GanciCedal^®

Gancicedal® 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 using pre-emptive therapy in patients with drug-induced immuno-suppression (for example following organ transplantation or cancer chemotherapy).

 Gancicedal® is also indicated from birth for the:

• Prevention of CMV disease using universal prophylaxis in patients with drug-induced immuno-suppression (for example following organ transplantation or cancer chemotherapy).

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

• Hypersensitivity to the active substance or valganciclovir or to any of the excipients such as Sodium hydroxide and Hydrochloric acid
• Breast-feeding

.Warnings and Precautions:

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 Gancicedal® 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 Gancicedal® 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.

Gancicedal® 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.

The use of Gancicedal® 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. Refer to treatment guidelines.

Myelosuppression

Gancicedal® 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. 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 Gancicedal® therapy.

Renal impairment

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

Use with other medicines

Convulsions have been reported in patients taking imipenem-cilastatin and ganciclovir. Gancicedal® should not be used concomitantly with imipenem-cilastatin unless the potential benefits outweigh the potential risks. Patients treated with ganciclovir and didanosine, medicines known to be myelosuppressive or affecting renal function, should be closely monitored for signs of added toxicity.

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

Renal function

The use of Zoledronic Acid in patients with severe renal impairment (creatinine clearance < 35 ml/min) is contraindicated due to an increased risk of renal failure in this population. Renal impairment has been observed following the administration of Zoledronic Acid, espe-cially in patients with pre-existing renal dysfunction or other risks including advanced age, concomitant nephrotoxic medicinal products, concomitant diuretic therapy, or dehydration occurring after Zoledronic Acid administration. Renal impairment has been observed in patients after a single administration. Renal failure requiring dialysis or with a fatal outcome has rarely occurred in patients with underlying renal impairment or with any of the risk factors described above.

The following precautions should be taken into account to minimise the risk of renal ad-verse reactions:

• Creatinine clearance should be calculated based on actual body weight using the Cock-croft-Grault formula before each Zoledronic Acid dose.
• Transient increase in serum creatinine may be greater in patients with underlying im-paired renal function.
• Monitoring of serum creatinine should be considered in at-risk patients.
• Zoledronic Acid should be used with caution when concomitantly used with other medici-nal products that could impact renal function.
• Patients, especially elderly patients and those receiving diuretic therapy, should be appro-priately hydrated prior to administration of Zoledronic Acid.
• A single dose of Zoledronic Acid should not exceed 5 mg and the duration of infusion should be at least 15 minutes.

Hypocalcaemia

Pre-existing hypocalcaemia must be treated by adequate intake of calcium and vitamin D

before initiating therapy with Zoledronic Acid. Other disturbances of mineral metabolism must also be

effectively treated (e.g. diminished parathyroid reserve, intestinal calcium malabsorption). Physicians should consider clinical monitoring for these patients.

Elevated bone turnover is a characteristic of Paget’s disease of the bone. Due to the rapid onset of effect of zoledronic acid on bone turnover, transient hypocalcaemia, sometimes symptomatic, may develop and is usually maximal within the first 10 days after infusion of Zoledronic Acid.

Adequate calcium and vitamin D intake are recommended in association with Zoledronic Acid administration. In addition, in patients with Paget’s disease, it is strongly advised that adequate supplemental calcium corresponding to at least 500 mg elemental calcium twice daily is ensured for at least 10 days following Zoledronic Acid administration.

Patients should be informed about symptoms of hypocalcaemia and receive adequate clin-ical monitoring during the period of risk. Measurement of serum calcium before infusion of Zoledronic Acid is recommended for patients with Paget´s disease.

Severe and occasionally incapacitating bone, joint and/or muscle pain have been infre-quently reported in patients taking bisphosphonates, including Zoledronic Acid.

Osteonecrosis of the jaw (ONJ)

ONJ has been reported in the post-marketing setting in patients receiving Zoledronic Acid for osteoporosis.

The start of treatment or of a new course of treatment should be delayed in patients with unhealed open soft tissue lesions in the mouth. A dental examination with preventive den-tistry and an individual benefit-risk assessment is recommended prior to treatment with Zoledronic Acid in patients with concomitant risk factors.

The following should be considered when evaluating a patient’s risk of developing ONJ:

–  Potency of the medicinal product that inhibits bone resorption (higher risk for highly potent compounds), route of administration (higher risk for parenteral administration) and cumula-tive dose of bone resorption therapy.

 – Cancer, co-morbid conditions (e.g. anaemia, coagulopathies, infection), smoking.

–  Concomitant therapies: corticosteroids, chemotherapy, angiogenesis inhibitors, radiother-apy to head and neck.

– Poor oral hygiene, periodontal disease, poorly fitting dentures, history of dental disease, invasive dental procedures, e.g. tooth extractions.

All patients should be encouraged to maintain good oral hygiene, undergo routine dental check-ups, and immediately report any oral symptoms such as dental mobility, pain or swelling, non-healing of sores or discharge during treatment with zoledronic acid. While on treatment, invasive dental procedures should be performed with caution and avoided in close proximity to zoledronic acid treatment.

The management plan for patients who develop ONJ should be set up in close collabo-ration between the treating physician and a dentist or oral surgeon with expertise in ONJ. Temporary

interruption of zoledronic acid treatment should be considered until the condition resolves and contributing risk factors are mitigated where possible.

Osteonecrosis of the external auditory canal

Osteonecrosis of the external auditory canal has been reported with bisphosphonates, mainly in association with long-term therapy. Possible risk factors for osteonecrosis of the external auditory canal include steroid use and chemotherapy and/or local risk factors such as infection or trauma. The possibility of osteonecrosis of the external auditory canal should be considered in patients receiving bisphosphonates who present with ear symptoms in-cluding chronic ear infections.

Atypical fractures of the femur

Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bis-phosphonate therapy, primarily in patients receiving long-term treatment for osteoporosis. These transverse or short oblique fractures can occur anywhere along the femur from just below the lesser trochanter to just above the supracondylar flare. These fractures occur after minimal or no trauma and some patients experience thigh or groin pain, often asso-ciated with imaging features of stress fractures, weeks to months before presenting with a completed femoral fracture. Fractures are often bilateral; therefore, the contralateral femur should be examined in bisphosphonate-treated patients who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. Discontinuation of bisphosphonate therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient, based on an individual benefit risk assessment.

During bisphosphonate treatment patients should be advised to report any thigh, hip or groin pain and any patient presenting with such symptoms should be evaluated for an incomplete femur fracture.

Acute phase reactions

Acute phase reactions (APRs) or post-dose symptoms such as fever , myalgia , flu-like symptoms, arthralgia and headache have been observed, the majority of which occurred within three days following Zoledronic acid administration.

APRs may sometimes be serious or prolonged in duration. The incidence of post-dose symptoms can be reduced with the administration of paracetamol or ibuprofen shortly following Zoledronic acid administration. It is also advisable to postpone treatment if the patient is clinically unstable due to an acute medical condition and an APR could be prob-lematic.

General

Other products containing zoledronic acid as an active substance are available for oncolo-gy indications. Patients being treated with Zoledronic acid should not be treated with such products or any other bisphosphonate concomitantly, since the combined effects of these agents are unknown.

This medicinal product contains less than 1 mmol sodium (23 mg) per 100 ml vial of Zole-dronic acid, i.e. essentially “sodium free”.

Dosage:

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:

There is limited information  about Gancicedal® use in children under 12 years. 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:

There is limited information  about Gancicedal® use in children under 12 years. 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 s 16 years of age.

The recommended once daily dose of ganciclovir given as an intravenous infusion over one hour is based on Body Surface Area (BSA) using the Mosteller BSA formula and creatinine clearance derived from Schwartz formula (CrCLS) and is calculated using the equations below. The duration of universal prophylaxis is based on the risk of CMV disease and should be de-termined on an individual basis. Paediatric dose (mg) = 3 x BSA x CrCLS (see Mosteller BSA formula and Schwartz Creatinine Clearance formula below). If the calculated Schwartz creatinine clearance exceeds 150 mUmin/1.73m2, then a maximum value of 150 mUmin/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 5 16 years of age) with renal impairment receiving a pro-phylactic 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

Dose Adjustments Recommendations

 Renal impairment

For patients with renal impairment, the dose of Gancicedal® should be modified according to creatinine clearance as shown in the table below.

Dose modifications for patients with renal impairment:

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 patients with renal impairment, serum creatinine or estimated creatinine-clearance levels should be monitored.

Severe leucopenia, neutropenia, anaemia, thrombocytopenia and pancytopenia

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.

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

Method of Administration:

Caution:

Gancicedal® 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 Gancicedal®.

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

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

Gancicedal® is a powder for solution for infusion. After reconstitution Gancicedal® 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.

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

Since Gancicedal® is considered a potential teratogen and carcinogen in humans, caution should be taken in its handling.

Preparation of the reconstituted concentrate

Aseptic technique should be used throughout to reconstitute lyophilised Gancicedal®.

1. 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 Gancicedal®.
2. 2. The vial should be gently swirled in order to ensure complete wetting of the product.
3. 3. The vial should be gently rotated/ swirled for some minutes to obtain a clear reconstituted solution.
4. 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 Gancicedal® range in colour from colourless to light yellow.

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 Gancicedal®.

Gancicedal® should not be mixed with other intravenous products.

The diluted solution should then be infused intravenously over 1 hour. 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.

Like all medicines, this medicine can cause side effects, although not everybody gets them. Side effects with Gancicedal® may include:

• >10%:

Dermatologic: Diaphoresis (12%)

Gastrointestinal: Diarrhea (44%), anorexia (14%), vomiting (13%)

Hematologic & oncologic: Thrombocytopenia (57%), leukopenia (41%), anemia (16% to 26%), neutropenia (ANC <500/mm3: 12% to 14%)

Infection: Sepsis (15%)

Ophthalmic: Retinal detachment (11%; relationship to ganciclovir not established)

Renal: Increased serum creatinine (2% to 14%)

Miscellaneous: Fever (48%)

• 1-10%:

Central nervous system: Chills (10%), neuropathy (9%)

Dermatologic: Pruritus (5%)

• <1%:

 Postmarketing, and/or case reports: Alopecia, brain disease, bronchospasm, cardiac arrhythmia, cataract, cholestasis, coma, dyspnea, edema, eosinophilia, exfoliative dermatitis, extrapyramidal reaction, hemorrhage, hepatic failure, hepatitis, hypersensitivity reaction (including anaphylaxis), pancreatitis, pancytopenia, psychosis, pulmonary fibrosis, renal failure, rhabdomyolysis, seizure, SIADH (syndrome of inappropriate antidiuretic hormone secretion), Stevens-Johnson syndrome, torsades de pointes, urticaria, vision loss

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. Please report any adverse drug reactions via contacting Cedal Nano.(1)

Overdosage

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.

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.

Paediatric population

No specific information available

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 Gancicedal® 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.

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.

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.

Paediatric population

Interaction studies have only been performed in adults.

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. Therefore, Gancicedal® should not be used in pregnant women unless the clinical need for treatment of the woman outweighs the potential teratogenic risk to the foetus.

Breast feeding

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 Gancicedal®.

Paediatric Use

There is limited information on how safe or effective Gancicedal® is in children under 12 years.

Geriatric Use

Clinical studies of ganciclovir did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Ganciclovir is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because renal clearance decreases with age, Gancicedal® should be administered to elderly patients with special consideration of their renal status. Renal function should be monitored and dosage adjustments should be made accordingly

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.

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 Gancicedal® unless it is certain that the female partner is not at risk of pregnancy.

Effects on ability to drive and use machines

Gancicedal® may have a major influence on the ability to drive and use machines.

How Supplied

Gancicedal® is a white to off white powder for concentrate for solution for infusion, supplied in a singled dose glass vial. Reconstituted solutions of Gancicedal® range in colour from colourless to light yellow.

Handling and disposal

Caution should be exercised in the handling of Gancicedal®.

Since Gancicedal® 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. Gancicedal® solutions are alkaline (pH ~11). If such contact occurs, wash thoroughly with soap and water, rinse eyes thoroughly with plain water.

Disposal

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

Shelf life

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 Gancicedal® 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.

Storage

Store the dry powder at a temperature below 30 °C and away from moisture.

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