Cymevene

New Zealand - English - Medsafe (Medicines Safety Authority)

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Active ingredient:
Ganciclovir sodium 543 mg equivalent to 500 mg ganciclovir;  
Available from:
Pharmaco (NZ) Ltd
INN (International Name):
Ganciclovir sodium 543 mg (= 500 mg ganciclovir)
Dosage:
500 mg
Pharmaceutical form:
Powder for infusion
Composition:
Active: Ganciclovir sodium 543 mg equivalent to 500 mg ganciclovir  
Units in package:
Vial, glass, 5 dose units
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Corden Pharma Colorado Inc
Therapeutic indications:
Iindicated for the prophylaxis of CMV infection and disease following bone marrow and solid organ transplantation in patients at risk of CMV disease.
Product summary:
Package - Contents - Shelf Life: Vial, glass, - 5 dose units - 36 months from date of manufacture stored at or below 30°C 12 hours reconstituted stored at or below 25°C
Authorization number:
TT50-4795
Authorization date:
1990-06-21

Cymevene

®

contains the active ingredient

ganciclovir

Cymevene

181205

Consumer Medicine Information

What is in this leaflet

This leaflet answers some common

questions about Cymevene.

It does not contain all the available

information.

It does not take the place of talking

to your doctor or pharmacist.

All medicines have risks and

benefits. Your doctor has weighed

the risks of you being given

Cymevene injection against the

benefits they expect it will have for

you.

If you have any concerns about

being given this medicine, ask

your doctor or pharmacist.

Keep this leaflet.

You may need to read it again.

What Cymevene is

used for

Cymevene contains the active

ingredient ganciclovir.

Cymevene belongs to a class of

medicines used to treat viral

infections. It works by stopping

certain viruses from growing in the

body.

Cymevene acts against a certain

type of herpes virus called

cytomegalovirus

or CMV. CMV

causes infections mainly in people

with poor immunity. Poor

immunity can be caused by

HIV/AIDS or some transplant

medications.

Cymevene helps control CMV eye

infections in AIDS patients and in

other patients who have poor

immunity, which if left untreated

can cause blindness. Cymevene is

not a cure for CMV eye infections

and is not effective against any

underlying HIV infection.

Cymevene may also be used to treat

CMV lung infections in bone

marrow transplant patients.

Cymevene may also be used to

prevent CMV infection and disease

in patients following bone marrow

or solid organ transplantation.

Ask your doctor if you have any

questions about why Cymevene

has been prescribed for you.

Your doctor, however, may have

prescribed Cymevene for another

purpose.

Cymevene is not addictive.

This medicine is available only with

a doctor’s prescription.

Before you are given

Cymevene

Animal and other laboratory studies

have shown Cymevene has caused

infertility, birth defects and cancer.

It is possible that these effects may

also occur in humans.

When you must not be

given it

Do not use Cymevene if

1. you have had an allergic

reaction to Cymevene or

Vitrasert

®

implant, or

valganciclovir (Valcyte

®

)

Some of the symptoms of an

allergic reaction may include:

shortness of breath

wheezing or difficulty breathing

swelling of the face, lips, tongue

or other parts of the body

rash, itching or hives on the

skin.

2. you have very low blood counts

for platelets (which help clotting)

or neutrophils (a type of white

blood cell which defends against

infection) or haemoglobin (a

substance that carries oxygen in

the blood)

3. you are pregnant

your baby may absorb this

medicine in the womb and

therefore there is a possibility of

harm to the baby

4. you are breast-feeding or

intend to breast-feed

Cymevene may pass into breast

milk and therefore there is a

possibility that the breast-fed

baby may be affected

5. the package is torn or shows

signs of tampering

6. the expiry date (EXP) printed

on the pack has passed.

If you take this medicine after

the expiry date has passed, it

may not work as well.

If you are not sure if you should

be receiving Cymevene, talk to

your doctor.

Use in Children

There is very little information

available on the use of Cymevene in

children less than 12 years and

safety and effectiveness in children

has not yet been proven. Children

that take Cymevene, when grown-

up, have an increased risk of cancer

and, also, adverse effects when

trying to have children of their own.

Therefore Cymevene should only be

used if these risks are outweighed

by the benefits of treatment.

Before you are given it

Tell your doctor if

1.

you are allergic to medicines

like aciclovir (e.g. Zovirax

®

,

Cymevene

CMI 181205

2 of 4

Acyclo-V

®

, Acihexal

®

, Lovir

®

or Zyclir

®

), valaciclovir (e.g.

Valtrex

®

, Zelitrex

®

,

Xerebid

®

,

Valnir

®

), famciclovir (e.g.

Famvir

®

), penciclovir (e.g.

Vectavir

®

).

These medicines are from the

same class as Cymevene and

allergic reactions may occur.

2.

you are allergic to any other

medicines, foods, dyes or

preservatives.

3.

you have any other health

problems, especially the

following:

you have a history of low blood

counts for platelets

(thrombocytopenia),

neutrophils (neutropenia) or red

blood cells/haemoglobin

(anaemia)

you have or previously have had

poor kidney function

4.

you are pregnant or plan to

become pregnant

5.

you are breast feeding or plan

to breast feed

6.

you are a woman who could

become pregnant and you are

not using contraception

you must use a reliable form

of contraception during

Cymevene therapy, and for

at least 30 days after

stopping CYMEVNE, unless

you are not sexually active.

6.

you are a sexually active man

you should use condoms during

and for at least 90 days

following treatment with

CYMEVNE unless it is certain

that your female partner is not

at risk of pregnancy.

If you have not told your doctor

about any of the above, tell them

before you start taking

Cymevene.

Taking other medicines

Tell your doctor if you are taking

any other medicines, including

any that you have bought from a

pharmacy, supermarket or health

food shop.

Some medicines may interfere with

Cymevene. These medicines

include:

probenecid (e.g. Benemid

zidovudine (AZT, Retrovir

Combivir

didanosine (ddI or Videx

imipenem/cilastatin (Primaxin

medicines for the treatment of

cancer

other medicines for the

treatment of HIV or HIV-

related infections

mycophenolate mofetil

(CellCept

), a medicine used to

prevent rejection of

transplanted organs

other medicines used to prevent

rejection of transplated organs.

These medicines may be affected by

Cymevene, or may affect how well

it works. You may need to receive

different amounts of your medicine,

or you may need to receive different

medicines. Your doctor will advise

you.

Your doctor or pharmacist has more

information on medicines to be

careful with or avoid while

receiving Cymevene.

Ask your doctor or pharmacist if

you are not sure about this list of

medicines.

How Cymevene is

given

Cymevene is added to an infusion

bag and given as a ‘drip’ into a

vein, usually over a period of one

hour. Cymevene is usually given

once or twice a day.

Your doctor will decide what dose

of Cymevene you will receive. This

depends on how serious your

infection is as well as your kidney

function.

While you are

receiving Cymevene

Things you must do

Tell all doctors, dentists and

pharmacists who are treating you

that you are being given

Cymevene.

See your doctor regularly so that

your CMV disease, blood cell

counts and any other potential

side effects may be monitored

carefully.

If blood cell counts are low then

this may reduce your ability to fight

infection, or for your blood to clot

efficiently. If left undetected these

effects on blood cells may

contribute to death or serious

illness.

If you have a CMV eye infection,

you must also see your doctor

regularly to monitor the condition

of your retina (part of the eye).

Tell your doctor if you become

pregnant while receiving

Cymevene.

If there is a possibility of your

partner becoming pregnant, a

barrier contraceptive should be

used while receiving Cymevene

and for 90 days after stopping.

Things you must not do

Do not take any other medicines

whether they require a

prescription or not, without first

telling your doctor or consulting a

pharmacist.

Things to be careful of

Be careful driving or operating

machinery until you know how

Cymevene affects you.

Cymevene may cause dizziness,

confusion or seizures (fits) in some

people and therefore may affect

alertness. Make sure you know how

you react to Cymevene before you

drive a car or operate machinery or

do anything else that could be

Cymevene

CMI 181205

3 of 4

dangerous if you are drowsy, dizzy

or not alert.

Side Effects

Tell your doctor or pharmacist as

soon as possible if you do not feel

well after you have been given

Cymevene.

Cymevene helps most people with

CMV infections but it may have

unwanted side effects in some

people.

Unwanted effects may be due to

Cymevene, other medications, or

any disease or condition you may

also have. You should notify your

doctor if these or any other effects

occur.

All medicines can have side effects.

Sometimes they are serious, most of

the time they are not. You may

need medical treatment or a change

of therapy if you get some of the

side effects.

Ask your doctor or pharmacist to

answer any questions you may

have.

Do not be alarmed by this list of

possible side effects. You may not

experience any of them.

Many unwanted effects commonly

reported in people with HIV appear

to be related to their medical

condition. The following list are

unwanted effects seen in people

receiving intravenous Cymevene

which may or may not be caused by

their medication:

low white blood cell counts

anaemia (low red blood cell

counts).

diarrhoea

nausea and/or vomiting

feeling of weakness

weight loss

low blood platelet count

other infections

injection site soreness or

redness.

Tell your doctor if you notice any

of the following and they are

worrying you:

pain

loss of feeling or tingling

itching

skin rash

difficulty in swallowing

cough

nervousness or feeling anxious

confusion

headache

fluid buildup

indigestion

shortness of breath.

If you notice any of the following

you should see your doctor

immediately:

a deterioration or worsening of

your eye sight even if you are

receiving Cymevene

bruising or purple spots

any sign of infection such as

fever, chills, sore throat or

mouth ulcers

rapid or irregular heartbeat or

sudden fevers

tiredness

severe allergic reactions causing

swelling, rash or itching

severe blisters and bleeding in

the lips eyes, mouth, nose and

genitals

pain or inflammation in your

chest, stomach or intestines

bleeding (haemorrhage)

collapse, numbness or weakness

of the arms or legs, headache,

dizziness and confusion, visual

disturbance, difficulty

swallowing, slurred speech and

loss of speech

pain, swelling or joint stiffness

seizures (fits)

change in the amount of urine

you pass.

This is not a complete list of all

possible side effects. Others may

occur in some people and there may

be some side effects not yet known.

Tell your doctor if you notice

anything else that is making you

feel unwell, even if it is not on this

list.

Ask your doctor or pharmacist if

you don’t understand anything in

this list.

After receiving

Cymevene

Storage

Cymevene vials and infusion bags

will be stored in the pharmacy or on

the ward.

Product Description

What Cymevene looks like

Cymevene is available as a freeze-

dried powder in clear glass vials. It

will be made up into an infusion bag

before being given to you.

Ingredients

Active ingredient

Each 10 mL Cymevene vial

contains:

543 mg of ganciclovir sodium

equivalent to 500 mg of

ganciclovir

There are no other ingredients in

Cymevene vials.

Cymevene does not contain gluten,

lactose, sucrose, tartrazine or any

other azo dyes.

Cymevene

CMI 181205

4 of 4

Distributor

Cymevene is distributed by:

Pharmaco (NZ) Ltd

4 Fisher Crescent

Mt Wellington

Auckland 1060

Telephone: 09 377 3336

This leaflet was prepared on 5

December 2018.

NEW ZEALAND DATA SHEET

Cymevene

DS 181120

1.

PRODUCT NAME

Cymevene

500 mg powder for intravenous infusion

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 500 mg of ganciclovir (as ganciclovir sodium).

After reconstitution with 10 mL of water for injections, each mL provides 50 mg of

ganciclovir.

Cymevene is available as the sterile lyophilised powder containing ganciclovir sodium 543

mg equivalent to ganciclovir 500 mg and sodium 43 mg (2 mEq).

Excipients with known effect: approximately 43 mg (2 mEq) sodium.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Powder for concentrate for solution for infusion (powder for infusion)

White to off-white solid cake.

Ganciclovir, when formulated as monosodium salt in the intravenous (IV) dosage form, is a

white to off-white lyophilised powder.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Cymevene (ganciclovir) administered as the

IV infusion is indicated for the palliative

treatment of confirmed sight-threatening cytomegalovirus (CMV) disease in AIDS and other

severely immunocompromised individuals. It is indicated for the treatment of confirmed

CMV pneumonitis in bone marrow transplant patients. It is also indicated for the prophylaxis

of CMV infection and disease following bone marrow and solid organ transplantation in

patients at risk of CMV disease.

NOTE:

Cymevene (ganciclovir) is not indicated for congenital or neonatal CMV disease; nor

for the treatment of CMV infection in non-immunocompromised individuals.

4.2

Dose and method of administration

General

Cymevene

must

reconstituted

diluted

under

supervision

healthcare

professional and administered as an intravenous infusion (see section 4.2).

Caution: Cymevene must only be administered by IV infusion over 1 hour, preferably via a

plastic

cannula,

into

vein

with

adequate

blood

flow

(intramuscular

subcutaneous

injection may result in severe tissue irritation due to the high pH (~11) of ganciclovir

NEW ZEALAND DATA SHEET

Cymevene

DS 181120

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).

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

Because of individual patient variations in the clinical response of CMV disease and the

sensitivity to the myelosuppressive effects of Cymevene, the treatment of each patient with

Cymevene should be individualised on a case-by-case basis. Changes in dose should be

based on regular clinical evaluations as well as by regular haematologic monitoring.

Standard dosage for Treatment of CMV Disease

Dosage for patients with normal renal function

Induction Treatment

Cymevene 5 mg/kg given as an IV infusion over 1 hour every 12 hours (10 mg/kg/day) for 14

to 21 days

Maintenance Treatment

For immunocompromised patients at risk of relapse maintenance therapy may be given.

The recommended dose is Cymevene 6 mg/kg given over 1 hour, once daily, 5 days per

week, or 5 mg/kg once daily 7 days per week.

The duration of maintenance treatment should be determined on an individual basis.

Treatment of Disease Progression

Any patient in whom the disease progresses, either while on maintenance treatment or

because treatment with Cymevene was withdrawn, may be re-treated using the IV induction

treatment regimen. The frequency and duration of response in such patients has not been

adequately established.

Indefinite treatment may

be required in patients with AIDS, but even with continued

maintenance treatment, patients may have progression of CMV disease.

Standard dosage for the Prevention of CMV Disease in Transplant Recipients for Patients

with Normal Renal Function

The duration of treatment with Cymevene solution in transplant recipients is based on the risk

of CMV disease and should be determined on an individual basis.

Liver Transplantation

The recommended initial dosage of Cymevene solution is 5 mg/kg infused at a constant rate

over 1 hour every 12 hours (10 mg/kg/day) for 7 to 14 days, followed by 5 mg/kg once daily

7 days a week or 6 mg/kg once daily 5 days a week for up to 100 days post-transplant.

Heart Transplantation

The recommended initial dosage of Cymevene solution is 5 mg/kg infused at a constant rate

over 1 hour every 12 hours (10 mg/kg/day) for 14 days, followed by 6 mg/kg once daily 5

days a week for up to 100 days post-transplant.

In a controlled clinical trial in heart allograft recipients, the onset of newly diagnosed CMV

disease occurred after treatment with IV Cymevene was stopped at day 28 post-transplant,

NEW ZEALAND DATA SHEET

Cymevene

DS 181120

suggesting that continued dosing may be necessary to prevent late occurrence of CMV

disease in this patient population.

Bone Marrow Transplantation

The recommended initial dosage of Cymevene solution is 5 mg/kg infused at a constant rate

over 1 hour every 12 hours (10 mg/kg/day) for 7 days, followed by 5 mg/kg once daily 7 days

a week for up to 100 to 120 days post-transplant.

In controlled clinical trials in bone marrow allograft recipients, CMV disease occurred in

several patients who discontinued treatment with Cymevene solution prematurely.

Other Transplantations

The recommended initial dosage of Cymevene solution is 5 mg/kg infused at a constant rate

over 1 hour every 12 hours (10 mg/kg/day) for 7 to 14 days, followed by 5 mg/kg once daily

7 days a week or 6 mg/kg once daily on 5 days a week.

Special Dosage Instructions

Renal Impairment

For patients with impaired renal function, the IV dose of Cymevene should be modified as

shown in the table below.

The following recommended dosages in renal impairment are not based on experience in

patients with AIDS.

Table 1: Cymevene dosing for renally impaired patients

Creatinine

Clearance

Serum

Creatinine

Cymevene

Induction

Dose

Dosing

Interval

Cymevene

Maintenance

Dose

Dosing

Interval

(mL/min)

(micromol/L)

(mg/kg)

(hours)

(mg/kg)

(hours)

< 125

50 - 69

125 - 175

25 - 49

176 - 350

1.25

NEW ZEALAND DATA SHEET

Cymevene

DS 181120

Creatinine

Clearance

Serum

Creatinine

Cymevene

Induction

Dose

Dosing

Interval

Cymevene

Maintenance

Dose

Dosing

Interval

10 - 24

> 350

1.25

0.625

< 10

> 350 (and on

haemodialysis)

1.25

3 times per

week,

following

haemodialysis

0.625

3 times per

week

following

haemodialysis

To calculate an estimated creatinine clearance:

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

Hepatic impairment

The safety and

efficacy

of Cymevene have not been studied in patients with hepatic

impairment (see section 5.2).

Elderly

No studies on the efficacy or safety of Cymevene have been conducted specifically in elderly

patients. Since elderly individuals may have reduced renal function, Cymevene should be

administered to the elderly patients with care and with special consideration of their renal

status (see section 4.2).

Paediatric population

Safety and efficacy of ganciclovir in paediatrics 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. Method of Administration

Based on patient weight the appropriate calculated dose volume should be removed from the

vial (Cymevene concentration 50 mg/mL) and added to an acceptable infusion fluid (typically

100 mL) for delivery over the course of one hour. Infusion concentrations greater than 10

mg/mL are not recommended. The following infusion fluids are compatible with Cymevene:

normal saline, glucose 5% in water, Ringer's Injection, Ringer-Lactate Solution for Injection.

For instructions on reconstitution and dilution of the medicine before administration, see

section 6.6.

4.3

Contraindications

NEW ZEALAND DATA SHEET

Cymevene

DS 181120

Cymevene is contraindicated in pregnant women, nursing mothers, and in patients who are

hypersensitive to ganciclovir, valganciclovir or to any of the excipients.

Cymevene should not be administered to patients if the absolute neutrophil count falls below

0.5 x 109/L (500 cells/µL) or platelet count

below 2.5 x 1010/L (25,000/µL) or the

haemoglobin is less than 80 g/L (8 g/dL).

The safety and efficacy of Cymevene have not been evaluated for prophylaxis of CMV

disease in donor negative/receptor negative (D-/R-) transplant patients, or in populations

other than those stated under Therapeutic Indications, section 4.1.

4.4

Special warnings and precautions for use

General

main

clinical

toxicities

ganciclovir

include

leucopenia,

anaemia

thrombocytopenia.

Cymevene is only indicated in those patients as outlined under Therapeutic Indications in

section 4.1 where the potential benefits to the patient outweigh the risks stated herein. It is

recommended that complete blood counts and platelet counts be monitored during therapy.

diagnosis

retinitis

should

made

indirect

ophthalmoscopy.

Other

conditions in the differential diagnosis of CMV retinitis included candidiasis, toxoplasmosis,

histoplasmosis,

retinal

scars,

cotton

wool

spots,

which

produce

retinal

appearance similar to CMV. For this reason it is essential that the diagnosis of CMV be

established by an ophthalmologist familiar with the presentation of these conditions. The

diagnosis of CMV retinitis may be supported by culture of CMV in the urine, blood, throat,

or other sites, but a negative culture does not rule out CMV retinitis.

HIV+ Patients with CMV Retinitis: Ganciclovir is not a cure for CMV retinitis, and

immunocompromised patients may continue to experience progression of retinitis during or

following

treatment.

Patients

should

advised

have

ophthalmologic

follow-up

examinations at a minimum of every 4 to 6 weeks while being treated with Cymevene. Some

patients will require more frequent follow-up.

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 Cymevene to patients with known hypersensitivity to

aciclovir or penciclovir, (or to their prodrugs, valaciclovir or famciclovir respectively).

Mutagenicity, teratogenicity, fertility and contraception

In animal studies ganciclovir was found to be mutagenic, teratogenic, carcinogenic and to

impair

fertility.

Cymevene

should

therefore

considered

potential

teratogen

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 foetus and to

use contraceptive measures. Based on clinical and nonclinical studies, Cymevene may cause

temporary or permanent inhibition of spermatogenesis in males (see

sections 4.6, 4.8 and

5.3).

NEW ZEALAND DATA SHEET

Cymevene

DS 181120

Ganciclovir caused point mutations and chromosomal damage in mammalian cells

in vitro

in vivo

. Ganciclovir was clastogenic in the mouse micronucleus assay. Ganciclovir was

not mutagenic in the Ames Salmonella assay.

Myelosuppression

Severe leucopenia, neutropenia, anaemia, thrombocytopenia, pancytopenia, bone marrow

depression and aplastic anaemia have been observed in patients treated with Cymevene (see

sections 4.2 and 4.8).

Cymevene should, therefore, be used with caution in patients with pre-existing cytopenias, or

who have received or are receiving myelosuppressive medicines or irradiation. Cytopenia

may occur at any time during treatment and may increase with continued dosing. Cell counts

usually begin to recover within 3 to 7 days of discontinuing the medicine. Colony-

stimulating factors have been shown to increase neutrophil counts in patients receiving

ganciclovir for treatment of CMV retinitis.

Neutropenia:

Patients

receiving ganciclovir have manifested neutropenia (neutrophil count <

1 x 10

/L). Data from treatment with IV Cymevene indicates neutropenia typically occurs

during the first or second week of induction therapy and prior to administration of a total

cumulative dose of 200 mg/kg, but may occur at any time during treatment. With IV therapy

neutropenia has occurred in up to 40% of patients. Evidence of recovery of cell counts

usually occurs within 3 to 7 days after either discontinuing the medicine or decreasing the

dosage. The risk of neutropenia may not necessarily be predicted from pre-treatment cell

counts. Cymevene should not be administered if the absolute neutrophil count is below 0.5 x

Thrombocytopenia (platelet count < 5.0 x 10

/L) has been observed in patients treated with

ganciclovir. Data from studies of IV Cymevene indicates that patients with initial platelet

counts < 1.0 x 10

/L appear to be at increased risk of this toxicity. Cymevene should not be

initiated if the absolute platelet count is < 2.5 x 10

Anaemia (haemoglobin < 95 g/L) has been observed in patients treated with ganciclovir.

Cymevene should not be administered if the haemoglobin is < 80 g/L.

Bone Marrow Transplantation

Cymevene should not be administered to bone marrow transplant patients in the early post-

transplant phase, but withheld until early signs of haemopoetic recovery are evident, usually

at about three weeks post-transplantation.

Intravenous Administration

In clinical studies with Cymevene, the maximum dose studied has been 6 mg/kg given by IV

infusion over a period of one hour. It is likely that larger doses, or more rapid infusions,

could result in increased toxicity, and therefore, it is recommended that the dosage regimen

be strictly adhered to.

Administration of Cymevene by IV infusion should be accompanied by adequate hydration,

since ganciclovir is excreted by the kidneys and normal clearance depends upon adequate

renal

function.

renal

function

impaired,

dosage

adjustments

based

serum

creatinine/creatinine clearance, are required (see

section

4.2).

NEW ZEALAND DATA SHEET

Cymevene

DS 181120

Cymevene solutions have a high pH (range 9 to 11) and may cause phlebitis and/or pain at

the site of IV infusion. Care must be taken to infuse Cymevene solutions only into veins with

adequate blood flow to afford rapid dilution and distribution.

Use in Patients with Renal Impairment

Cymevene should be used with caution in patients renal impairment. Both the plasma half-

life of ganciclovir as well as peak plasma levels are increased in patients with elevated serum

creatinine levels. In a very small number of patients who were undergoing dialysis,

ganciclovir plasma levels were reduced by approximately 50% following haemodialysis.

In patients with impaired renal function, dosage adjustments based on creatinine clearance

are required (see section 4.2). Serum creatinine/creatinine clearance should be monitored at

least once every two weeks.

Paediatric Use

higher

risk

hematological

cytopenias

neonates

infants

warrants

careful

monitoring of blood counts in these age groups. Monitoring of liver function abnormalities,

renal function and gastrointestinal fluid loss is also recommended in paediatric patients. The

use of ganciclovir in paediatric patients warrants caution due to the probability of long-term

carcinogenicity and reproductive toxicity. Administration to children should be undertaken

only after careful evaluation and only if, in the opinion of the physician, the potential benefits

of treatment outweigh these considerable risks. Cymevene is not indicated for the treatment

of congenital or neonatal CMV infection.

Effect on Laboratory Tests

Due to the frequency of neutropenia, leucopenia, anaemia or thrombocytopenia observed in

patients receiving Cymevene, it is recommended that complete blood counts and platelet

counts

performed

frequently,

especially

patients

whom

ganciclovir

other

nucleoside analogues have previously resulted in leucopenia, or in whom neutrophil counts

are < 1.0 x 10

/L at the beginning of treatment. In patients with severe leucopenia,

neutropenia,

anaemia

and/or

thrombocytopenia,

recommended

that

treatment

with

haematopoietic growth factors and/or dose interruption be considered. Because dosing with

Cymevene should be modified in patients with renal impairment, patients should have serum

creatinine or creatinine clearance values followed carefully.

Excipients

Cymevene contains 2 mmol (43 mg) sodium per 500mg dose. To be taken into consideration

by patients on a controlled sodium diet.

4.5

Interaction with other medicines and other forms of interaction

Probenecid

Probenecid given with oral ganciclovir resulted in statistically decreased renal clearance of

ganciclovir by 20% leading to statistically significant increased exposure (40%). These

changes were consistent with a mechanism of interaction involving competition for renal

tubular excretion. Therefore, patients taking probenecid and Cymevene should be closely

monitored for ganciclovir toxicity.

Didanosine

Didanosine plasma concentrations were found to be consistently raised when given with IV

ganciclovir. At IV doses of 5 and 10 mg/kg/day ganciclovir, an increase in AUC of

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didanosine ranging from 38 to 67% was observed confirming a pharmacokinetic interaction

during the concomitant administration of these drugs. Patients should be monitored closely

for didanosine toxicity, including pancreatitis (see section 4.8).

Imipenem-cilastatin

Seizures

have

been

reported

patients

receiving

ganciclovir

imipenem-cilastatin

concomitantly, and a pharmacodynamic interaction between these two drugs cannot be

discounted. These drugs should not be used concomitantly unless the potential benefits

outweigh the risks (see section 4.4).

Zidovudine

Both zidovudine and ganciclovir can cause neutropenia and anaemia and a pharmacodynamic

interaction may occur during concomitant administration of these drugs. Some patients

receiving

these

medicines

concomitantly

increased

risk

developing

these

conditions and may not tolerate concomitant therapy at full dosage. Regular haematological

monitoring should be performed and dose adjustment may be required.

Potential Drug Interactions

Toxicity may be enhanced when ganciclovir is co-administered with other medicines known

myelosuppressive

associated

with

renal

impairment.

This includes

nucleoside

analogues (e.g. zidovudine, didanosine, stavudine), immunosuppressants (e.g. ciclosporin,

tacrolimus, mycophenolate mofetil), antineoplastic agents (e.g. doxorubicin, vinblastine,

vincristine,

hydroxyurea)

anti-infective

agents

(e.g.

trimethroprim/sulphonamides,

dapsone, amphotericin B, flucytosine, pentamidine). Therefore, these medicines should only

be considered for concomitant use with ganciclovir if the potential benefits outweigh the

potential risks.

4.6

Fertility, pregnancy and lactation

Pregnancy

Use in Pregnancy - Category D

In animal studies ganciclovir was associated with reproductive toxicity and teratogenicity

(see sections 4.4 and 5.3). The safety of Cymevene in 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 foetus.

The safe use of Cymevene during labour and delivery has not been established.

Data obtained using an

ex vivo

human placental model show that ganciclovir crosses the

placenta and that simple diffusion is the most likely mechanism of transfer. The transfer was

not saturable over a concentration range of 1 to 10 mcg/mL and occurred by passive

diffusion.

Ganciclovir

been

shown

embryotoxic

rabbits

mice

following

administration, and teratogenic in rabbits (see section 5.3).

Breast-feeding

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It is not known if Cymevene is excreted in human milk but animal data indicates that

ganciclovir is excreted in the milk of lactating rats. Since many medicines are, and because of

the potential for serious adverse reactions from ganciclovir in nursing infants, Cymevene

should not be given to breastfeeding mothers. Alternatively, mothers should be instructed to

discontinue nursing if they are receiving Cymevene. The minimum time interval before

breastfeeding can safely be resumed after the last dose of Cymevene is unknown.

Contraception in males and females

Women

reproductive

potential

should

advised

effective

method

contraception

during

least

days

after

treatment.

Sexually

active

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 pregnancy (see

sections 4.4 and 5.3).

Fertility

In animal studies ganciclovir was found to impair 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.

follow-up,

approximately

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.

4.7

Effects on 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 convulsions, dizziness, and confusion may

occur in patients taking Cymevene. If they occur, such effects may affect tasks requiring

alertness including the patient’s ability to drive and operate machinery.

4.8

Undesirable effects

Valganciclovir

pro-drug

ganciclovir,

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)

valganciclovir

(WV1537,

WV15705).

Exception

made

agranulocytosis,

granulocytopenia and anaphylactic reaction; the frequencies of which are derived from post-

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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

some

differences

frequency

certain

reactions.

Intravenous

ganciclovir

associated

with

lower

risk

diarrhea

compared

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.

Paediatric population

Based on the cumulative experience, including valganciclovir pediatric studies, the overall

safety profile of ganciclovir in the pediatric population appears similar to the safety profile

established in adults. There is a higher risk of hematological cytopenias in neonates and

infants (see section 4.4)

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

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