1.1 THERAPEUTIC / PHARMACOLOGIC
CLASS OF DRUG: Antiviral
ATC code: J05AB06
1.2 TYPE OF DOSAGE FORM
Powder for concentrate for solution for infusion
1.3 ROUTE OF ADMINISTRATION
Intravenous (IV) infusion
1.4 STERILE / RADIOACTIVE STATEMENT
Sterile product
1.5 QUALITATIVE AND QUANTITATIVE
Active ingredient: Ganciclovir I.P. in the form of the sodium salt. Vials containing dry substance equivalent to 500 mg ganciclovir I.P. and approximately 43 mg (2 mEq) sodium. Excipients: Sodium Hydroxide, Hydrochloric Acid, Water for Injection, Nitrogen.
Cymevene vials are indicated for the treatment of cytomegalovirus (CMV) disease in immunocompromised individuals and for the prevention of CMV disease in patients with drug-induced immunosuppression following organ transplantation or cancer chemotherapy.
2.2 DOSAGE AND ADMINISTRATION
General:
Cymevene must be reconstituted and diluted under the supervision of a healthcare professional and administered as an intravenous infusion (see section 4.2 Special Instructions for Use, Handling and Disposal).
Caution:
Cymevene must only be administered by IV infusion over 1 hour, preferably via a plastic cannula, into
a vein with adequate blood flow (intramuscular or subcutaneous injection may result in severe tissue irritation due to the high pH (~11) of ganciclovir solutions). Do not administer by rapid or bolus IV injection because the resulting excessive plasma levels may increase the toxicity of Cymevene (see section 4.2 Special Instructions for Use, Handling and Disposal).
The recommended dosage, frequency, or infusion rates should not be exceeded.
Dosage for patients with normal renal function
Induction treatment: 5 mg/kg given as an IV 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 IV 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.
Treatment of disease progression: Any patient, in whom CMV disease progresses, either while on maintenance treatment or because treatment with Cymevene has been withdrawn, may be re-treated using the induction treatment regimen.
Dosage for patients with normal renal function
Prophylaxis: 5 mg/kg given as an IV 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 and should be determined on an individual basis. Pre-emptive therapy: Induction treatment: 5 mg/kg given as an IV infusion over one hour, every 12 hours for 7 – 14 days. Maintenance treatment: 5 mg/kg given as an IV 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 is based on the risk of CMV disease and should be determined on an individual basis. Children Safety and efficacy of ganciclovir in pediatrics have not been established, including use for the treatment of congenital or neonatal CMV infections. 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 (see section 3.2.5 Pharmacokinetics in Special Populations, Children). Geriatric patients No studies have been conducted in adults older than 65 years of age. Since renal clearance decreases with age, Cymevene should be administered to geriatric patients with special consideration of their renal status (see Table 1 and section 3.2.5 Pharmacokinetics in Special Populations, Geriatric population). Renal impairment For patients with renal impairment, the dose of Cymevene should be modified as shown in the table below. Table 1: Cymevene dosing for renally impaired patients. 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 hemodialysis 0.625 mg/kg 3x/wk after hemodialysis Estimated creatinine clearance can be related to serum creatinine by the following formulae: For males: (140 – age [years]) x (body weight [kg]) (72) x (0.011 x serum creatinine [micromol/L]) For females: 0.85 x male value As dosage modifications are recommended in patients with renal impairment, serum creatinine or estimated creatinineclearance levels should be monitored carefully. Hepatic impairment The safety and efficacy of Cymevene have not been studied in patients with hepatic impairment (see section 3.2.5 Pharmacokinetics in Special Populations, Hepatic impairment). 2.3 CONTRAINDICATIONS Cymevene is contraindicated in patients with hypersensitivity to ganciclovir, valganciclovir or to any of the excipients. 2.4 WARNINGS AND PRECAUTIONS 2.4.1 General Cross hypersensitivity Due to the similarity of the chemical structure of ganciclovir and that of aciclovir and penciclovir, a crosshypersensitivity reaction between these drugs is possible. Caution should therefore be used when prescribing Cymevene to patients with known hypersensitivity to aciclovir or penciclovir, (or to their prodrugs, valaciclovir or famciclovir respectively). Mutagenicity, teratogenicity, carcinogenicity, fertility and contraception In animal studies, ganciclovir was found to be mutagenic, teratogenic, carcinogenic and to impair fertility. Cymevene should therefore be considered a potential teratogen and carcinogen in humans with the potential to cause birth defects and cancers. Prior to initiation of ganciclovir treatment, patients should be advised of the potential risks to the fetus and to use contraceptive measures. Based on clinical and nonclinical studies, Cymevene may cause temporary or permanent inhibition of spermatogenesis (see sections 2.5.1. Females and Males of Reproductive Potential, 2.5.2 Pregnancy, 2.5.3 Lactation, 2.6 Undesirable effects, 3.3 Nonclinical Safety and 4.2 Special Instructions for Use, Handling and Disposal). Myelosuppression Cymevene should be used with caution in patients with pre-existing hematological cytopenia or a history of drug-related hematological cytopenia and in patients receiving radiotherapy. Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, bone marrow failure and aplastic anemia have been observed in patients treated with Cymevene. 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 hemoglobin is less than 8 g/dL, (see section 2.6 Undesirable Effects). It is recommended that complete blood counts including platelet counts be monitored in all patients during therapy, particularly in patients with renal impairment (see section 2.4.4 Laboratory Tests). In patients with severe leukopenia, neutropenia, anemia and/or thrombocytopenia, treatment with hematopoietic growth factors and/or the interruption of therapy is recommended (see section 2.6 Undesirable Effects). Use with other medicines Seizures have been reported in patients taking imipenemcilastatin and ganciclovir. Cymevene should not be used concomitantly with imipenem-cilastatin unless the potential benefits outweigh the potential risks (see section 2.8 Interactions with other Medicinal Products and other Forms of Interactions). Zidovudine and Cymevene each have the potential to cause neutropenia and anemia. Some patients may not tolerate concomitant therapy at full dosage (see section 2.8 Interactions with other Medicinal Products and other Forms of Interactions). Didanosine plasma concentrations may increase during concomitant use with Cymevene; therefore, patients should be closely monitored for didanosine toxicity (see section 2.8 Interactions with other Medicinal Products and other Forms of Interactions). Concomitant use of other drugs that are known to be myelosuppressive or associated with renal impairment with Cymevene may result in added toxicity (see section 2.8 Interactions with other Medicinal Products and other Forms of Interactions). 2.4.2 Drug Abuse and Dependence No information is available for drug abuse and dependence with Cymevene. 2.4.3 Ability to Drive and Use Machines No studies on the effect on the ability to drive and use machines have been performed. Based on the adverse reaction profile, ganciclovir may have a minor influence on the ability to drive and use machines. Adverse reactions, for example seizures, dizziness and confusion may occur in patients receiving Cymevene (see section 2.6 Undesirable Effects). If they occur, such effects may affect tasks requiring alertness including the patient’s ability to drive and operate machinery. 2.5 USE IN SPECIAL POPULATIONS 2.5.1 Females and Males of Reproductive Potential Fertility In animal studies ganciclovir was found to impair fertility (see section 3.3.3 Impairment of Fertility). In a clinical study renal transplant patients receiving Valcyte (which is a pro-drug of Cymevene) for CMV prophylaxis for up to 200 days were compared to an untreated control group. Spermatogenesis was inhibited during treatment with Valcyte. At follow-up, approximately six months after treatment discontinuation, the mean sperm density in treated patients was comparable to that observed in the untreated control group. In Valcyte treated patients, all patients with normal sperm density (n=7) and 8/13 patients with low sperm density at baseline, recovered to normal counts after treatment cessation. In the control group, all patients with normal sperm density (n=6) and 2/4 patients with low sperm density at baseline, had normal density at the end of follow-up. Contraception Women of reproductive potential should be advised to use effective contraception during and for at least 30 days after treatment. Sexually active men are recommended to use condoms during and for at least 90 days after cessation of treatment with Cymevene, unless it is certain that the female partner is not at risk of becoming pregnant (see sections 2.4.1 Warnings and Precautions General, Mutagenicity, teratogenicity, carcinogenicity, fertility and contraception and3.3.4 Reproductive Toxicity). 2.5.2 Pregnancy In animal studies ganciclovir was associated with reproductive toxicity and teratogenicity (see section 3.3.3 Impairment of Fertility and 3.3.4Reproductive Toxicity). The safety of Cymevene pregnant women has not been established. However, ganciclovir readily diffuses across the human placenta. The use of Cymevene should be avoided in pregnant women unless the benefit to the mother outweighs the potential risk to the fetus. The safe use of Cymevene during labor and delivery has not been established. 2.5.3 Lactation Peri- and postnatal development has not been studied with ganciclovir but the possibility of ganciclovir being excreted in breast milk and causing serious adverse reactions in the nursing infant cannot be discounted. Human data are not available but animal data indicates that ganciclovir is excreted in the milk of lactating rats. Therefore, a decision should be made to discontinue the drug or discontinue nursing taking into consideration the potential benefit of Cymevene to the nursing mother. 2.5.4 Pediatric Use See section 2.2.1 Special Dosage Instructions and 3.2.5 Pharmacokinetics in Special Populations. 2.5.5 Geriatric Use See section 2.2.1 Special Dosage Instructions and 3.2.5 Pharmacokinetics in Special Populations. 2.5.6 Renal Impairment In patients with impaired renal function, dosage adjustments based on creatinine clearance are required (see Special dosage instructions and Pharmacokinetics in special populations) (see section 2.2.1 Special Dosage Instructions and 3.2.5 Pharmacokinetics in Special Populations). 2.5.7 Hepatic Impairment The safety and efficacy of Cymevene have not been studied in patients with hepatic impairment (see section 2.2.1 Special Dosage Instructions and 3.2.5 Pharmacokinetics in Special Populations). 2.6 UNDESIRABLE EFFECTS 2.6.1 Clinical Trials Valganciclovir is a pro-drug of ganciclovir, and adverse reactions associated with valganciclovir can be expected to occur with ganciclovir. Therefore, adverse drug reactions reported with IV or oral ganciclovir (no longer available) or with valganciclovir are included in the table of adverse reactions (see Table 2). In patients treated with ganciclovir/valganciclovir the most serious and frequent adverse drug reactions are hematological reactions and include neutropenia, anemia and thrombocytopenia. 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 (GAN1697, GAN1653, GAN2304, GAN1774, GAN2226, AVI034, GAN041) or valganciclovir (WV1537, WV15705). Exception is made for agranulocytosis, granulocytopenia and anaphylactic reaction; the frequencies of which are derived from post-marketing experience. Frequencies are presented as percentages and as CIOMS frequency categories defined as 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 diarrhea compared to oral valganciclovir. Pyrexia, candida infections, depression, severe neutropenia (ANC < 500μL) and skin reactions are reported more frequently in patients with HIV. Renal and hepatic dysfunction is reported more frequently in organ transplant recipients. Table 2 Frequency of Ganciclovir/Valganciclovir ADRs Reported in HIV Patients Receiving Maintenance Therapy (n=1704) ADR (MedDRA) System Organ Class Percentage Frequency Category Infections and infestations: Candida infections including oral candidiasis 22.42% Very common Upper respiratory tract infection 16.26% Sepsis 6.92% Common Influenza 3.23% Urinary tract infection 2.35% Cellulitis 1.47% Blood and lymphatic disorders: Neutropenia 26.12% Very common Anemia 19.89% Thrombocytopenia 7.34% Common Leucopenia 3.93% Pancytopenia 1.06% Bone marrow failure 0.29% Uncommon Aplastic anemia 0.06% Rare Agranulocytosis* 0.02% Granulocytopenia* 0.02% Immune system disorders: Hypersensitivity 1.12% Common Anaphylactic reaction* 0.02% Rare Metabolic and nutrition disorders: Decreased appetite 12.09% Very common Weight decreased 6.46% Common Psychiatric disorders: Depression 6.69% Common Confusional state 2.99% Anxiety 2.64% Agitation 0.59% Uncommon Psychotic disorder 0.23% Thinking abnormal 0.18% Hallucinations 0.18% Nervous system disorders: Headache 17.37% Very common Insomnia 7.22% Common Neuropathy peripheral 6.16% Dizziness 5.52% Paraesthesia 3.58% Hypoaesthesia 2.58% Seizures 2.29% Dysgeusia (taste disturbance) 1.35% Tremor 0.88% Uncommon Eye disorders: Retinal detachment** 8.04% Common Visual impairment 7.57% Vitreous floaters 3.99% Eye pain 2.99% Conjunctivitis 1.58% Macular edema 1.06% Ear and labyrinth disorders: Ear pain 1.17% Common Deafness 0.65% Uncommon Cardiac disorders: Arrhythmia 0.47% Uncommon Vascular disorders: Hypotension 2.05% Common Respiratory, thoracic and mediastinal disorders: Cough 18.31% Very common Dyspnoea 11.80% ADR (MedDRA) System Organ Class Percentage Frequency Category Gastrointestinal disorders: Diarrhea 34.27% Very common Nausea 26.53% Vomiting 14.67% Abdominal pain 10.97% Constipation 8.39% Common Dyspepsia 4.81% Flatulence 4.69% Abdominal pain upper 4.58% Mouth ulceration 3.17% Dysphagia 2.93% Abdominal distention 2.29% Pancreatitis 1.64% Hepato-biliary disorders: Blood alkaline phosphatase increased 3.58% Common Hepatic function abnormal 3.23% Aspartate aminotransferase increased 1.88% Alanine aminotransferase increased 1.23% Skin and subcutaneous tissues disorders: Dermatitis 11.80% Very common Night sweats 7.92% Common Pruritus 4.58% Rash 2.52% Alopecia 1.29% Dry skin 0.94% Uncommon Urticaria 0.70% Musculo-skeletal and connective tissue disorders: Back pain 4.46% Common Myalgia 3.52% Arthralgia 3.35% Muscle spasms 2.99% Renal and urinary disorders: Renal impairment 2.52% Common Creatinine clearance renal decreased 2.35% Blood creatinine increased 1.88% Renal failure 0.76% Uncommon Hematuria 0.70% Reproductive system and breast disorders: Infertility male 0.23% Uncommon General disorders and administration site conditions: Pyrexia 33.51% Very common Fatigue 18.96% Injection site reaction 6.98% Common Pain 5.81% Chills 5.40% Malaise 2.11% Asthenia 2.00% Chest pain 0.88% Uncommon * The frequencies of these adverse reactions are derived from post-marketing experience. ** Retinal detachment has only been reported in studies in AIDS patients treated with Cymevene for CMV retinitis. 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. The cell count usually normalizes within 2 to 5 days after discontinuation of the drug or dose reduction (see section 2.4 Warnings and Precautions). 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 2.4 Warnings and Precautions). Severe thrombocytopenia may be associated with potentially life-threatening bleeding. Laboratory Abnormalities Laboratory abnormalities in HIV infected patients Laboratory abnormalities reported from three clinical trials in HIV infected patients receiving intravenous ganciclovir as maintenance treatment for CMV retinitis are listed below in Table 3. One hundred seventy-nine patients were eligible for the laboratory abnormality analysis. Table 3 Laboratory abnormalities Laboratory abnormalities N=179 Neutropenia (ANC /mm3) < 00 25.1 % 500 – < 750 14.3 % 750 – < 1000 26.3 % Anemia (hemoglobin g/dL) < 6.5 4.6 % 6.5 – < 8.0 16.0 % 8.0 – < 9.5 25.7 % Thrombocytopenia (platelets/mm3) < 25000 2.9 % 25000 – < 50000 5.1 % 50000 – < 100000 22.9 % Serum creatinine (mg/dL) >2.5 1.7 % >1.5 – 2.5 13.9 %
