Last Updated on eMC 15-11-2017 View medicine  | Roche Products Limited Contact details

When a pharmaceutical company changes an SPC or PIL, a new version is published on the eMC.  For each version, we show the dates it was published on the eMC and the reasons for change.

Reasons for adding or updating:

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Fertility, pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text
  • Change to section 4.8 - Undesirable effects - how to report a side effect

Date of revision of text on the SPC:09-10-2017

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



 

4.2       Posology and method of administration

 

[ … ]

 

Hepatic impairment

 

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

 

Severe leucopenialeukopenia, neutropenia, anaemia, thrombocytopenia and pancytopenia

 

[ … ]

 

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 4.25.2).

 

[ … ]

 

 

4.4     Special warnings and precautions for use

 

[ … ]

 

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 leucopenialeukopenia, neutropenia, anaemia, thrombocytopenia, pancytopenia and bone marrow depression 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. 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 leucopenialeukopenia during previous therapy with other myelotoxic substances, and those with renal impairment, this monitoring should be performed daily.

 

For patients with severe leucopenialeukopenia, 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).

 

[ … ]

 

 

4.5       Interaction with other medicinal products and other forms of interaction

 

[ … ]

 

 

Mycophenolate mofetil, stavudine, trimethoprim and zidovudine

 

No significant pharmacokinetic interactions were observed when ganciclovir was administered in combination with either: mycophenolate mofetil, stavudine, trimethoprim or zidovudine.

 

[ … ]

 

 

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, vincristine, vinblastine, doxorubicin, amphotericin B, trimethoprim/sulphamethoxazole), immunosuppressants (e.g., ciclosporin, tacrolimus, mycophenolate mofetil) antineoplastic agents ,(e.g. vincristine, vinblastine, doxorubicin trimethoprim/sulphamethoxazole, and hydroxyurea) as well as nucleoside analogues (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).

 

[ … ]

 

 

4.6     Fertility, pregnancy and lactation

 

[ … ]

 

 

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).

 

 

 

4.8    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 common 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. 

 

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

LeucopeniaLeukopenia

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

Convulsion

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:

Arrhythmias

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 tissues disorders:

Dermatitis

Very common

Night sweats

Common

Pruritus

Rash

Alopecia

Dry skin

Uncommon

 

Urticaria

Musculo-skeletal 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

 

 

Infections and infestations:

 

Common (³ 1/100, < 1/10):

Sepsis

Cellulitis

Urinary tract infection

Candida infections including oral candidiasis.

Blood and lymphatic disorders:

 

Very common (³ 1/10):

Neutropenia

Anaemia.

Common (³ 1/100, <1/10):

Thrombocytopenia

Leucopenia

Pancytopenia

Uncommon (³ 1/1000, < 1/100):

Bone marrow failure

Rare (³ 1/10000, < 1/1000)

Agranulocytosis*

Aplastic anaemia*

Granulocytopenia*

Immune system disorders:

 

Uncommon (³ 1/1000, < 1/100):

Anaphylactic reaction

Metabolic and nutrition disorders:

 

Common (³ 1/100, < 1/10):

Decreased appetite

Anorexia

Weight decreased

Psychiatric disorders:

 

Common (³ 1/100, < 1/10):

Depression

Anxiety

Confusional state

Thinking abnormal

Uncommon (³ 1/1000, < 1/100):

Agitation

Psychotic disorder

Rare (³ 1/10000, < 1/1000)

Hallucinations*

Nervous system disorders:

Common (³ 1/100, < 1/10):

 

Headache

 

Insomnia

Dysgeusia (taste disturbance)

Hypoaesthesia

Paraesthesia

Neuropathy peripheral

Convulsion

Dizziness

Uncommon (³ 1/1000, < 1/100):

Tremor

Eye disorders:

 

Common (³ 1/100, < 1/10):

Macular oedema

Retinal detachment

Vitreous floaters

Eye pain

Uncommon (³ 1/1000, < 1/100):

Visual impairment

Conjunctivitis

Ear and labyrinth disorders:

 

Common (³ 1/100, < 1/10):

Ear pain

Uncommon (³ 1/1000, <1/100):

Deafness

Cardiac disorders:

 

Uncommon (³ 1/1000, < 1/100):

Cardiac arrhythmias

Vascular disorders:

 

Uncommon (³ 1/1000, < 1/100):

Hypotension

Respiratory, thoracic and mediastinal disorders:

 

Very common (³ 1/10):

Dyspnoea

Common (³ 1/100, < 1/10):

Cough

Gastrointestinal disorders:

 

Very common (³ 1/10):

Diarrhoea

Common (³ 1/100, < 1/10):

Nausea

Vomiting

Abdominal pain

Abdominal pain upper

Constipation

Flatulence

Dysphagia

Dyspepsia

Uncommon (³ 1/1000, < 1/100):

Abdominal distention

Mouth ulceration

Pancreatitis

Hepato-biliary disorders:

 

Common (³ 1/100, < 1/10):

Hepatic function abnormal

Blood alkaline phosphatase increased

Aspartate aminotransferase increased

Uncommon (³ 1/1000, < 1/100):

Alanine aminotransferase increased

Skin and subcutaneous tissues disorders:

 

Common (³ 1/100, < 1/10):

Dermatitis

Night sweats

Pruritus

Uncommon (³ 1/1000, < 1/100):

Alopecia

Urticaria

Dry skin

Rare (³ 1/10000, < 1/1000)

Rash*

Musculo-skeletal and connective tissue disorders:

 

Common (³ 1/100, < 1/10):

Back pain

Myalgia

Arthralgia

Muscle spasms

Renal and urinary disorders:

 

Common (³ 1/100, < 1/10):

Creatinine clearance renal decreased

Renal impairment

Blood creatinine increased 

Uncommon (³ 1/1000, < 1/100):

Haematuria

Renal failure

Reproductive system and breast disorders:

 

Uncommon (³ 1/1000, < 1/100):

Male infertility

General disorders and administration site conditions:

 

Common (³ 1/100, < 1/10):

Fatigue

Pyrexia

Chills

Pain

Chest pain

Malaise

Asthenia

Injection site reaction

Note: 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.

* 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=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%.  

 

[ … ]

 

 

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, 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

 

[ … ]

 

 

 

5.2     Pharmacokinetic properties

 

[ … ]

 

 

 

Patients with renal impairment

 

The total plasma body clearance of ganciclovir is linearly correlated with creatinine clearance.  In patients with mild, moderate, and severe renal impairment, mean systemic clearances of 2.1, 1 and 0.3 mL/min/kg were observed.  Patients with renal impairment have an increased elimination half‑life. In patients with severe renal impairment elimination half-life was increased by 10-fold and, depending on renal function, it ranges from about 6 to 17 hours (see section 4.2 for dose modifications required in patients with renal impairment).

 

Serum creatinine (mmol/L)

Creatinine clearance
(mL/min)

Mean Ganciclovir  systemic plasma clearance
(mL/min)

Mean Ganciclovir Plasma half-life
(hours)

< 125

³ 70

208

3.0

125-175

50-69

102

4.8

176-350

25-49

87

5.5

> 350

10-24

34

11.5

 

[ … ]

 

Patients with hepatic impairment

The safety and efficacy of Cymevene 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 (see section 4.2).

 

[ … ]

 

Elderly

 

No studies have been conducted in adults older than 65 years of age (see section 4.2).

 

 

 

10.     DATE OF REVISION OF THE TEXT

 

09 October 2017

 

 

Reasons for adding or updating:

  • Change to section 6.5 - Nature and contents of container
  • Change to section 9 - Date of first authorisation/renewal of the authorisation
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:27-10-2016

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



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.



 

9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

 

Date of first authorisation: 15 June 1988

Date of latest renewal: 7 February 200628 April 2016

 

 

10.     DATE OF REVISION OF THE TEXT

 

28 April 201627 October 2016

 

Detailed information on this medicinal product is available on the Medicines and Healthcare Products Regulatory Agency (MHRA) website : http://www.mhra.gov.uk

Reasons for adding or updating:

  • Change to section 1 - Name of the medicinal product
  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 3 - Pharmaceutical form
  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Fertility, pregnancy and lactation
  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.8 - Undesirable effects - how to report a side effect
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 5.4 - Radiation dosimetry
  • Change to section 6.1 - List of excipients
  • Change to section 6.2 - Incompatibilities
  • Change to section 6.3 - Shelf life
  • Change to section 6.4 - Special precautions for storage
  • Change to section 6.5 - Nature and contents of container
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 7 - Marketing authorisation holder
  • Change to section 8 - Marketing authorisation number(s)
  • Change to section 9 - Date of first authorisation/renewal of the authorisation
  • Change to section 10 - Date of revision of the text
  • Improved presentation of SPC

Date of revision of text on the SPC:28-04-2016

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

The whole SPC has been updated / re-arranged in-line with Article 30 Harmonisation Procedure.

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

Ganciclovir 500mg

Each vial contains 500 mg of ganciclovir (as ganciclovir sodium 543mg).

 

After reconstitution with 10 mL of water for injections, each mL provides 50 mg of ganciclovir.

 

Excipient(s) with known effect: approximately 43 mg (2 mEq) sodium.

 

For the full list of excipients, see section 6.1.

 

3.       PHARMACEUTICAL FORMform

Sterile, freeze-dried

Powder for concentrate for solution for infusion (powder for reconstitution with Water for Injection.concentrate).

White to off-white solid cake.

 

4.       Clinical particulars

 

4.1     Therapeutic indications

 

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

 

-                      treatment of life-threatening or sight-threatening cytomegalovirus (CMV) infectionsdisease in immunocompromised individuals.  These states include acquired immunodeficiency syndrome (AIDS), iatrogenicpatients;

 

-                      prevention of CMV disease in patients with drug-induced immunosuppression associated with (for example following organ transplantation, or cancer 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.

 

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

 

4.2       Posology and method of administration

 

PosologyFor 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 infectiondisease in adults and adolescents from 12 years of age with normal renal function

Initial (induction)

-    Induction treatment:  5mg5 mg/kg infused at a constant rategiven as an intravenous infusion over 1one hour, every 12 hours (10mg/kg/day) for 14 to  - 21 days.

 

Long-term (maintenance) -   Maintenance treatment:  For immunocompromised patients at risk of relapse of CMV retinitis a coursemaintenance 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 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 recommendedtreatment should be determined on an individual basis, local treatment guidelines should be consulted.

 

-    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 retinitisCMV disease progresses, either while on maintenance treatment or because treatment with Cymeveneganciclovir has been withdrawn, may be re-treated using the induction treatment regimen.


 

Prevention of CMV disease in adults and adolescents from 12 years of age with normal renal function using prophylaxis or pre-emptive therapy

Induction regimen:  5mg/kg infused

-    Prophylaxis:

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 prophylaxis is based on the risk of CMV disease, local treatment guidelines should be consulted.

 

-    Pre-emptive therapy:

Induction therapy: 5 mg/kg given as an intravenous infusion over one hour, every 12 hours (10mg/kg/day) for 7 to  – 14 days.

 

Maintenance regimen:  Intravenoustherapy: 5 mg/kg given as an intravenous infusion of 6mg/kg over one hour, once daily 5on 7 days per week, or 5mg6 mg/kg once daily 7on 5 days per week. The duration of maintenance therapy is recommendedbased on the risk of CMV disease, local treatment guidelines should be consulted.

 

Renal impairment

 

For Special dosage instructions

patients

Patients with renal impairment:

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

 

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

Dose modifications for patients with renal impairment:

 

 

CrCl

Induction dose of ganciclovir

Maintenance dose

³ 70ml>70 mL/min

5.0mg0 mg/kg every 12 hoursq12h 

5.0 mg/kg/day

50 - 69ml-69 mL/min

2.5mg5 mg/kg every 12 hoursq12h  

2.5 mg/kg/day

25 - 49ml-49 mL/min

2.5mg5 mg/kg/day  

1.25 mg/kg/day

10 - 24ml-24 mL/min

1.25mg/kg/day 

0.625 mg/kg/day

< 10ml10 mL/min

1.25mg25 mg/kg/day
 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 males:  (140 – age [years]) x (body weight [kg])

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

 

For females:  0.85 x male value

 

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

 

Severe 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

See section 4.4 Special warnings and precautions for use before initiation of therapytreatment.

 

If there is a significant deterioration ofthe blood cell counts are significantly reduced during therapy with Cymeveneganciclovir, treatment with haematopoetichaematopoietic growth factors and/or dose interruptiondiscontinuation of treatment should be considered (see sectionsections 4.4 Special warnings and precautions for use and section 4.8 Undesirable effects).

 

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 4.2).

 

Paediatric population

 

Information on the safety and efficacy of ganciclovir in children under 12 years of age, including neonates, is limited (see sections 4.4, 4.8 and 5.1). Currently available paediatric data are described in sections 5.1 and 5.2, but no recommendation on a posology can be made. Therapeutic guidelines should be consulted.

 

Method of administration

 

CautionCymevene 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:

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

 over 1 hour at a concentration not exceeding 10 mg/mL. Do

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

Caution - i.m. or s.c.

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, or and infusion rates should not be exceeded.

 

CautionCymevene 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.

 

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

 

Since ganciclovir is exercised in theconsidered a potential teratogen and carcinogen in humans, caution should be taken in its handling of Cymevene, (see section 6.6 Instructions for use and handling, and disposal.).

 

1.1                 Contra-indications

Cymevene is contra-indicated in patients with hypersensitivity to ganciclovir 4.3 Contraindications

 

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

 

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 Cymeveneganciclovir and that of aciclovir and valaciclovirpenciclovir, a cross-hypersensitivity reaction between these drugs is possible.  Therefore,Caution should therefore be used when prescribing Cymevene is contra-indicated into patients with known hypersensitivity to aciclovir andor penciclovir (or to their prodrugs, valaciclovir. or famciclovir respectively). 

 

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

 

1.1                 Special warnings and precautions for use

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, aspermatogenic and, carcinogenic and a suppressor of femaleto impair fertility.  CymeveneIt 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 (see section 5.3 Preclinical safety data).  It is also considered likely that Cymevene causes temporary or permanent inhibition of spermatogenesis.  Women.  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 practisepractice 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 datasections 4.6, 4.8 and 5.3).

 

The use of Cymevene in children and adolescentsganciclovir 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.

 

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/mL, or the platelet count is less than 25000/mL, or the haemoglobin level is less than 8g/dL (see section 4.2 ). Refer to treatment guidelines.Posology and method of administration, Special dosage instructions and section 4.8 Undesirable effects).

 

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 leucopenia, neutropenia, anemia, thrombocytopenia, pancytopenia and bone marrow depression 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 andincluding platelet counts be monitored during therapy.  Increased haematological monitoring may be warranted in patients with renal impairment.  In patients developingDuring 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 leucopenia during previous therapy with other myelotoxic substances, and those with renal impairment, this monitoring should be performed daily.

 

For patients with severe leucopenia, neutropenia, anaemia and/or thrombocytopenia, it is recommended thatto consider the use of treatment with haematopoietic growth factors and/or dosethe interruption be considered (see section 4.2 Posology and method of administration, Special dosage instructions and section 4.8 Undesirable effectsof ganciclovir therapy (see sections 4.2 and 4.8).

 

Renal impairment

 

PatientsIn patients with impaired renal function, dosage adjustments based on creatinine clearance are at increased risk of toxicity (especially haematological toxicity). Dosage reduction is required (see section 4.2 Posology and method of administration, Special dosage instructions sections 4.2 and section 5.2 Pharmacokinetic properties, Pharmacokinetics in special populations). ).

 

Use with other medicines

 

Convulsions have been reported in patients taking imipenem-cilastatin and ganciclovir.  CymeveneGanciclovir 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 Cymeveneganciclovir and (a) didanosine, (b) drugs that aremedicines known to be myelosuppressive (e.g. zidovudine), or (c) substancesor affecting renal function, should be closely monitored for signs of added toxicity (see section 4.5 ).

 

Excipients

 

This medicinal product contains 2 mmol (43mg) sodium per 500 mg dose. To be taken into consideration by patients on a controlled sodium diet.

 

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

 

Interaction with other medicaments and other forms of interactionPharmacokinetic interactions

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, and led to statistically significantlyclinically significant increased exposure (40%).  These changes were consistent with a mechanism. Such an effect is also anticipated during concomitant administration of interaction involving competition for renal tubular secretionintravenous ganciclovir and probenecid.  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 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 Special warnings and precautions for use).  4.4).

 

Mycophenolate Mofetilmofetil, stavudine, trimethoprim and zidovudine

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.

 

Zalcitabine

No

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 givenwas administered in combination.  with either: mycophenolate mofetil, stavudine, trimethoprim or zidovudine.

 

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

Cytochrome P450 isoenzymes play no role in ganciclovir pharmacokinetics.  As a consequence, pharmacokinetic interactions with, for example, protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are unlikely due to the lack of P450 involvement in the metabolism of ganciclovirare not anticipated.

 

Pharmacodynamic interactions
 

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).

 

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 known to be myelosuppressive or associated with renal impairment (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, adriamycindoxorubicin, amphotericin B, mycophenolate mofetil, trimethoprim/sulpha combinations,sulphamethoxazole, and hydroxyurea) as well as nucleoside analogues and hydroxyurea.

(including zidovudine).

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). 4.4).

 

Paediatric population

 

Interaction studies have only been performed in adults.

 

4.6     Fertility, pregnancy Pregnancy and lactation

 

Fertility

 

In animal studies ganciclovir impaired fertility in male and female mice. Based on the occurrence of aspermatogenesis at ganciclovir exposures below therapeutic levels in animal studies, it is considered likely that ganciclovir may cause temporary or permanent inhibition of human spermatogenesis (see section 4.4).

 

Pregnancy

 

The safety of Cymeveneganciclovir for use in human pregnancy pregnant women has not been established. Ganciclovir However, ganciclovir readily diffuses across the human placenta.  Based on its pharmacological mechanism of action and In animals studies ganciclovir was associated with reproductive toxicity observed in animal studies with ganciclovir (see section 5.3 Preclinical safety data), there is a theoretical risk of and teratogenicity in humans. (see sections 4.4 and 5.3). Therefore, Cymeveneganciclovir should not be given used in pregnant women unless the clinical need for treatment of the woman outweighs the potential teratogenic risk to pregnant women as there is a high likelihood of damage to the developing the foetus.

 

WomenContraception 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 shouldmust be advised to practisepractice 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 section sections 4.4 and 5.3 Preclinical safety data).

 

Breastfeeding

 

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 nursingbreastfed infant cannot be discounted. excluded. Therefore, breastfeeding must be discontinued.  during treatment with ganciclovir (see section 4.3).

 

4.7     Effects on ability to drive and use machines

No studies on the effects

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

 

4.8       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.

 

Undesirable effects

 

Summary of the safety profile

 

In patients who were being treated with ganciclovir the most serious and common adverse drug reactions are haematological side effects werereactions and include neutropenia, anaemia and thrombocytopenia. 

 

Adverse reactions reported with i.v. ganciclovir, oral ganciclovir and valganciclovirOther adverse drugs reactions 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...  

 

Tabulated list of adverse reactions



Infections and infestations:

 

Common (³ 1/100, < 1/10):

Sepsis (bacteraemia, viraemia), cellulitis, urinary

Cellulitis

Urinary tract infection,

Candida infections including oral candidiasis.

Blood and lymphatic disorders:

 

Very common (³ 1/10):

neutropenia, anaemia.Neutropenia

Anaemia.

Common (³ 1/100, <1/10):

thrombocytopenia, leucopenia, pancytopenia.Thrombocytopenia

Leucopenia

Pancytopenia

Uncommon (³ 1/1000, < 1/100):

boneBone marrow depression.failure

Rare (³ 1/10000, < 1/1000)

Agranulocytosis*

Aplastic anaemia*

Granulocytopenia*

Immune system disorders:

 

Uncommon (³ 1/1000, < 1/100):

anaphylacticAnaphylactic reaction.

Metabolic and nutrition disorders:

 

Common (³ 1/100, < 1/10):

Decreased appetite

Anorexia

Weight decreased, anorexia.

Psychiatric disorders:

 

Common (³ 1/100, < 1/10):

depression, anxiety, confusion,Depression

Anxiety

Confusional state

Thinking abnormal thinking.

Uncommon (³ 1/1000, < 1/100):

agitation, psychoticAgitation

Psychotic disorder.

Rare (³ 1/10000, < 1/1000)

Hallucinations*

Nervous system disorders:

Common (³ 1/100, < 1/10):

 

Headache

Common (³ 1/100, < 1/10):

headache, insomnia, dysgeusiaInsomnia

Dysgeusia (taste disturbance), hypoaesthesia, paraesthesia,)

Hypoaesthesia

Paraesthesia

Neuropathy peripheral

Convulsion neuropathy, convulsions, dizziness (excluding vertigo).

Dizziness

Uncommon (³ 1/1000, < 1/100):

tremor.Tremor

Eye disorders:

 

Common (³ 1/100, < 1/10):

macularMacular oedema, retinal

Retinal detachment, vitreous

Vitreous floaters, eye

Eye pain.

Uncommon (³ 1/1000, < 1/100):

vision abnormal, conjunctivitis.Visual impairment

Conjunctivitis

Ear and labyrinth  disorders:

 

Common (³ 1/100, < 1/10):

earEar pain.

Uncommon (³ 1/1000, <1/100):

deafness.Deafness

Cardiac disorders:

 

Uncommon (³ 1/1000, < 1/100):

Cardiac arrhythmias.

Vascular disorders:

 

Uncommon (³ 1/1000, < 1/100):

hypotension. Hypotension

Respiratory, thoracic and mediastinal disorders:

 

Very common (³ 1/10):

dyspnoea.Dyspnoea

Common (³ 1/100, < 1/10):

cough.Cough

Gastrointestinal disorders:

 

Very common (³ 1/10):

diarrhoea.Diarrhoea

Common (³ 1/100, < 1/10):

nausea, vomiting, abdominalNausea

Vomiting

Abdominal pain, abdominal

Abdominal pain upper, constipation, flatulence, dysphagia, dyspepsia.

Constipation

Flatulence

Dysphagia

Dyspepsia

Uncommon (³ 1/1000, < 1/100):

abdominalAbdominal distention, mouth ulcerations, pancreatitis.

Mouth ulceration

Pancreatitis

Hepato-biliary disorders:

 

Common (³ 1/100, < 1/10):

hepaticHepatic function abnormal, blood

Blood alkaline phosphatase increased, aspartate

Aspartate aminotransferase increased.

Uncommon (³ 1/1000, < 1/100):

alanineAlanine aminotransferase increased.

Skin and subcutaneous tissues disorders:

 

Common (³ 1/100, < 1/10):

dermatitis, nightDermatitis

Night sweats, pruritus.

Pruritus

Uncommon (³ 1/1000, < 1/100):

alopecia, urticaria, dryAlopecia

Urticaria

Dry skin.

Rare (³ 1/10000, < 1/1000)

Rash*

Musculo-skeletal and connective tissue disorders:

 

Common (³ 1/100, < 1/10):

back pain, myalgia, arthralgia, muscle cramps.Back pain

Myalgia

Arthralgia

Muscle spasms

Renal and urinary disorders:

 

Common (³ 1/100, < 1/10):

creatinineCreatinine clearance renal decreased, renal

Renal impairment.

Blood creatinine increased  

Uncommon (³ 1/1000, < 1/100):

haematuria, renalHaematuria

Renal failure.

Reproductive system and breast disorders:

 

Uncommon (³ 1/1000, < 1/100):

maleMale infertility.

General disorders and administration site conditions:

 

Common (³ 1/100, < 1/10):

fatigue, pyrexia, rigors,Fatigue

Pyrexia

Chills

Pain

Chest pain, chest pain, malaise, asthenia, injection

Malaise

Asthenia

Injection site reaction (intravenous ganciclovir only).

Investigations:

 

Common (³ 1/100, < 1/10):

weight decreased, blood creatinine increased.


Note: 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.

* 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).

 

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.

 

Convulsions

 

Convulsions 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 AIDS 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 under 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. However, the rates of certain adverse reactions, such as pyrexia and abdominal pain, which may be characteristic of the paediatric population, occur more often in paediatric than in adult patients. Neutropenia also occurs more often in paediatric patients, but there is no correlation between neutropenia and infectious adverse reactions in the paediatric population.

 

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 (see details below).via Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard.

4.9       Overdose

Overdose experience with intravenous ganciclovir

 

 

Symptoms

 

Reports of overdoses with intravenousi.v. 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 experiencedthe reports were either not associated with any adverse reactions, or included one or more of the following adverse eventsreactions listed below:

 

     Haematological toxicity -: myelosuppression including 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, diarrhoea, vomiting.

     Neurotoxicity -: generalised tremor, convulsion.

 

In addition, one adult received an excessive volume of i.v. ganciclovir solutionManagement

 

Ganciclovir is removed 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 hydrationhaemodialysis, therefore haemodialysis may be of benefit in reducing blood plasma levelsdrug exposure in patients who receive an overdose of ganciclovir (see section 5.2 Pharmacokinetic properties, Patients undergoing haemodialysis).

 

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 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).

 

specific information available

 

5.       PHARMACOLOGICAL PROPERTIES

5.1     Pharmacodynamic properties

 

Pharmacotherapeutic group: ATC code: J 05 A B 06 (anti-infectives for systemic use, antiviralsAntivirals for systemic use, direct acting antivirals, nucleosides and nucleotides excluding reverse transcriptase inhibitors)., ATC code: J05AB06.

 

Mechanism of action

 

Ganciclovir is a synthetic analogue of 2’-deoxyguanosine, which inhibits replication of herpes viruses both 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 assessmentevaluation 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 toa result of 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 0.08mM (0.02mg/ml) to 14 mM (3.5mg/ml).

 

Antiviral Activity

 

The in vitro antiviral activity, measured as IC50 of ganciclovir against CMV, is in the range of 0.08 mM (0.02 mg/ml) to 14 mM (3.57 mg/ml).

 

Clinical efficacy and safety

 

Viral resistance

 

The possibility of viral resistance should be considered forin patients who repeatedly showachieve a poor clinical response or experience persistentcontinuous viral excretion during therapy.  CMV resistanttreatment.

 

Viral resistance 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 withViruses containing mutations in the UL97 gene are resistant to ganciclovir alone, whereas virusviruses with mutations in the UL54 gene are resistant to ganciclovir but may show cross-resistance to other antivirals with a similar mechanism of action and vice versathat also target viral polymerase.

 

The working definition of CMV resistance to ganciclovir based on in vitro antiviral assays is an IC50 value ³ 12.0mM with values > 6.0mM < 12.0mM 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.

 

Paediatric population

 

In a prospective study of 76 previously untreated , 36 severely immunocompromised AIDS patients with CMV retinitis starting therapy with paediatric patients (6 months - 16 years of age) with HIV and CMV infection received intravenous ganciclovir at a dose of 5 mg/kg per day for 2 days followed by oral ganciclovir (iv induction / iv maintenance or iv induction / oral maintenance), the number of patients carrying resistant virus (IC50 > 6.0mM) increased with time of for a median of 32 weeks. Ganciclovir was effective with a toxicity profile similar to that seen in adults. Ganciclovir was associated with a decrease in the detection of CMV by culture or polymerase chain reaction. Neutropenia was the only severe adverse drug reaction observed during the study and although none of the children required treatment; 3.7%, 5.4%, 11.4% and 27.5% of those still on cessation, 4 required granulocyte colony‑stimulating factor (G-CSF) treatment at baseline, 3, 6 and 12 months respectively.  Similarly in another study of AIDS patients with CMV retinitis treated for ³ 3 months with ivto maintain absolute neutrophil counts > 400 cells/mm3.

 

In a retrospective study, 122 paediatric liver transplantation recipients (16 days – 18 years of age, median age 2.5 years) received a minimum of 14 days of intravenous ganciclovir 7.85 mg/kg twice a day followed by pre‑emptive CMV PCR monitoring. Forty‑three patients were considered high-risk for CMV and 79 were routine-risk.  Asymptomatic CMV infection was detected by PCR in 34.4% of patients carried virus with IC50 ³ 12.0mM.  Combined data from 4 clinical studies of the treatment of CMV retinitis indicated an incidence of resistance (IC50 > 6.0mM) of 3.2% (median exposure 75 days) for iv subjects and was more likely in high‑risk than in routine‑risk recipients (58.1% vs. 21.8%, p = 0.0001).  Twelve subjects (9.8%) developed CMV disease (8 high-risk vs. 4 routine-risk, p = 0.03).  Three subjects developed acute rejection within 6 months of detection of CMV, but CMV was preceded by rejection in 13 subjects.  There were no deaths secondary to CMV.  A total of 38.5% of subjects were spared antiviral medications beyond their initial postoperative prophylaxis.

 

In a retrospective analysis, the safety and efficacy of ganciclovir and 6.5% (median exposure 165 days) for was compared to valganciclovir in 92 paediatric kidney and/or liver transplant patients (7 months -18 years of age, median age 9 years). All children received intravenous ganciclovir 5 mg/kg twice daily for 2 weeks following transplantation.  Children treated before 2004 then received oral ganciclovir. 30 mg/kg/dose up to 1 g/dose three times daily (n = 41), while children treated after 2004 received valganciclovir up to 900 mg once daily (n = 51).  The overall incidence of CMV was 16% (15/92 patients).  Time to onset of CMV infection was comparable in both groups. 

 

1.1                 Pharmacokinetic properties

Systemic expo