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
COMPOSITION
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.
2. CLINICAL PARTICULARS
2.1 THERAPEUTIC INDICATION(S)
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.
STANDARD DOSAGE FOR TREATMENT OF CMV
DISEASE
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withdrawn, may be re-treated using the induction treatment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.
STANDARD DOSAGE FOR PREVENTION OF CMV
DISEASE USING PROPHYLAXIS OR PREEMPTIVE
THERAPY
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)
<500 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 %
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