CYMEVENE Powder for concentrate for solution Ref.[8186] Active ingredients: Ganciclovir

Posology

Treatment of CMV disease

Adults and Paediatric Population ≥12 years of age with normal renal function

• Induction treatment: 5 mg/kg given as an intravenous infusion over one hour, every 12 hours for 14 – 21 days.
• Maintenance treatment: For immunocompromised patients at risk of relapse maintenance therapy may be given. 5 mg/kg given as an intravenous infusion over one hour, once daily on 7 days per week or 6 mg/kg once daily on 5 days per week. The duration of maintenance treatment should be determined on an individual basis, local treatment guidelines should be consulted.
• Treatment of disease progression: Any patient, in whom CMV disease progresses, either while on maintenance treatment or because treatment with ganciclovir has been withdrawn, may be re-treated using the induction treatment regimen.

Paediatric population from birth to <12 years of age

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

Prevention of CMV disease using pre-emptive therapy

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

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

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

Paediatric population from birth to <12 years of age

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

Prevention of CMV disease using universal prophylaxis

Adults and paediatric population >16 years of age

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

Paediatric population from birth to ≤16 years of age

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

Paediatric dose (mg) = 3 x BSA x CrCLS (see Mostellar BSA formula and Schwartz Creatinine Clearance formula below).

If the calculated Schwartz creatinine clearance exceeds 150 mL/min/1.73m², then a maximum value of 150 mL/min/1.73m² should be used in the equation:

where k = 0.33 for patients <1 year of age with low birth weight, 0.45 for patients aged < 2 years, 0.55 for boys aged 2 to < 13 years and girls aged 2 to 16 years, and 0.7 for boys aged 13 to 16 years. Refer to adult dosing for patients older than 16 years of age.

The k values provided are based on the Jaffe method of measuring serum creatinine, and may require correction when enzymatic methods are used.

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

Special dosage instructions

Renal impairment

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

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

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

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

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

Hepatic impairment

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

Severe leukopenia, neutropenia, anaemia, thrombocytopenia and pancytopenia

See section 4.4 before initiation of treatment.

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

Elderly

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

Method of administration

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

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

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

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

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

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

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).

Symptoms

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

• Haematological toxicity: myelosuppression including pancytopenia, bone marrow failure, leukopenia, neutropenia, granulocytopenia
• Hepatotoxicity: hepatitis, liver function disorder
• Renal toxicity: worsening of haematuria in a patient with pre-existing renal impairment, acute kidney injury, elevated creatinine.
• Gastrointestinal toxicity: abdominal pain, diarrhoea, vomiting
• Neurotoxicity: generalised tremor, seizure

Management

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

Additional information on special populations

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

Paediatric population

No specific information available

3 years.

After reconstitution: Chemical and physical in-use stability has been demonstrated for the reconstituted product 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 2-8°C (do not freeze).

From a microbiological point of view, the Cymevene infusion solution should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and should not be longer than 24 hours at 2°C to 8°C, unless reconstitution and dilution have taken place in controlled and validated aseptic conditions.

This medicinal product does not require any special storage conditions.

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

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.

Caution should be exercised in the handling of Cymevene.

Since Cymevene is considered a potential teratogen and carcinogen in humans, caution should be observed in its handling. Avoid inhalation or direct contact of the powder contained in the vials or direct contact of the reconstituted solution with the skin or mucous membranes. Cymevene solutions are alkaline (pH ~11). If such contact occurs, wash thoroughly with soap and water, rinse eyes thoroughly with plain water.

Preparation of the reconstituted concentrate

Aseptic technique should be used throughout to reconstitute lyophilised Cymevene.

1. The flip-off cap should be removed to expose the central portions of the rubber stopper. Draw 10 mL of water for injection into a syringe, then slowly inject through the centre of the rubber stopper into the vial pointing the needle towards the wall of the vial. Do not use bacteriostatic water for injection containing parabens (para-hydroxybenzoates), since these are incompatible with Cymevene.

2. The vial should be gently swirled in order to ensure complete wetting of the product.

3. The vial should be gently rotated/ swirled for some minutes to obtain a clear reconstituted solution.

4. The reconstituted solution should be checked carefully to ensure that the product is in solution and practically free from visible particles prior to dilution with compatible solvent. Reconstituted solutions of Cymevene range in colour from colourless to light yellow.

For storage conditions of the reconstituted concentrate, see sections 6.3.

Preparation of final diluted solution for infusion

Based on patient weight the appropriate volume should be removed with a syringe from the vial and further diluted into an appropriate infusion solution. Add a volume of 100ml of diluent to the reconstituted solution. Infusion concentrations greater than 10mg/mL are not recommended.

Sodium chloride, dextrose 5%, Ringer’s or lactated Ringer’s solutions are determined chemically or physically compatible with Cymevene.

Cymevene should not be mixed with other intravenous products.

The diluted solution should then be infused intravenously over 1 hour as directed in section 4.2. Do not administer by intramuscular or subcutaneous injection because this may result in severe tissue irritation due to the high pH (~11) of ganciclovir solution.

For storage conditions of the diluted solution for infusion, see section 6.3.

Disposal

For single use only. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.