs is possible. Therefore, Cymevene is contraindicated in patients with hypersensitivity to aciclovir and valaciclovir.

Cymevene is contra-indicated during pregnancy and lactation (see section 4.6 Pregnancy and lactation).

4.4. Special Warnings and Precautions for Use

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, aspermatogenic and carcinogenic and a suppressor of female fertility. Cymevene should therefore be considered a potential teratogen and carcinogen in humans with the potential to cause birth defects and cancers (see section 5.3 Preclinical safety data). It is also considered likely that Cymevene causes temporary or permanent inhibition of spermatogenesis. Women of child bearing potential must be advised to use effective contraception during 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 section 4.6 Pregnancy and lactation, section 4.8 Undesirable effects and section 5.3 Preclinical safety data).

The use of Cymevene in children and adolescents warrants extreme caution due to the potential for long-term carcinogenicity and reproductive toxicity. The benefits of treatment should outweigh the risks.

Severe leucopenia, neutropenia, anaemia, thrombocytopenia, pancytopenia, bone marrow depression and aplastic anaemia have been observed in patients treated with Cymevene. Therapy should not be initiated if the absolute neutrophil count is less than 500 cells/pL, or the platelet count is less than 25000/pL, or the haemoglobin level is less than 8g/dL (see section 4.2 Posology and method of administration , Special dosage instructions and section 4.8 Undesirable effects).

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.

It is recommended that complete blood counts and platelet counts be monitored during therapy. Increased haematological monitoring may be warranted in patients with renal impairment. 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 Posology and method of administration, Special dosage instructions and section 4.8 Undesirable effects).

In patients with impaired renal function, dosage adjustments based on creatinine clearance are required (see section 4.2 Posology and method of administration, Special dosage instructions and section 5.2 Pharmacokinetic properties, Pharmacokinetics in special populations).

Convulsions have been reported in patients taking imipenem-cilastatin and ganciclovir. Cymevene should not be used concomitantly with imipenem-cilastatin unless the potential benefits outweigh the potential risks (see section

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

Patients treated with Cymevene and (a) didanosine, (b) drugs that are known to be myelosuppressive (e.g. zidovudine), or (c) substances affecting renal function, should be closely monitored for signs of added toxicity (see section

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

4.5. Interactions with Other Medicaments and Other Forms of Interaction 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 Special warnings and precautions for use).

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 Cymevene should be closely monitored for ganciclovir toxicity.

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 Special warnings and precautions for use).

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 6g/day, an increase in the AUC of didanosine ranging from 84 to 124% has been observed, and likewise at intravenous doses of 5 and 10mg/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 Special warnings and precautions for use).

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 coadministered, the dose recommendation of ganciclovir should be observed and the patients monitored carefully.

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.

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

At clinically relevant concentrations, there is unlikely to be either a synergistic or antagonistic effect on the inhibition of either HIV in the presence of ganciclovir or CMV in the presence of a variety of antiretroviral drugs. Metabolic interactions with, for example, protease inhibitors and nonnucleoside reverse transcriptase inhibitors (NNRTIs) are unlikely due to the lack of P450 involvement in the metabolism of ganciclovir.

Other potential drug interactions

Toxicity may be enhanced when ganciclovir 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.

Since ganciclovir is excreted through the kidney (section 5.2), toxicity may also be enhanced during co-administration of ganciclovir 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 concomitant use with ganciclovir only if the potential benefits outweigh the potential risks (see section 4.4 Special warnings and precautions for use).

4.6 Fertility, pregnancy and lactation

The safety of Cymevene for use in human pregnancy has not been established. 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 Preclinical safety data), there is a theoretical risk of teratogenicity in humans. Therefore, Cymevene should not be given to pregnant women as there is a high likelihood of damage to the developing foetus.

Women of childbearing potential must be advised to use effective contraception during treatment. Male patients should be advised to practise barrier contraception during, and for at least 90 days following treatment unless it is certain that the female partner is not at risk of pregnancy (see section 5.3 Preclinical safety data).

It is unknown if ganciclovir is excreted in breast milk, but the possiblity of ganciclovir being excreted in the breast milk and causing serious adverse reactions in the nursing infant cannot be discounted. Therefore, breastfeeding must be discontinued.

4.7. Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed.

Convulsion, sedation, dizziness, ataxia and/or confusion have been reported with the use of Cymevene. If they occur, such effects may affect tasks requiring alertness including the patient’s ability to drive and operate machinery.

4.8 Undesirable effects

In patients who were being treated with ganciclovir the most common haematological side effects were neutropenia, anaemia and thrombocytopenia.

Adverse reactions reported with i.v. ganciclovir, oral ganciclovir and valganciclovir are presented in the table below. Valganciclovir is a pro-drug of ganciclovir, and adverse reactions associated with valganciclovir can be expected to occur with ganciclovir. The frequency groupings of these adverse events are based upon the frequency recorded in clinical trials with CMV retinitis patients with AIDS and in clinical trials with solid organ transplant patients.

Infections and infestations:
Common (> 1/100, < 1/10):	Sepsis (bacteraemia, viraemia), cellulitis, urinary tract infection, oral candidiasis.
Blood and lymphatic disorders:
Very common (> 1/10):	neutropenia, anaemia.
Common (> 1/100, <1/10):	thrombocytopenia, leucopenia, pancytopenia.
Uncommon (> 1/1000, < 1/100):	bone marrow depression.
Immune system disorders:
Uncommon (> 1/1000, < 1/100):	anaphylactic reaction.
Metabolic and nutrition disorders:
Common (> 1/100, < 1/10):	appetite decreased, anorexia.
Psychiatric disorders:
Common (> 1/100, < 1/10):	depression, anxiety, confusion, abnormal thinking.
Uncommon (> 1/1000, < 1/100):	agitation, psychotic disorder.
Nervous system disorders:
Common (> 1/100, < 1/10):	headache, insomnia, dysgeusia (taste disturbance), hypoaesthesia, paraesthesia, peripheral neuropathy, convulsions, dizziness (excluding vertigo).
Uncommon (> 1/1000, < 1/100):	tremor.
Eye disorders:
Common (> 1/100, < 1/10):	macular oedema, retinal detachment, vitreous floaters, eye pain.
Uncommon (> 1/1000, < 1/100):	vision abnormal, conjunctivitis.
Ear and labyrinth disorders:
Common (> 1/100, < 1/10):	ear pain.
Uncommon (> 1/1000, <1/100):	deafness.

Cardiac disorders:
Uncommon (> 1/1000, < 1/100):	arrhythmias.
Vascular disorders:
Uncommon (> 1/1000, < 1/100):	hypotension.
Respiratory, thoracic and mediastinal disorders:
Very common (> 1/10):	dyspnoea.
Common (> 1/100, < 1/10):	cough.

Gastrointestinal disorders:

Very common (> 1/10):    diarrhoea.

Common (> 1/100, < 1/10):    nausea, vomiting, abdominal pain, abdominal pain upper, constipation,

flatulence, dysphagia, dyspepsia.

Uncommon (> 1/1000, < 1/100):    abdominal distention, mouth ulcerations, pancreatitis.

Hepato-biliary disorders:

Common (> 1/100, < 1/10):

Uncommon (> 1/1000, < 1/100)

Skin and subcutaneous tissues disorders:

Common (> 1/100, < 1/10):    dermatitis, night sweats, pruritus.

Uncommon (> 1/1000, < 1/100):    alopecia, urticaria, dry skin.

Musculo-skeletal and connective tissue disorders:

Common (> 1/100, < 1/10):    back pain, myalgia, arthralgia, muscle cramps.

Renal and urinary disorders:

Common (> 1/100, < 1/10):

Uncommon (> 1/1000, < 1/100)

Reproductive system and breast disorders:

Uncommon (> 1/1000, < 1/100):    male infertility.

General disorders and administration site conditions:

Common (> 1/100, < 1/10):    fatigue, pyrexia, rigors, pain, chest pain, malaise, asthenia, injection site

reaction (intravenous ganciclovir only).

Investigations:

Common (> 1/100, < 1/10):    weight decreased, blood creatinine increased.

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 (see details below).

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

4.9 Overdose

Overdose experience with intravenous ganciclovir

Reports of overdoses with intravenous ganciclovir 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 - pancytopenia, bone marrow depression, medullary aplasia, leucopenia, 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, diarrhea, vomiting

-    Neurotoxicity - generalised tremor, convulsion

In addition, one adult received an excessive volume of i.v. ganciclovir solution by intravitreal injection, and experienced temporary loss of vision and central retinal artery occlusion secondary to increased intraocular pressure related to the injected fluid volume.

Haemodialysis and hydration may be of benefit in reducing blood plasma levels in patients who receive an overdose of ganciclovir (see section 5.2 Pharmacokinetic properties, Patients undergoing haemodialysis).

Overdose experience with valganciclovir

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).

5.    Pharmacological Properties

5.1    Pharmacodynamic Properties

Pharmacotherapeutic group: ATC code: J 05 A B 06 (anti-infectives for systemic use, antivirals for systemic use, direct acting antivirals, nucleosides and nucleotides excluding reverse transcriptase inhibitors).

Ganciclovir is a synthetic analogue of 2’-deoxyguanosine which inhibits replication of herpes viruses in vitro and in vivo. Sensitive human viruses include human cytomegalovirus (HCMV), herpes simplex virus-1 and -2 (HSV-1 and HSV-2), human herpes virus-6, 7 and 8 (HHV-6, HHV-7, HHV-8), Epstein-Barr virus (EBV) and varicella zoster virus (VZV) and hepatitis B virus. Clinical studies have been limited to assessment of efficacy in patients with CMV infection.

In CMV infected cells ganciclovir is initially phosphorylated to ganciclovir monophosphate by the viral protein kinase, UL97. Further phosphorylation occurs by several cellular kinases to produce ganciclovir triphosphate, which is then slowly metabolised intracellularly. This has been shown to occur in HSV- and HCMV-infected cells with half-lives of 18 and between 6 and 24 hours respectively after removal of extracellular ganciclovir. As the phosphorylation is largely dependent on the viral kinase, phosphorylation of ganciclovir occurs preferentially in virus-infected cells.

The virustatic activity of ganciclovir is due to the inhibition of viral DNA synthesis by: (1) competitive inhibition of incorporation of deoxyguanosine triphosphate into DNA by DNA polymerase and (2) incorporation of ganciclovir triphosphate into viral DNA causing termination of, or very limited, viral DNA elongation. The in vitro anti-viral activity, measured as IC₅₀ of ganciclovir against CMV, is in the range of 0.08pM (0.02pg/ml ) to 14 pM (3.5pg/ml).

Viral resistance

The possibility of viral resistance should be considered for patients who repeatedly show poor clinical response or experience persistent viral excretion during therapy. CMV resistant to ganciclovir can arise after prolonged treatment or prophylaxis with ganciclovir by selection of mutations in either the viral protein kinase gene (UL97) responsible for ganciclovir monophosphorylation and/or, but less frequently, in the viral polymerase gene (UL54). Virus with mutations in the UL97 gene are resistant to ganciclovir alone, whereas virus with mutations in the UL54 gene may show crossresistance to other antivirals with a similar mechanism of action and vice versa.

The working definition of CMV resistance to ganciclovir based on in vitro antiviral assays is an IC₅₀ value > 12.0pM with values > 6.0pM < 12.0pM being considered as indicating intermediate resistance. By these definitions up to 4% of untreated patients have CMV isolates with IC50 values that meet the criteria for either resistance or intermediate resistance.

In a prospective study of 76 previously untreated severely immunocompromised AIDS patients with CMV retinitis starting therapy with ganciclovir (iv induction / iv maintenance or iv induction / oral maintenance), the number of patients carrying resistant virus (IC₅₀ > 6.0pM) increased with time of treatment; 3.7%, 5.4%, 11.4% and 27.5% of those still on treatment at baseline, 3, 6 and 12 months respectively. Similarly in another study of AIDS patients with CMV retinitis treated for > 3 months with iv ganciclovir 7.8% of patients carried virus with IC₅₀ > 12.0pM. Combined data from 4 clinical studies of the treatment of CMV retinitis indicated an incidence of resistance (IC50 > 6.0pM) of 3.2% (median exposure 75 days) for iv ganciclovir and 6.5% (median exposure 165 days) for oral ganciclovir..

5.2 Pharmacokinetic properties

Systemic exposure

The systemic exposure (AUC0-24) reported following dosing with a single 1-hour iv infusion of 5mg/kg ganciclovir in HIV+/CMV+ patients ranged from 21.4 ± 3.1 (N=16) to 26.0 ± 6.06 (N=16) pg.h/ml . In this patient population

peak plasma concentration (C_max) ranged from 8.27 ± 1.02 (N=16) to

9.03 ± 1.42 (N=16)|ig/ml .

Distribution

For iv ganciclovir, the volume of distribution is correlated with body weight with values for the steady state volume of distribution ranging from 0.536 ±

0.078 (N = 15) to 0.870 ± 0.116 (N = 16) L/kg. Cerebrospinal fluid concentrations obtained 0.25 - 5.67 hours post-dose in 2 patients who received 2.5mg/kg ganciclovir i.v. every 8 hours or every 12 hours ranged from 0.50 to 0.68pg/ml representing 24 - 67% of the respective plasma concentrations. Binding to plasma proteins was 1 - 2% over ganciclovir concentrations of 0.5 and 51pg/ml.

Intra-ocular concentrations of ganciclovir range from 40 to 200% of those measured simultaneously in plasma following administration of i.v. ganciclovir. Average intravitreal concentrations following induction and maintenance dosing with i.v. ganciclovir were 1.15 and 1.0 pg/ml respectively. Half-life of ganciclovir within the eye is much longer than that in plasma with estimates ranging from 13.3 to 18.8 hours.

Metabolism and elimination

When administered i.v., ganciclovir exhibits linear pharmacokinetics over the range of 1.6 - 5.0mg/kg. Renal excretion of unchanged drug by glomerular filtration and active tubular secretion is the major route of elimination of ganciclovir. In patients with normal renal function, 89.6 ± 5.0% (N=4) of iv administered ganciclovir was recovered unmetabolized in the urine. In subjects with normal renal function, systemic clearance ranged from 2.64 ± 0.38ml/min/kg (N=15) to 4.52 ± 2.79ml/min/kg (N=6) and renal clearance ranged from 2.57 ± 0.69ml/min/kg (N=15) to 3.48 ± 0.68ml/min/kg (N=16), corresponding to 90% - 101% of administered ganciclovir. Half-lives in subjects without renal impairment ranged from 2.73 ± 1.29 (N=6) to 3.98 ± 1.78 hours (N=8).

Pharmacokinetics in special populations

Renal impairment

Renal impairment leads to altered kinetics of ganciclovir as indicated below.

Ganciclovir
Serum	Systemic plasma	Plasma half-
creatinine	clearance	life
(micromol/l)	(ml/min/kg)	(hours)

Patients undergoing haemodialysis

Haemodialysis reduces plasma concentrations of ganciclovir by about 50% after both iv and oral administration (see section 4.9 Overdosage).

During intermittent haemodialysis, estimates for the clearance of ganciclovir ranged from 42 to 92 ml/min, resulting in intra-dialytic half-lives of 3.3 to 4.5 hours. Estimates of ganciclovir clearance for continuous dialysis were lower (4.0 to 29.6 ml/min) but resulted in greater removal of ganciclovir over a dose interval. For intermittent haemodialysis, the fraction of ganciclovir removed in a single dialysis session varied from 50% to 63%.

Paediatric patients

Ganciclovir pharmacokinetics were also studied in 10 children, aged 9 months to 12 years. The pharmacokinetic characteristics of ganciclovir are similar after single and multiple (every 12 hours) i.v. doses (5mg/kg). After the administration of a 5mg/kg single dose, exposure as measured by mean AUC^ was 19.4 ± 7.1 p,g.h/ml, the steady-state volume of distribution reported was 0.68 ± 0.20 l/kg, C_max was 7.59 ± 3.21pg/ml, systemic clearance was 4.66 ± 1.72ml/min/kg, and t_1/2 was 2.49 ± 0.57 hours. The pharmacokinetics of i.v. ganciclovir in children are similar to those observed in adults.

Elderly patients

No studies have been conducted in adults older than 65 years of age.

5.3 Preclinical Safety Data

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 (see section

4.4 Special warnings and precautions for use).

Based upon animals studies where aspermatogenesis was induced at ganciclovir systemic exposures below therapeutic levels, it is considered likely that ganciclovir could cause inhibition of human spermatogenesis.

Data obtained using an ex vivo human placental model show that ganciclovir crosses the placenta and that simple diffusion is the most likely mechanism of transfer. The transfer was not saturable over a concentration range of 1 to 10 mg/ml and occurred by passive diffusion.

6.1 List of excipients

None.

6.2    Incompatibilities

The dry powder should not be reconstituted with bacteriostatic water containing parabens, since these are incompatible with ganciclovir sterile powder and may cause precipitation.

6.3    Shelf Life

36 months.

6.4 Special Precautions for Storage

Undiluted vials: Do not store above 30°C.

From a microbiological point of view, the product should be used immediately after reconstitution and dilution. If the product is not used immediately, the inuse storage times and conditions prior to use are the responsibility of the user. Following reconstitution and dilution, the following in-use storage times should be followed unless reconstitution and dilution has taken place in controlled and validated aseptic conditions.

In-use storage time for the reconstituted vial should not be longer than 12 hours. Do not refrigerate.

In-use storage time for the infusion solution should not be longer than 24 hours when stored in a refrigerator at 2 -8°C. Freezing is not recommended.

6.5 Nature and contents of container

Single-dose glass vials of 10 mL with fluoro-resin laminated/siliconised rubber stopper and aluminum closure with flip-off cap.

Available in packs of 1 vial or 5 vials.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Caution should be exercised in the handling of Cymevene Since Cymevene is considered a potential teratogen and carcinogen in humans, caution should be exercised in its handling (see section 4.4 Special warnings and precautions for use). Avoid inhalation or direct contact of the powder contained in the vials or direct contact of the reconstituted solution with the skin or mucous membranes. Cymevene solutions are alkaline (pH approximately 11). If such contact occurs, wash thoroughly with soap and water, rinse eyes thoroughly with sterile water, or plain water if sterile water is unavailable.

Method of preparation of Cymevene solution

1.    Lyophilized Cymevene should be reconstituted by injecting 10ml of sterile Water for Injections into the vial. Do not use bacteriostatic water for injection containing parabens (para-hydroxybenzoates), since these are incompatible with Cymevene sterile powder and may cause precipitation.

2.    The vial should be shaken to dissolve the drug.

3.    Reconstituted solution should be inspected for particulate matter prior to proceeding with the admixture preparation.

4.    Reconstituted solution in the vial is stable at room temperature for 12 hours. It should not be refrigerated.

Preparation and administration of infusion solution

Based on patient weight the appropriate calculated dose volume should be

removed from the Cymevene vial (concentration 50 mg/ml) and added to an

acceptable infusion fluid. Normal saline, dextrose 5% in water, Ringer’s or

lactated Ringer’s solution are determined chemically or physically compatible

with Cymevene. Infusion concentrations greater than 10mg/ml are not

recommended.

Cymevene should not be mixed with other iv products.

Because Cymevene is reconstituted with nonbacteriostatic sterile water, the infusion solution should be used as soon as possible and within 24 hours of dilution in order to reduce the risk of bacterial contamination.

The infusion solution should be refrigerated. Freezing is not recommended.

Any unused product or waste material should be disposed of in accordance with local requirements.

Administrative Data 7. Marketing Authorisation Holder

Roche Products Limited

6 Falcon Way,

Shire Park,

Welwyn Garden City Hertfordshire AL7 1TW

8. Marketing Authorisation Number

PL 00031/0465

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 15 June 1998 Date of latest renewal: 28 April 2016

10 DATE OF REVISION OF THE TEXT

27/10/2016

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