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Composition autopsy ganciclovir has been found to be concen

Active ingredient: ganciclovir. trated in the kidneys, with smaller quantities in the
One vial contains 500mg of ganciclovir in the form liver, lungs and testes.
of the sodium salt. Concentrations of ganciclovir in the cerebrospinal
Properties fluid are 767% of the maximum plasma concen
trations. The steadystate volume of distribution is
Ganciclovir is a synthetic nucleoside analogue of
3345l/1.73m2 in patients with normal renal func
guanine that inhibits replication of herpes viruses
tion. Plasma protein binding is 1-2%. It is not known
both in vitro and in vivo. In vitro it is 1030 times
if ganciclovir is excreted in human breast milk.
more active than aciclovir against various strains of
cytomegalovirus. Metabolism and Elimination
After penetrating infected cells, ganciclovir is trans Apart from undergoing phosphorylation, ganciclovir
former, by kinase into ganciclovir triphosphate, is not metabolized. It is mainly excreted unchanged
which inhibits viral DNA synthesis by (1) competi via the kidneys (about 90% in patients with nor
tively inhibiting the incorporation of deoxyguanosine mal renal function). The plasma halflife is 2.91.3
triphosphate (dGTP) and (2) through direct incorpo hours, depending on renal status. Plasma clearance
ration into DNA, resulting in inhibition of viral repli is about 3.6ml/min/kg (which correlates well with
creatinine clearance).
cation. Sensitive human viruses include cytomega
lovirus (CMV), herpes simplex virus (HSV) types I Pharmacokinetics in special clinical situations.
and II, EpsteinBarr virus (EBV) and varicellazoster Renal impairment: The plasma halflife is prolonged
virus (VZV). The median inhibitory concentration and the plasma concentration increased in patients
(IC50) of ganciclovir in vitro varies depending on the with a creatinine clearance <50ml/min.
strain of CMV tested. The average value is 4mol/l. Elderly patients: Dose adjustment may be required
By contrast, it is a far less potent inhibitor of mam depending on renal status.
malian cell proliferation in vitro. The IC50 in the most Dialysis patients: Ganciclovir is dialysable (hemo
sensitive cell type, bone marrow colony forming dialysis and peritoneal dialysis). Hemodialysis may
cells, is 39.0mmol/l. reduce ganciclovir plasma concentrations by about
Pharmacokinetics 50%.
Due to the relatively high toxicity of ganciclovir, no Indications
pharmacokinetic studies have been performed in Cymevene is indicated for the treatment of life or
healthy volunteers. Consequently all data are from sightthreatening CMV disease in immunocom
patients. promised individuals. This includes retinitis, colitis,
pneumonia and other visceral disease of systemic
infection without confirmed visceral disease. The
Plasma concentrations of between 3.1 and 21.7mg/I
safety and efficacy of Cymevene have been con
(mean 8.3mg/I) are reached after infusion of 5mg/ firmed only in severe CMV infections; they have
kg bodyweight over one hour. not been confirmed in congenital or neonatal CMV
Distribution infections or in CMV infections in non-immunocom
The precise distribution of ganciclovir to the vari promised patients. Appropriate laboratory tests (cul
ous tissues and body fluids in man is not known. At ture, antigens, etc.) should be carried out to confirm
the etiologic diagnosis. Where retinitis is suspected, ment in AIDS patients with CMV retinitis (possibly
the diagnosis should be based on the presence of related to treatment).
typical retinal lesions, supported by positive culture Respiratory system: Occasionally: dyspnea. Rarely:
from blood, urine or other sites. A diagnosis of CMV asthmalike symptoms, cough, nosebleeds.
infection should not be made solely on the basis of a Gastrointestinal tract: Occasionally: nausea, vomit
positive antibody test or histological confirmation of ing, diarrhea, anorexia, bleeding, abdominal pain.
viral inclusions in a biopsy sample. Rarely: throat pain, sensation of fullness, constipa
Contraindications tion, hematemesis.
Cymevene is contraindicated during pregnancy Liver function: Occasionally: increased SGOT and
and in patients with hypersensitivity to ganciclo bilirubin. Rarely: increased SGPT.
vir or aciclovir. Cymevene must not be given if Renal function: Occasionally: increased nonprotein
the neutrophil count is less than 500cells/I and/ nitrogen and plasma creatinine due to reduced cre
or the platelet count is less than 25,000cells/l. atinine clearance (particularly in patients with pre
Ganciclovir is not approved for treatment of chil existing renal impairment), hyponatremia. Rarely:
dren and adolescents under 18 years of age, hematuria, urinary frequency.
because of the lack of clinical experience with the Hypersensitivity Reactions: Occasionally: skin rash,
drug in these age groups. pruritus, urticaria. Rarely: alopecia.
Side Effects Based on the results of animal studies it is consid
Hematology: Reversible neutropenia (neutrophils ered likely that ganciclovir causes temporary or per
<1000cells/I), seen in 38% of patients and throm manent inhibition of spermatogenesis. These stud
bocytopenia (platelets <50,000 cells/I), seen in ies also indicate that suppression of fertility in men
19% of patients, are the most conspicuous adverse may occur. Because of this, during treatment with
reactions and are dose limiting. Cymevene men must not father children and women
Anemia and eosinophilic disorders occur occasionally. must use effective contraception.
Due to the frequency of leukopenia, it is recom Warnings
mended that leukocyte counts be performed every Because of its relatively high toxicity, ganciclovir
two days during the first two weeks of therapy. may be used only in severe CMV infections and
Blood counts should be performed daily in patients not in other viral diseases. Due to its carcinogenic
in whom Cymevene has previously resulted in leu potential, medical staff should handle ganciclovir
kopenia or who have pretreatment leukocyte counts with caution.
of less than 2000cells/l. Precautions
Cardiovascular system: Occasionally: hypotension, Neutropenia (neutrophils <1000 cells/I) has
hypertension, tachycardia, hemorrhage. Rarely: been observed in 38% of patients treated with
anginalike pain, syncope, myocardial infarction, Cymevene. It generally appears during the first or
arrhythmia, thrombophlebitis. second week of treatment and before a cumula
Central nervous system: Occasionally: confusion, tive dose of 200mg/kg has been given. The leuko
seizures, dizziness, headache, abnormal thoughts, cyte count usually returns to normal 37 days after
dementia, depression, hallucinations, paresthesia, discontinuation of treatment or dose reduction. As
psychosis, somnolence, lightheadedness, stupor. no correlation has been established between the
Rarely: restlessness, amnesia, ataxia, insomnia, frequency of neutropenia and pretreatment leuko
manic reactions, nervousness, sweating. cyte counts, it is not possible to predict the poten
Sensory organs: Rarely: deafness, retinal detach tial risk. Nonetheless, caution is required in patients
with previous neutropenic reactions to other medi Special Remarks
cations. Thrombocytopenia (platelets <50,000cells/ Incompatibilities
I) has been observed in 19% of patients treated Solutions containing parabens cause precipitation of
with Cymevene. This reaction occurs more often ganciclovir.
in patients treated with immunosuppressant drugs
than in AIDS patients. The risk of thrombocytope Stability
nia is greater if the pretreatment platelet count is This medicine should not be used after the expi
less than 100,000cells/l. As Cymevene is elimi ry date (EXP) shown on the pack. After prepara
nated via the kidneys, adequate hydration should tion from the powder, keep the Cymevene solution
be maintained during treatment. If renal function is at room temperature (15-25C) and use within 12
impaired, the dosage must be adjusted in accor hours. After dilution, refrigerate the infusion solution
dance with the creatinine clearance (see Dosage (28C) and use within 24 hours.
and Administration). Due to their high pH (911),
Cymevene solutions may cause phlebitis and/ Drug Interactions
or pain at the site of infusion. Veins with adequate It is possible that probenecid, like other drugs
blood flow should therefore be chosen to permit that inhibit renal tubular secretion or resorp
rapid dilution and distribution. The safety and effica tion, may reduce renal clearance of ganciclovir
cy of Cymevene have not been evaluated in elderly and prolong its plasma halflife. It is also possi
patients. Caution should be exercised if Cymevene ble that concomitant administration of cytostatics
is administered to such patients and special consid (dapsone, pentamidine, flucytosine, vincristine,
eration given to their renal status. vinblastine, doxorubicin), amphotericin B, sulfon
amide/trimethoprim combinations or other nucle
Pregnancy, Nursing Mothers
oside analogues may potentiate the toxic effect
Ganciclovir is contraindicated during pregnancy and
of Cymevene. Concomitant administration of zid
ovudine during induction therapy with Cymevene
The animal studies performed to date indicate that in AIDS patients is NOT recommended. Current
Cymevene has mutagenic and teratogenic proper data show that concomitant administration of
ties. In one 18month study in mice ganciclovir was zidovudine and Cymevene at the recommend
found to be carcinogenic at oral doses of 20 and ed dosages during maintenance treatment with
1000mg/kg/day. With the exception of histiocytic
Cymevene results in severe neutropenia in most
sarcoma of the liver, all ganciclovirinduced tumors
patients. Concomitant treatment with ganciclovir
were epithelial or vascular in origin. No carcinogen
and high doses of -lactam antibiotics may lead
ic effect was observed with a dose of 1mg/kg/day.
to generalized seizures.
Cymevene must be considered a potential carcino
gen in humans. Dosage and Administration
Overdosage Normal Dosage
Eleven cases of shortterm ganciclovir overdose have Induction treatment (adults): In patients with normal
been reported, with reversible neutropenia observed function, 5mg/kg given as an intravenous infusion
in three patients. There is no specific treatment for over one hour, every 12 hours (10mg/kg/day) for
overdosage. Systematic and supportive therapy such 1421 days.
as hemodialysis and forced diuresis may be effective Maintenance treatment (adults): In patients whose
in accelerating elimination of ganciclovir. Measures immune status remains depressed, and who are
must be taken to protect the patient against neutrope thus at risk of relapse, a dose of 6mg/kg/day, five
nia until marrow recovery is assured. days per week, may be used.
Special Dosage Instruction (adults) The following infusion fluids are compatible with
For patients with renal impairment the dosage Cymevene: physiological saline, dextrose 5% and
should be adjusted as shown in the following table: Ringers or lactated Ringers solution. The infusion
solution must be used within 24 hours of dilution and
Creatinine Clearance Dose (mg/kg) Dose interval
(ml/min/1.73m )
(hours) should be refrigerated (28C). Do not freeze.
>50 5.0 12
2550 2.5 12
1025 2.5 24
010 1.25 24
For maintenance treatment half the corresponding
dose used for induction treatment should be given
once daily.
Do not administer by rapid intravenous injection.
The toxicity of Cymevene may be increased as a
result of excessive plasma levels.
Intramuscular or subcutaneous injection may result
in severe tissue irritation due to the high pH (911)
of Cymevene solutions.
Precautions during preparation of ganciclovir solu-
tions: Due to the high pH (911) ganciclovir solutions
must be prepared with caution. Use of rubber gloves
and protective eye glasses is recommended. If acci
dental contact with the skin or mucous membranes
occurs, wash the affected area thoroughly with soap
and water; if the product comes into contact with the
eyes, rinse with plain water for 15 minutes. In addi
tion, the same precautions as for cytostatic agents
are recommended for Cymevene.
Reconstituted solution: Dissolve the contents of one
vial of lyophilized Cymevene (500mg) by adding
10ml of sterile water for injection and shaking vigor
ously. The solution must be clear. Do not use bac
teriostatic water for injection containing parabens,
as these are incompatible with Cymevene and may
cause precipitation. The solution is stable at room
temperature for 12 hours. It should not be refriger
Infusion solution: The appropriate dose volume
of reconstituted sodium (concentration 50 mg/
mI) should be added to an infusion fluid (normally
100ml); the infusion concentration should not be
greater than 10mg/ml) for infusion over one hour.