This information is intended for use by health professionals

1. Name of the medicinal product

Ganciclovir 500 mg powder for concentrate for solution for infusion

2. Qualitative and quantitative composition

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

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

Excipient(s) with known effect: approximately 45 mg (2 mEq) sodium.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Powder for concentrate for solution for infusion (powder for concentrate).

White lyophilized cake.

4. Clinical particulars

4.1 Therapeutic indications

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

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

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

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

4.2 Posology and method of administration

Posology

Treatment of CMV disease in adults and adolescents from 12 years of age with normal renal function

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

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

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in whom CMV disease progresses, either while on maintenance treatment or because treatment with ganciclovir has been withdrawn, may be re-treated using the induction treatment regimen.

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

- 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 for 7 – 14 days.

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

Renal impairment

For patients with renal impairment, the dose of ganciclovir should be modified according to creatinine clearance as shown in the table below (see sections 4.4 and 5.2).

Dose modifications for patients with renal impairment.

CrCl

Induction dose

Maintenance dose

>70 mL/min

5.0 mg/kg q12h

5.0 mg/kg/day

50-69 mL/min

2.5 mg/kg q12h

2.5 mg/kg/day

25-49 mL/min

2.5 mg/kg/day

1.25 mg/kg/day

10-24 mL/min

1.25mg/kg/day

0.625 mg/kg/day

<10 mL/min

1.25 mg/kg 3x/wk after haemodialysis

0.625 mg/kg 3x/wk after haemodialysis

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

For males:

For females: 0.85 x male value

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

Severe leucopenia, neutropenia, anaemia, thrombocytopenia and pancytopenia

See section 4.4 before initiation of treatment.

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

Elderly

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

Caution:

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

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

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

Ganciclovir is a powder for solution for infusion. After reconstitution ganciclovir 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 considered a potential teratogen and carcinogen in humans, caution should be taken in its handling (see section 6.6).

4.3 Contraindications

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

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 ganciclovir and that of aciclovir and penciclovir, a cross-hypersensitivity reaction between these drugs is possible. Caution should therefore be used when prescribing Ganciclovir to patients with known hypersensitivity to aciclovir or penciclovir (or to their prodrugs, valaciclovir or famciclovir respectively).

Mutagenicity, teratogenicity, carcinogenicity, fertility, and contraception

Prior to initiation of ganciclovir treatment, patients should be advised of the potential risks to the foetus. In animal studies ganciclovir was found to be mutagenic, teratogenic, aspermatogenic, carcinogenic and to impair fertility. It is considered likely that ganciclovir causes temporary or permanent inhibition of spermatogenesis (see sections 4.6, 4.8 and 5.3).

Ganciclovir should therefore be considered a potential teratogen and carcinogen in humans with the potential to cause birth defects and cancers. Therefore, women of child bearing potential must be advised to use effective contraception during treatment and for at least 30 days thereafter. Men must be advised to practice barrier contraception during treatment, and for at least 90 days thereafter, unless it is certain that the female partner is not at risk of pregnancy (see sections 4.6, 4.8 and 5.3).

The use of ganciclovir warrants extreme caution, especially in the paediatric population due to the potential for long-term carcinogenicity and reproductive toxicity. The benefits of treatment should be carefully considered in each case and should clearly outweigh the risks (see section 4.2). Refer to treatment guidelines.

Myelosuppression

Ganciclovir 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 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 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 to consider the use of treatment with haematopoietic growth factors and/or the interruption of ganciclovir therapy (see sections 4.2 and 4.8).

Renal impairment

Patients with impaired renal function are at increased risk of toxicity (especially haematological toxicity). Dosage reduction is required (see sections 4.2 and 5.2).

Use with other medicines

Convulsions have been reported in patients taking imipenem-cilastatin and ganciclovir. Ganciclovir should not be used concomitantly with imipenem-cilastatin unless the potential benefits outweigh the potential risks (see section 4.5).

Patients treated with ganciclovir and didanosine, medicines known to be myelosuppressive or affecting renal function, should be closely monitored for signs of added toxicity (see section 4.5).

Excipients

This medicinal product contains 2 mmol (45mg) 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

Pharmacokinetic interactions

Probenecid

Probenecid given with oral ganciclovir resulted in statistically decreased renal clearance of ganciclovir, and led to clinically significant increased exposure. Such an effect is also anticipated during concomitant administration of intravenous ganciclovir and probenecid. Therefore, patients taking probenecid and Ganciclovir should be closely monitored for ganciclovir toxicity.

Didanosine

Didanosine plasma concentrations were found to be consistently raised when given with ganciclovir. At intravenous doses of 5 and 10 mg/kg/day, an increase in the AUC of didanosine ranging from 38% to 67% has been observed. There was no clinically significant effect on ganciclovir concentrations. Patients should be closely monitored for didanosine toxicity (see section 4.4).

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.

Other antiretrovirals

Cytochrome P450 isoenzymes play no role in ganciclovir pharmacokinetics. As a consequence, pharmacokinetic interactions with protease inhibitors and non-nucleoside reverse transcriptase inhibitors are not anticipated.

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 other drugs known to be myelosuppressive or associated with renal impairment (such as dapsone, pentamidine, flucytosine, vincristine, vinblastine, doxorubicin, amphotericin B, mycophenolate mofetil, trimethoprim/sulphamethoxazole, and hydroxyurea) as well as nucleoside analogues (including zidovudine). Therefore, these drugs should be considered for concomitant use with ganciclovir only if the potential benefits outweigh the potential risks (see section 4.4).

Paediatric population

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Fertility

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 ganciclovir for use in pregnant women has not been established. However, ganciclovir readily diffuses across the human placenta. In animals studies ganciclovir was associated with reproductive toxicity and teratogenicity (see sections 4.4 and 5.3). Therefore, ganciclovir should not be used in pregnant women unless the clinical need for treatment of the woman outweighs the potential teratogenic risk to the foetus.

Contraception in males and females

As a result of the potential for reproductive toxicity and teratogenicity, women of childbearing potential must be advised to use effective contraception during and for at least 30 days after treatment. Male patients must be advised to practice barrier contraception during and for at least 90 days following treatment with ganciclovir unless it is certain that the female partner is not at risk of pregnancy (see sections 4.4 and 5.3).

Breastfeeding

It is unknown if ganciclovir is excreted in human breast milk, but the possibility of ganciclovir being excreted in breast milk and causing serious adverse reactions in the breastfed infant cannot be excluded. Therefore, breastfeeding must be discontinued during treatment with ganciclovir (see section 4.3).

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

In patients treated with ganciclovir the most serious and common adverse drug reactions are haematological reactions and include neutropenia, anaemia and thrombocytopenia. Other adverse drugs reactions are presented in the table below.

Infections and infestations:

Common (≥ 1/100, < 1/10)

Sepsis

Cellulitis

Urinary tract infection

Candida infections including 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

Rare (≥ 1/1000, < 1/1000):

Agracnulocytosis*

Aplastic anemia*

Granulocytopenia*

Immune system disorders:

Uncommon (≥ 1/1000, < 1/100):

Anaphylactic reaction

Metabolic and nutrition disorders:

Common (≥ 1/100, < 1/10):

Decreased appetite

Anorexia

Weight decreased

Psychiatric disorders:

Common (≥ 1/100, < 1/10):

Depression

Anxiety

Confusional state

Thinking abnormal

Uncommon (≥ 1/1000, < 1/100):

Agitation

Psychotic disorder

Rare (≥ 1/1000, < 1/1000):

Hallucinations*

Nervous system disorders:

Common (≥ 1/100, < 1/10):

Headache

Insomnia

Dysgeusia (taste disturbance)

Hypoaesthesia

Paraesthesia

Neuropathy peripheral

Convulsion

Dizziness

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):

Visual impairment

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):

Cardiac 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 ulceration

Pancreatitis

Hepato-biliary disorders:

Common (≥ 1/100, < 1/10):

Hepatic function abnormal

Blood alkaline phosphatase increased

Aspartate aminotransferase increased.

Uncommon (≥ 1/1000, < 1/100):

Alanine aminotransferase increased.

Skin and subcutaneous tissues disorders:

Common (≥ 1/100, < 1/10):

Dermatitis

Night sweats

Pruritus.

Uncommon (≥ 1/1000, < 1/100):

Alopecia

Urticaria

Dry skin.

Rare (≥ 1/1000, < 1/1000):

Rash *

Musculo-skeletal and connective tissue disorders:

Common (≥ 1/100, < 1/10):

Back pain

Myalgia

Arthralgia

Muscle spasms.

Renal and urinary disorders:

Common (≥ 1/100, < 1/10):

Creatinine clearance renal decreased

Renal impairment

Blood creatinine increased

Uncommon (≥ 1/1000, < 1/100):

Haematuria,

Renal failure.

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

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).

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 Ganciclovir for CMV retinitis.

Injection site reactions

Injection site reactions occur commonly in patients receiving ganciclovir. Ganciclovir 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 via the national reporting system listed in Appendix V.

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, 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

Management

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

Additional information on special populations

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

Paediatric population

No specific information available

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antivirals 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), varicella-zoster virus (VZV), and hepatitis B virus. Clinical studies have been limited to evaluation 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 6−24 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 a 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

Antiviral Activity

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

Clinical efficacy and safety

Viral resistance

The possibility of viral resistance should be considered in patients who repeatedly achieve a poor clinical response or experience continuous viral excretion during treatment.

Viral resistance to ganciclovir can arise by selection of mutations in the viral kinase gene (UL97) responsible for ganciclovir monophosphorylation and/or the viral polymerase gene (UL54). Viruses containing mutations in the UL97 gene are resistant to ganciclovir alone, whereas viruses with mutations in the UL54 gene are resistant to ganciclovir but may show cross-resistance to other antivirals that also target viral polymerase.

Paediatric population

In a prospective study, 36 severely immunocompromised 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 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 cessation, 4 required granulocyte colony-stimulating factor (G-CSF) treatment to 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 5 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 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 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.

In a randomised, controlled study, 100 neonates (≤1 month of age) with symptomatic congenital CMV disease with CNS involvement received 6 weeks of intravenous ganciclovir 6 mg/kg every 12 hours or no treatment. Of the 100 patients enrolled, 42 met all study criteria and had both baseline and 6-month follow up audiometric evaluations. Of these, 25 received ganciclovir and 17 received no treatment. Twenty-one of 25 ganciclovir recipients had improved hearing or maintained normal hearing from baseline to 6 months compared with 10/17 control patients (84% and 59%, respectively p = 0.06). None of the ganciclovir recipients had worsening hearing from baseline to 6 months, compared with 7 control patients (p < 0.01). By one year after baseline, 5/24 ganciclovir recipients and 13/19 control patients had worsening hearing (p < 0.01). During the course of the study, 29/46 ganciclovir-treated patients had neutropenia, compared with 9/43 control patients (p < 0.1). There were 9 deaths during the study, 3 in the ganciclovir group and 6 in the control group. No deaths were related to study medication.

In a Phase III, randomised, controlled study, 100 neonates (3-33 days of age, median age 12 days) with severe symptomatic congenital CMV with CNS involvement, received either intravenous ganciclovir 6 mg/kg twice daily for 6 weeks (n = 48) or no antiviral treatment (n = 52). Infants who received ganciclovir had improved neurodevelopmental outcomes at 6 and 12 months compared with those who did not receive antiviral treatment. Although ganciclovir recipients had fewer delays and more normal neurological outcomes, most were still behind what would be considered normal development at 6 weeks, 6 months, or 12 months of age. Safety was not assessed in this study.

A retrospective study investigated the effect of antiviral treatment on late-onset hearing loss in infants with congenital CMV infection (4-34 months of age, mean age 10.3±7.8 months, median age 8 months). The study included 21 infants with normal hearing at birth who developed late-onset hearing loss. Antiviral treatment consisted of either:

- Intravenous ganciclovir 5 mg/kg daily for 6 weeks followed by oral valganciclovir 17 mg/kg twice daily for 6 weeks then daily until 1 year of age, or

- Oral valganciclovir 17 mg/kg twice daily for 12 weeks then daily for 9 months.

None of the children required a cochlear implant and hearing loss improved in 83% of ears affected by hearing loss at baseline. Neutropenia was the only side effect reported and it was not necessary to discontinue treatment in any patient.

5.2 Pharmacokinetic properties

The pharmacokinetic properties of ganciclovir have been evaluated in HIV- and CMV-seropositive patients, patients with AIDS and CMV retinitis, and in solid organ transplant patients.

Distribution

The volume of distribution of intravenously administered ganciclovir is correlated to body weight. The steady state volume of distribution has a range of 0.54−0.87 L/kg. Plasma protein binding was 1%−2% over ganciclovir concentrations of 0.5 and 51 µg/mL. Ganciclovir penetrates the cerebrospinal fluid, where concentrations observed reach 24%−67% of the plasma concentrations.

Biotransformation

Ganciclovir is not metabolised to a significant extent.

Elimination

Ganciclovir is predominantly eliminated by renal excretion via glomerular filtration and active tubular secretion of unchanged ganciclovir. In patients with normal renal function, more than 90% of the intravenously administered ganciclovir dose is recovered unchanged in the urine within 24 hours. The mean systemic clearance ranged from 2.64 ± 0.38 mL/min/kg (N = 15) to 4.52 ± 2.79 mL/min/kg (N = 6) and renal clearance ranged from 2.57 ± 0.69 mL/min/kg (N = 15) to 3.48 ± 0.68 mL/min/kg (N = 20), 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).

Linearity/non-linearity

Intravenous ganciclovir exhibits linear pharmacokinetics over the range of 1.6−5.0 mg/kg.

Patients with renal impairment

The total plasma 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 and, depending on renal

Serum creatinine
(µmol/L
)

Creatinine clearance
(mL/min)

Mean Ganciclovir systemic plasma clearance (mL/min)

Mean Ganciclovir Plasma half-life (hours)

< 125

≥ 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 Renal Impairment Undergoing Haemodialysis

Haemodialysis reduces plasma concentrations of ganciclovir by about 50% after intravenous administration during a 4-hour haemodialysis session.

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

Paediatric Population

The pharmacokinetics of intravenous ganciclovir were investigated in neonates aged 2−49 days following doses of 4 mg/kg (N = 14) and 6 mg/kg (N = 13). Mean Cmax was 5.5 ± 6 µg/mL at 4 mg/kg and 7.0 ± 1.6 µg/mL at 6 mg/kg. Mean values for the steady state volume of distribution (0.7 L/kg) and systemic clearance (3.15 ± 0.47 mL/min/kg at 4 mg/kg and 3.55 ± 0.35 mL/min/kg at 6 mg/kg) were comparable to those observed in adults with normal renal function.

Pharmacokinetics of intravenous ganciclovir were also studied in infants and children with normal renal function and aged 9 months−12 years. The pharmacokinetic characteristics of ganciclovir were the same after single and multiple (q12h) 5 mg/kg intravenous doses. Exposure as measured by mean AUC0−∞ on Days 1 and 14 were 19.4 ± 7.1 and 24.1 ± 14.6 µg.h/mL, respectively, and the corresponding Cmax values were 7.59 ± 3.21 µg/mL (Day 1) and 8.31 ± 4.9 µg/mL (Day 14). The range of exposures was comparable to those observed in adults. The corresponding values of mean systemic clearance, mean renal clearance, and mean elimination half-life were 4.66 ± 1.72 mL/min/kg, 3.49 ± 2.40 mL/min/kg, and 2.49 ± 0.57 h, respectively. The pharmacokinetics of intravenous ganciclovir in infants and children were consistent with those observed in neonates and adults.

Elderly

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

6. Pharmaceutical particulars

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.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life

36 months.

After reconstitution:

Chemical and physical in-use stability has been demonstrated for 12 hours at 25°C.

After dissolving with water for injections. Do not refrigerate or freeze.

From a microbiological point of view, the reconstituted solution should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

After dilution:

Chemical and physical in-use stability has been demonstrated for 24 hours at 2° to 8° C.

From a microbiological point of view, the product should be used immediately. If not used immediately, the in use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 – 8°C, unless reconstitution has been taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

Undiluted vials: This medicinal product does not require any special storage conditions

For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3

6.5 Nature and contents of container

Single-dose glass vials of 10 mL (Type I, clear glass) with a (grey) chlorobutyl rubber stopper and aluminium cap.

Available in packs of 5 vial or 25vials.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Caution should be exercised in the handling of Ganciclovir

Since Ganciclovir 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. Ganciclovir 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 Ganciclovir solution

1. Lyophilised Ganciclovir 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 Ganciclovir 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 Ganciclovir 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 Ganciclovir. Infusion concentrations greater than 10mg/ml are not recommended.

Ganciclovir should not be mixed with other iv products.

Because Ganciclovir 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.

7. Marketing authorisation holder

Laboratorio Reig Jofre, S.A.

Gran Capitan 10

08970 Sant Joan Despí (Barcelona)

Spain

8. Marketing authorisation number(s)

PL 25174/0033

9. Date of first authorisation/renewal of the authorisation

18/04/2017

10. Date of revision of the text

18/04/2017