Consumer medicine information

Cymevene

Ganciclovir

BRAND INFORMATION

Brand name

Cymevene

Active ingredient

Ganciclovir

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Cymevene.

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 other drugs from the same family: valganciclovir (Valcyte®); aciclovir (e.g. Zovirax®, Acyclo-V®, Acihexal®, Lovir® or Zyclir®); valaciclovir (e.g. Valtrex®, Zelitrex®, Xerebid®, Valnir®)
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.
  1. 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)
  2. you are pregnant
your baby may absorb this medicine in the womb and therefore there is a high likelihood of harm to the baby
  1. 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
  1. the package is torn or shows signs of tampering
  2. 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 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 any other medicines, foods, dyes or preservatives.
Especially any medicine which you have taken previously to treat your current condition (e.g. valganciclovir, valaciclovir)
  1. 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
  1. you are pregnant or plan to become pregnant
  2. you are breast feeding or plan to breast feed
  3. 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 CYMEVENE, unless you are not sexually active.
  1. you are a sexually active man
  • you should use condoms during and for at least 90 days following treatment with CYMEVENE 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 transplanted 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 drowsiness, 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 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.

Distributor

CYMEVENE is distributed by:

Pharmaco (Australia) Ltd
Suite 1A, Level 2
802 Pacific Highway
Gordon NSW 2072
AUSTRALIA

Under license of CHEPLAPHARM Arzneimittel GmbH, Germany

Please check with your pharmacist for the latest Consumer Medicine Information.

Australian Registration Number
AUST R 10047

This leaflet was prepared on 20 May 2019.

Published by MIMS October 2019

BRAND INFORMATION

Brand name

Cymevene

Active ingredient

Ganciclovir

Schedule

S4

 

1 Name of Medicine

Ganciclovir.

6.7 Physicochemical Properties

Ganciclovir is a synthetic nucleoside analogue of guanine. Its chemical name is 9-(1,3-dihydroxy-2-propoxymethyl) guanine. Ganciclovir has also been referred to as DHPG. Ganciclovir has a molecular formula of C9H13N5O4 and a molecular weight of 255.2.
Ganciclovir is a polar hydrophilic compound with a solubility of 2.6 mg/mL in water at 25°C (Hydrated Phase II polymorph) and an n-octanol/water partition coefficient of 0.022. The solubility of ganciclovir is independent of the crystalline phase composition. Ganciclovir has two dissociation constants: pKa1 = 2.2 and pKa2 = 9.4.

CAS number.

82410-32-0.

2 Qualitative and Quantitative Composition

Each Cymevene vial contains 500 mg of ganciclovir (as ganciclovir sodium 543 mg equivalent to ganciclovir 500 mg and sodium 43 mg (2 mEq) ganciclovir sodium).
After reconstitution with 10 mL of water for injections, each mL provides 50 mg of ganciclovir.
There are no excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Sterile lyophilised powder for intravenous infusion.
Ganciclovir, when formulated as monosodium salt in the intravenous (IV) dosage form, is a white to off-white lyophilised powder. The lyophilised powder has an aqueous solubility of greater than 50 mg/mL at 25°C. At physiological pH, ganciclovir sodium exists as the un-ionized form.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antivirals for systemic use, direct acting antivirals, nucleosides and nucleotides excluding reverse transcriptase inhibitors, ATC code: J05AB06.

Mechanism of action.

Ganciclovir is a synthetic nucleoside analogue of 2-deoxyguanosine that inhibits replication of herpes viruses both in vitro and in vivo. Sensitive human viruses include cytomegalovirus (HCMV), herpes simplex virus 1 and 2 (HSV-1 and HSV-2), herpes virus type 6, 7 and 8 (HHV-6, HHV-7, HHV-8), Epstein-Barr virus (EBV), varicella zoster virus (VZV) and hepatitis B virus. Ganciclovir was less potent against HHV-7 and HHV-8 than HHV-6. In vitro, synergy has been demonstrated between ganciclovir and foscarnet against CMV and herpes simplex virus Types 1 and 2 and between ganciclovir and beta-interferon against herpes simplex virus Type 2. Ganciclovir has been shown to be active against HCMV in human clinical studies.
A virus-encoded protein kinase homologue, encoded by the CMV gene UL97, has been demonstrated to control phosphorylation of ganciclovir in human CMV-infected cells. The product of the UL97 gene, along with cellular kinases which are induced upon CMV infection, appear to be responsible for phosphorylation of ganciclovir to its active triphosphate. It has been shown that there is as much as a 100-fold greater concentration of ganciclovir/ triphosphate in CMV-infected cells than in uninfected cells, indicating a preferential phosphorylation of ganciclovir in virus-infected cells. In vitro, ganciclovir-triphosphate is catabolised slowly, with 60% to 70% of the original level remaining in the infected cells 18 hours after removal of ganciclovir from the extracellular medium. The antiviral activity of ganciclovir/ triphosphate is believed to be the result of inhibition of viral DNA synthesis by two known modes: (1) competitive inhibition of viral DNA polymerases; (2) direct incorporation into viral DNA, resulting in eventual termination of viral DNA elongation. The cellular DNA polymerase alpha is also inhibited, but at a higher concentration than that required for inhibition of viral DNA polymerase.
The median concentration of ganciclovir that inhibits CMV replication (IC50) in vitro (laboratory strains or clinical isolates) has ranged from 0.08 to 14 microM (0.02 to 3.5 microgram/mL). Ganciclovir inhibits mammalian cell proliferation (TD50) in vitro at higher concentrations ranging from 40 to > 1000 microM (10 to > 250 microgram/mL). Ganciclovir has been shown to be more toxic in proliferating cells than in confluent, contact-inhibited cells (toxicity of 27 microM GCV in confluent MRC-5 cells = 0%, where as in proliferating MRC-5 cells = 26-44%). Bone marrow-derived colony-forming cells are more sensitive (TD50 2.7-12 microM; 0.68-3 microgram/mL). The relationship of in vitro sensitivity of CMV to ganciclovir and clinical response has not been established.

Viral resistance.

Viruses resistant to ganciclovir can arise after chronic dosing with ganciclovir or valganciclovir by selection of mutations in either the viral kinase gene (UL97) responsible for ganciclovir monophosphorylation or the viral polymerase gene (UL54). UL97 mutations arise earlier and more frequently than mutations in UL54. Virus containing mutations in the UL97 gene is resistant to ganciclovir alone, with M460V/I, H520Q, C592G, A594V, L595S, C603W being the most frequently reported ganciclovir resistance-associated substitutions. Mutations in the UL54 gene may show cross-resistance to other antivirals targeting the viral polymerase, and vice versa. Amino acid substitutions in UL54 conferring cross-resistance to ganciclovir and cidofovir are generally located within the exonuclease domains and region V, however amino acid substitutions conferring cross-resistance to foscarnet are diverse, but concentrate at and between regions II (codon 696-742) and III (codon 805-845). The possibility of viral resistance should be considered in patients who demonstrate poor clinical response or experience continuous viral excretion during treatment.
Emergence of viral resistance was reported in humans with AIDS and CMV retinitis and was associated with clinical failure of ganciclovir treatment. The number of patients with resistant isolates increased with duration of ganciclovir exposure, and was estimated to occur in 3% to 26% of patients after 3 to 9 months of treatment, respectively, and occurred with equal frequency in patients treated with IV and oral medicines.

Clinical trials.

Intravenous Cymevene in CMV retinitis.

The diagnosis of CMV retinitis should be made by indirect ophthalmoscopy. Other conditions in the differential diagnosis of CMV retinitis included candidiasis, toxoplasmosis, histoplasmosis, retinal scars, cotton wool spots, any of which may produce a 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.
Patients enrolled in the three controlled Cymevene IV/oral maintenance studies were 22 to 62 years of age with median baseline CD4 counts of 7.0 to 10.0 (range 0 to 320); the majority of patients were male (93 to 99%) and Caucasian (81 to 88%). Mean observation times for the three studies were from 42.5 to 47.0 days. The results of one of these studies is presented below (see ICM 1653).

ICM 1653.

In this randomised, open label, parallel group trial, conducted between March 1991 and November 1992, patients with AIDS and newly diagnosed CMV retinitis received a 3-week induction course of Cymevene solution, 5 mg/kg bd for 14 days followed by 5 mg/kg once daily for one additional week. Following the 21-day IV induction course, patients with stable CMV retinitis were randomised to receive 20 weeks of maintenance induction treatment with either Cymevene solution, 5 mg/kg once daily or Cymevene capsules 500 mg six times daily. The study showed that mean (95% CI) times to progression of CMV retinitis, as assessed by masked reading of fundus photographs was 57 days (44, 70) for patients on oral therapy compared to 62 days (50, 73) for patients on IV therapy. The difference (95% CI) in the mean time to progression between the oral and intravenous therapies (oral/IV) was -5 days (-22, 12). See Figure 1 for comparison of the proportion of patients remaining free of progression over time.

Intravenous Cymevene for prophylaxis of CMV disease in heart and bone marrow transplantation.

ICM 1496.

In a randomised, double blind, placebo-controlled study of the prophylaxis of tissue-invasive CMV in heart transplant patients who had asymptomatic infection or were receiving CMV seropositive organs, 149 patients aged 13 to 68 were enrolled (placebo n = 73 and ganciclovir n = 76) with the primary efficacy measure being CMV illness (defined as biopsy-proven CMV disease, CMV retinitis and/or CMV syndrome). Patients received placebo or ganciclovir 5 mg/kg every 12 hours for 14 days followed by 6 mg/kg once daily 5 days per week for 2 weeks (until day 25) whereupon CMV prophylaxis was discontinued and patients monitored until day 120 post-transplant. Doses were modified for renal function. Thirty-one of 73 placebo vs 12 of 76 ganciclovir patients developed CMV illness (42.5 vs. 15.8%, p = 0.0004). Additionally, the time from transplant to CMV illness was significantly longer in the ganciclovir group (p = 0.0001). A sustained antiviral effect was demonstrated by a significant difference in the incidence of positive CMV cultures at day 15 post-transplant (16.4 vs. 2.7%, p = 0.005) and continuing through days 29 and 60 (43.1 vs. 4.5%, p < 0.001; 56.4 vs. 19%, p < 0.001). The incidence of adverse events was similar in the two arms (see Table 5).

ICM 1689.

In a randomised, double blind, placebo-controlled study of the prophylaxis of tissue-invasive CMV in bone marrow transplant patients with asymptomatic infection, 72 patients aged 3 to 56 were enrolled (placebo n = 35, ganciclovir n = 37), with the primary efficacy endpoint being progression to life-threatening, biopsy-confirmed, tissue-invasive disease. Patients received placebo or ganciclovir 5 mg/kg twice daily for 7 days, followed by 5 mg/kg once daily until day 100 post-transplant (adjusted for renal function). The study was terminated after a planned interim analysis of 58 patients demonstrated a statistically significant decrease in CMV disease in the ganciclovir group. At day 100, 15 of 35 placebo patients vs 1 of 37 ganciclovir patients had developed CMV disease (42.9 vs. 2.7%, p = 0.00005). Additionally, there was a significant reduction in deaths from any cause in the ganciclovir arm (37.1 vs. 10.8%, p = 0.0096); none of the deaths in patients treated with ganciclovir occurred during the period in which the medicine was given. The time from transplant to CMV-related deaths was also significantly longer in the ganciclovir group (p = 0.0048). The significant difference in the incidence of CMV disease was maintained at 6 months after transplant, after prophylaxis had been ceased (42.9 vs. 16.2%, p = 0.013). The overall incidence of adverse events was similar, however more patients in the ganciclovir arm experienced absolute neutrophil counts below 1 x 109/L, often requiring dose modification.

Oral Cymevene for prophylaxis of CMV disease in liver transplantation.

In a multicentre, double-blind, randomised, placebo-controlled study of the efficacy and safety of ganciclovir capsules 3 g/day in the prevention of CMV disease in liver transplantation, prophylaxis was initiated within 10 days of transplantation in 304 patients and continued through week 14 after transplantation. The primary efficacy parameter was the prevention of CMV disease. The patients were also assessed for the incidence of CMV infection, other herpes virus infections, opportunistic infections, graft rejection and/or loss and patient survival. CMV disease was defined as one of the following: CMV syndrome (spiking fever with no response to antibiotics, malaise and/or fall in neutrophil counts over three consecutive daily measurements and with other causes excluded); CMV hepatitis, gastroenteritis, oesophagitis or colitis (confirmed by biopsy and other criteria); CMV pneumonia (confirmed with lavage and other criteria); CMV retinitis (by dilated fundus examination); or CMV encephalitis (by examination of cerebrospinal fluid). CMV infection was defined as one or more of the following: (1) CMV antigen detected in leukocytes; (2) a positive CMV culture obtained from any site in the body; and/or (3) seroconversion demonstrated by the appearance of IgG or IgM antibodies in a patient previously known to be seronegative.
In all, 19.5% of the placebo group vs. 4.8% of the ganciclovir group developed CMV disease (p < 0.001) and 9.8% vs. 0.7% developed tissue-invasive CMV disease by the 6-month timepoint. These reductions were observed irrespective of the recipient's gender, age, immunosuppression as well as whether the patient received antilymphocyte antibodies for induction of immunosuppression and/or the treatment of rejection. The time from transplant to first CMV infection was significantly increased in the ganciclovir group; 48.8% of the placebo vs. 11.4% of the ganciclovir group had developed infection by day 98 post-transplant. Severe adverse events were reported equally in the two groups. 97% of patients in the placebo arm and 94% in the ganciclovir arm maintained absolute neutrophil counts ≥ 1 x 109/L. (See Tables 6 and 7.)

5.2 Pharmacokinetic Properties

The pharmacokinetics of IV ganciclovir is linear over the range of 1.6 - 5.0 mg/kg. The systemic exposure (AUC0-∞) following a single dose of IV ganciclovir (5 mg/kg, 1 h infusion) in adult liver transplant patients was on average 50.6 microgram.h/mL (CV% 40). In this patient population peak plasma concentration (Cmax) was on average 12.2 microgram/mL (CV% 24). Whereas, following a dose of 5 mg/kg/day (n = 16) with IV ganciclovir the AUC0-24 and Cmax were 26.0 ± 6.06 and 9.03 ± 1.42 microgram/mL respectively. Most studies indicated that Cmin of ganciclovir (plasma level at 11 h after start of infusion) averaged 0.56 microgram/mL.

Absorption.

Not applicable.

Distribution.

For IV ganciclovir, the volume of distribution is correlated with body weight, with values for the steady state volume of distribution ranging from 0.54 to -0.87 L/kg. Ganciclovir penetrates the cerebrospinal fluid, and diffuses across the placenta. Binding to plasma proteins was 1% to 2% over ganciclovir concentrations of 0.5 and 51 microgram/mL. Therefore, medicine interactions involving binding site displacement are not expected.

Metabolism.

Ganciclovir is not metabolised to a significant extent.

Elimination.

Renal excretion of unchanged drug by glomerular filtration and active tubular secretion is the major route of elimination of ganciclovir. In patients with normal renal function, greater than 90% of of IV administered ganciclovir was recovered unmetabolised in the urine within 24 hours. Administration of a dose of 5 mg/kg IV ganciclovir as a 1 h infusion in 22 patients with normal renal function demonstrated that, the plasma halflife (t1/2) of ganciclovir averaged 2.9 ± 1.3 h and systemic clearance (Cliv) averaged 3.64 ± 1.86 mL/min/kg. Dose-dependent kinetics of ganciclovir over the dose range 1.6 to 5.0 mg/kg were demonstrated in as much as AUC for ganciclovir increased in proportion to the increase in dose by the systemic clearance and plasma t½ values were similar at all dose levels. In this patient population, greater than 90% of ganciclovir is recovered unmetabolised, in urine. Therefore, one would expect the renal status of patients to influence the kinetics of ganciclovir.

Special populations.

Renal impairment.

The total body clearance of ganciclovir is linearly correlated with creatinine clearance. In patients with mild, moderate, and severe renal impairment, mean systemic clearances of 2.1, 1.0 and 0.3 mL/min/kg were observed. Patients with renal impairment show an increased elimination half-life. In patients with severe renal impairment elimination half-life was increased by 10-fold.
As the major excretion pathway for ganciclovir is renal (glomerular filtration and active tubular secretion), the dosage of the medicine must be reduced according to serum creatinine/ creatinine clearance (see Section 4.2 Dose and Method of Administration, Renal impairment).

Haemodialysis.

Plasma concentrations of ganciclovir are reduced by about 50%-60% during a 4 hour hemodialysis session (see Section 4.9 Overdose).
During intermittent haemodialysis, estimates for the clearance of ganciclovir ranged from 42 to 92 mL/min, resulting in intra-dialytic half-lives of 3.3 to 4.5 hours. Estimates of ganciclovir clearance for continuous dialysis were lower (4.0 to 29.6 mL/min) but resulted in greater removal of ganciclovir over a dose interval. For intermittent haemodialysis, the fraction of ganciclovir removed in a single dialysis session varied from 50% to 63%.

Hepatic impairment.

No pharmacokinetic study has been conducted and no population PK data were collected in patients with hepatic impairment undergoing ganciclovir therapy. Hepatic impairment is not anticipated to affect the pharmacokinetics of ganciclovir since ganciclovir is excreted renally.

Paediatric patients.

The pharmacokinetics of IV ganciclovir were investigated across two studies in paediatric liver (N=18) and renal (N=25) transplant patients aged 3 months to 16 years and evaluated using a population pharmacokinetic model. The mean total clearance was 5.4 L/hr (90 mL/min) for a child with a creatinine clearance of 70.4 mL/min. The steady state volume of distribution and peripheral volume of distribution were on average 20 and 15 L, respectively. CrCL was identified as statistically significant covariate for ganciclovir clearance and height of the patient as statistically significant covariate for ganciclovir clearance, steady state volume and peripheral volume of distribution. Neither age, gender, nor types of organ transplant were significant covariates in these populations. Table 8 gives the estimated pharmacokinetic parameters by age group.
Pharmacokinetics of IV ganciclovir given according to the dosing regimen approved for adults (5 mg/kg IV infusion administered over 1 hour) were studied in a small group of infants and children with normal renal function, aged 9 months to 12 years (n=10, average 3.1 years). Exposure as measured by mean AUC on Days (n=10) 1 and AUC0-12 on Day 14 (n=7) were 19.4 ± 7.1 and 24.1 ± 14.6 microgram.h/mL with corresponding Cmax values of 7.59 ± 3.21 and 8.31 ± 4.9 microgram/mL (Days 1 and 14) respectively.
A trend towards lower exposures in younger paediatric patients was observed with body weight based dosing used in this study. In paediatric patients up to 5 years the average values for AUC0-∞ on Day 1 (n=7) and AUC0-12h on Day 14 (n=4) were 17.7 ± 5.5 and 17.1 ± 7.5 microgram.h/mL.
The ganciclovir IV dosing regimen based on BSA and renal function (3 x BSA x CrCLS) is derived from the paediatric dosing algorithm with valganciclovir, the oral pro-drug of ganciclovir. Pharmacokinetic simulations have confirmed that both dosing regimens provide similar ganciclovir exposures in the paediatric population from birth to 16 years. See Table 9.
The pharmacokinetics were also studied in 3 children with impaired renal function administered IV ganciclovir (1.25 mg/kg). The study showed these patients to have a Cmax of 3.66 microgram/mL, AUC 34.75 microgram.h/mL and t1/2 of 7.87 h.

Elderly patients.

No ganciclovir pharmacokinetic studies have been conducted in adults older than 65 years of age. However, because ganciclovir is mainly renally excreted and since renal clearance decreases with age a decrease in ganciclovir total body clearance and prolongation of ganciclovir elimination half-life can be anticipated in the elderly.

Oral ganciclovir.

The pharmacokinetics of ganciclovir following oral administration of Cymevene capsules have been evaluated in 500 immunocompromised adults. When administered orally ganciclovir exhibits linear kinetics up to a total daily dose of 4 g/day. When single doses of Cymevene capsules ranging from 500 mg to 2000 mg were administered to HIV-positive patients under fasting conditions, mean absolute bioavailability was 5.6% and 2.6% with the 500 mg dose and 2000 mg dose respectively. Absolute bioavailability of a single 1000 mg dose administered under fasted conditions in transplant patients was 7.2%. Following oral administration of a single 1000 mg dose of 14C-radiolabelled ganciclovir, 86% of administered ganciclovir was recovered in the faeces as unchanged drug, and 5% was recovered in the urine. No metabolite accounted for more than 1% to 2% of the radioactivity recovered in urine or faeces indicating that orally administered ganciclovir is excreted essentially unchanged.
A meal immediately prior to dosing with Cymevene capsules, 1000 mg every 8 hours, increased the mean steady state area under the serum concentration versus time curve (AUC) of ganciclovir by approximately 20%. Multiple dose pharmacokinetic studies were conducted using Cymevene capsules. At a dose of 1000 mg administered three times daily with food the mean steady state peak concentration of ganciclovir was 0.98 microgram/mL and the mean steady state morning trough concentration was 0.20 microgram/mL. The steady state AUC0-24 for this regimen was 13.0 microgram.hr/mL compared with 26.0 microgram.hr/mL for a single ganciclovir IV solution dose of 5 mg/kg (the standard maintenance regimen for treatment of CMV retinitis). The mean plasma t1/2 was 5.03 hours. The absolute bioavailability of multiple dose regimens of ganciclovir administered orally in doses of 3000 mg to 6000 mg daily in fed patients was approximately 6%.

5.3 Preclinical Safety Data

Carcinogenicity.

In animal studies ganciclovir was found to be mutagenic, teratogenic, aspermatogenic and carcinogenic. Cymevene should therefore be considered a potential teratogen and carcinogen in humans with the potential to cause birth defects and cancers. It is also considered likely that Cymevene causes temporary or permanent inhibition of spermatogenesis (see Section 4.6 Fertility, Pregnancy and Lactation; Section 4.8 Adverse Effects (Undesirable Effects)).
In an 18 month study, ganciclovir was carcinogenic in the mouse after oral doses of 20 mg/kg/day and 1000 mg/kg/day. All ganciclovir induced tumours were of epithelial or vascular origin, except for histiocytic sarcoma of the liver. Epithelial tumours involved a wide variety of tissues. No carcinogenic effects occurred at 1 mg/kg/day. Based on data on plasma drug concentrations, exposure of humans to ganciclovir would be greater than exposure of mice in the above study at 20 mg/kg. Thus, Cymevene should be considered a potential carcinogen in humans.

Genotoxicity.

Ganciclovir caused point mutations and chromosomal damage in mammalian cells in vitro and in vivo. Ganciclovir was clastogenic in the mouse micronucleus assay. Ganciclovir was not mutagenic in the Ames Salmonella assay.

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.

4.3 Contraindications

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/microL) or platelet count below 2.5 x 1010/L (25,000/microL) 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. See Section 4.1 Therapeutic Indications.

4.4 Special Warnings and Precautions for Use

The main clinical toxicities of ganciclovir include leucopenia, anaemia and thrombocytopenia.
In animal studies ganciclovir was found to be mutagenic, teratogenic, aspermatogenic, 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 (see Section 4.2 Dose and Method of Administration; Section 5.3 Preclinical Safety Data). 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 Section 4.6 Fertility, Pregnancy and Lactation; Section 4.8 Adverse Effects (Undesirable Effects)).
Cymevene is only indicated in those patients as outlined (see Section 4.1 Therapeutic Indications), 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.
The diagnosis of CMV retinitis should be made by indirect ophthalmoscopy. Other conditions in the differential diagnosis of CMV retinitis included candidiasis, toxoplasmosis, histoplasmosis, retinal scars, cotton wool spots, any of which may produce a 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 be advised to 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 acyclovir 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).

Haematologic.

Severe leucopenia, neutropenia, anaemia, thrombocytopenia, pancytopenia, bone marrow failure and aplastic anaemia have been observed in patients treated with Cymevene. 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 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects); Section 4.2 Dose and Method of Administration).
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.
Cymevene should not be administered to patients if the absolute neutrophil count falls below 0.5 x 109/L (500 cells/microL) or platelet count below 2.5 x 1010/L (25,000/microL) or the haemoglobin is less than 80 g/L (8 g/dL) (see Section 4.3 Contraindications).

Neutropenia.

Patients receiving ganciclovir have manifested neutropenia (neutrophil count < 1 x 109/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 109/L.

Thrombocytopenia.

Thrombocytopenia (platelet count < 5.0 x 1010/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 1011/L appear to be at increased risk of this toxicity. Cymevene should not be initiated if the absolute platelet count is < 2.5 x 1010/L.

Anaemia.

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 haemopoietic 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. If renal function is impaired, dosage adjustments based on serum creatinine/ creatinine clearance, are required (see Section 4.2 Dose and Method of Administration).
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.

Renal impairment.

Cymevene should be used with caution in patients with 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 Dose and Method of Administration, Renal impairment). Serum creatinine/creatinine clearance should be monitored at least once every two weeks.

Paediatric use.

Safety and efficacy of Cymevene in paediatrics has not been established. There has been very limited clinical experience in treating life- or sight-threatening cytomegalovirus disease with Cymevene in patients under the age of 12 years.
A higher risk of haematological cytopenias in neonates and 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 extreme 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.

Use in the 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 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration, Special dosage instructions, Renal impairment).

Effects 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 be performed frequently, especially in patients in whom ganciclovir or other nucleoside analogues have previously resulted in leucopenia, or in whom neutrophil counts are < 1.0 x 109/L at the beginning of treatment and particularly in patients with renal impairment. In patients with severe leucopenia, neutropenia, anaemia and/or thrombocytopenia, it is recommended that treatment with haematopoietic growth factors and/or dose interruption is recommended. Because dosing with Cymevene should be modified in patients with renal impairment, patients should have serum creatinine or creatinine clearance values followed carefully.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Imipenem-cilastatin.

Generalised seizures have been reported in patients receiving ganciclovir and imipenem-cilastatin concomitantly and a pharmacodynamic interaction between these two drugs cannot be discounted. These drugs should not be used concomitantly unless the potential benefit outweighs the risk (see Section 4.4 Special Warnings and Precautions for Use).

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 are at an increased risk of developing these conditions and may not tolerate concomitant therapy at full dosage. Regular haematological monitoring should be performed and dose adjustment may be required.

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 didanosine ranging from 38 to 67% was observed confirming a pharmacokinetic interaction during the concomitant administration of these drugs. Consequently, patients should be monitored closely for didanosine toxicity, including pancreatitis (see Section 4.8 Adverse Effects (Undesirable Effects)). If didanosine is given two hours prior to ganciclovir a 23% decrease in the AUC of ganciclovir occurs. There is no effect on the AUC of ganciclovir if the two medicines are given at the same time.

Probenecid.

At an oral dose of 1 g of Cymevene every 8 hours (n = 11), ganciclovir AUC0-8 increased 40% (95% CI: 6-85%) in the presence of probenecid, 500 mg every 6 hours. The increase in AUC0-8 was accompanied by a decrease in renal clearance of ganciclovir by 20%. 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. Consideration should also be given to other such medicines which inhibit renal tubular secretion, as these medicines may reduce renal clearance of Cymevene and thereby increase the plasma half-life of Cymevene.

Potential drug interactions.

Toxicity may be enhanced when ganciclovir is co-administered with other medicines known to be myelosuppressive or associated with renal impairment. This includes nucleoside analogues (e.g. zidovudine, didanosine, stavudine), immunosuppressants (e.g. cyclosporin, tacrolimus, mycophenolate mofetil), antineoplastic agents (e.g. doxorubicin, vinblastine, vincristine, hydroxyurea) and anti-infective agents (e.g. trimethoprim/sulfonamides, dapsone, amphotericin B, flucytosine, pentamidine), hydroxyurea and pegylated interferons/ribavirin. Therefore, these medicines should only be considered for concomitant use with ganciclovir if the potential benefits outweigh the potential risks.
No dose adjustment is required in case of stavudine, trimethoprim and cyclosporin.

4.6 Fertility, Pregnancy and Lactation

Effects on 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. 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 approximately six months 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.
Female mice exhibited decreased fertility, decreased mating behaviour and increased embryolethality after daily IV doses of 90 mg/kg. Daily IV doses of up to 20 mg/kg did not impair female fertility but doses as low as 5 mg/kg caused reduction in the birth weights of pups; higher doses were associated with hypoplasia of testes and seminal vesicles in male pups.
In male mice, fertility was decreased after daily IV doses of 2 mg/kg. These effects were reversible after daily IV doses of 2 mg/kg, but were irreversible or incompletely reversible after daily IV doses of 10 mg/kg. Ganciclovir has also caused hypospermatogenesis in dogs after daily IV doses of ≥ 0.4 mg/kg.
Animal data indicate that administration of ganciclovir causes inhibition of spermatogenesis and subsequent infertility in males. These effects were reversible at lower doses but irreversible at higher doses. Due to limitations of this study, these results are not sufficient to establish recovery of spermatogenesis. Animal data also indicate that suppression of fertility in females may occur. No human data are available in this regard but it is considered probable that such effects will occur in humans.
Although clinical data have not been obtained to support these animal findings, it is considered likely that Cymevene in the recommended doses will result in temporary or permanent inhibition of spermatogenesis in men. Permanent suppression of fertility in women may occur.
Because of the mutagenic potential of ganciclovir, women of reproductive potential should be advised to use an effective method of contraception during and for at least 30 days after treatment. Sexually active men should be advised to use condoms during and for at least 90 days following treatment with Cymevene unless it is certain that the female partner is not at risk of pregnancy (see Section 4.4 Special Warnings and Precautions for Use).
(Category D)
Cymevene may be teratogenic and/or embryotoxic at the dose levels recommended for human use. There have been no studies of Cymevene in pregnant women. The safety of Cymevene in pregnant women has not been established. Cymevene should not be given to pregnant women as there is a high likelihood of damage to the developing foetus (see Section 4.3 Contraindications).
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 microgram/mL and occurred by passive diffusion.
The safe use of Cymevene during labour and delivery has not been established.
Ganciclovir has been shown to be embryotoxic in rabbits and mice following IV administration, and teratogenic in rabbits. Foetal resorptions were present in at least 85% of rabbits and mice administered 60 mg/kg/day and 108 mg/kg/day, respectively (doses approximately equivalent to the recommended human dose - calculated on the basis of body surface area).
Daily IV doses of ganciclovir of 90 mg/kg administered to female mice prior to mating, during gestation, and during lactation caused hypoplasia of the testes and seminal vesicles in month-old offspring, as well as pathologic changes in the nonglandular region of the stomach. The drug exposure in mice as estimated by the AUC was approximately 1.6 x the human AUC.
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 (see Section 4.3 Contraindications). 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.

4.8 Adverse Effects (Undesirable Effects)

Clinical trial data.

Experience with intravenous ganciclovir.

HIV infected patients.

The safety of IV ganciclovir in AIDS patients was studied in several clinical trials. The pooled safety information of the use of IV ganciclovir in six clinical trials is displayed below in comparison to the control arm (oral placebo plus intravitreal ganciclovir implant) of one of these studies. Clinical adverse events, which occurred in more than 2% of patients taking ganciclovir intravenously, regardless of causal relationship or seriousness, but which occurred in a higher frequency in the IV ganciclovir arm compared to the control arm, are summarised in Table 2.
Injection site reactions occurred more frequently in patients taking IV ganciclovir than in the control group.

Transplant patients.

Several clinical trials have investigated IV ganciclovir for the treatment or prevention of CMV disease in transplant patients.
Clinical adverse events, which occurred in equal to or more than 5% of patients taking IV ganciclovir in three pooled bone marrow studies, regardless of causal relationship or seriousness, are summarised in Table 3. Adverse events which occurred in a higher frequency in the placebo/ observational control arm compared to the IV ganciclovir arm, have not been included in Table 3.
Clinical adverse events which occurred in equal to or more than 5% of patients taking IV ganciclovir in a placebo controlled heart transplant study, regardless of causal relationship or seriousness, but which occurred in a higher frequency in the IV ganciclovir arm (n = 76) compared to the placebo arm (n = 73), are listed below.

Body as a whole.

Headache (18%), infection (18%).

Metabolic and nutritional disorders.

Oedema (9%).

Central and peripheral nervous system.

Confusion (5%), peripheral neuropathy (7%).

Respiratory system.

Pleural effusion (5%).

Cardiovascular system.

Hypertension (20%).

Urogenital system.

Renal impairment (14%), renal failure (12%).

Paediatric population.

Based on the cumulative experience, including valganciclovir paediatric studies, the overall safety profile of ganciclovir in the paediatric population appears similar to the safety profile established in adults. There is a higher risk of haematological cytopenias in neonates and infants (see Section 4.4 Special Warnings and Precautions for Use, Paediatric use).

Other experience with intravenous and oral ganciclovir.

Other adverse events that were thought to be "probably" or "possibly" related to treatment with orally administered or intravenously administered Cymevene in clinical studies in either patients with AIDS or transplant recipients are listed below. These events all occurred with a frequency of less than 1%.

Body as a whole.

Cellulitis, enlarged abdomen, chest pain, chills, drug level increased, malaise, abscess, back pain, oedema, face oedema, injection site abscess, injection site oedema, injection site haemorrhage, injection site phlebitis, laboratory test abnormality, photosensitivity reaction, neck pain, neck rigidity, chills and fever.

Digestive system.

Eructation, mouth ulceration, constipation, dysphagia, faecal incontinence, haemorrhage, hepatitis, melaena, tongue disorder, aphthous stomatitis, gastritis.

Haemic and lymphatic system.

Hypochromic anaemia, pancytopenia, eosinophilia, marrow failure, splenomegaly.

Respiratory system.

Dyspnoea, cough increased.

Central nervous system.

Somnolence, dizziness, paraesthesia, abnormal thoughts or dreams, anxiety, euphoria, insomnia, abnormal gait, ataxia, confusion, dry mouth, hypaesthesia, manic reaction, agitation, amnesia, coma, depression, hypertonia, libido decreased, nervousness, psychosis, seizures, tremor trismus, emotional lability, hyperkinesia.

Skin and appendages.

Sweating, acne, maculopapular rash, dry skin, fixed eruption, herpes simplex, skin discolouration, urticarial, vesiculobullous rash.

Special senses.

Abnormal vision, taste perversion, vitreous disorder, eye pain, amblyopia, blindness, conjunctivitis, deafness, retinal detachment, glaucoma, retinitis, photophobia, tinnitus.

Metabolic and nutritional disorders.

Hypokalaemia, increases in creatinine, alkaline phosphatase, SGPT, SGOT, creatinine phosphokinase and lactic dehydrogenase.

Cardiovascular system.

Arrhythmia, hypertension, hypotension, deep thrombophlebitis, migraine, vasodilatation.

Urogenital system.

Breast pain, haematuria, increased serum urea, kidney failure, decreased creatinine clearance, abnormal kidney function, urinary frequency, urinary tract infection, impotence.

Musculoskeletal system.

Myasthenia, myalgia, bone pain.

Laboratory abnormalities.

Decreased blood sugar.
Note. The following adverse events reported in patients receiving ganciclovir potentially may be fatal: pancreatitis, sepsis, multiple organ failure.
In addition, the following adverse events were reported in at least one of the various clinical trials of Cymevene capsules for the prevention of CMV in HIV positive patients and/or transplant patients. The incidence was usually less than 2% or within 2% incidence of that reported for the placebo arm. These include weight loss, cholestatic jaundice, neuropathy, hyperglycaemia, leg cramps, amnesia, arthralgia, oesophagitis, myoclonus.

Post-marketing data.

The following are post-marketing events not listed above.

Listed below are adverse events reported spontaneously since the marketing introduction of Cymevene sterile powder and oral capsules that had not been reported during clinical trials. These events may have occurred as part of an underlying disease process. These voluntary reports include the following.

Body as a whole.

Rare: dysaesthesia. Very rare: allergic reaction, Stevens-Johnson syndrome, anaphylactic reaction, congenital anomaly, rhabdomyolysis.

Digestive system.

Very rare: perforated intestine, intestinal ulceration.

Hepatic system.

Rare: hepatic failure.

Haemic and lymphatic system.

Very rare: haemolytic anaemia. Rare: agranulocytosis and granulocytopenia.

Respiratory system.

Very rare: bronchospasm, pulmonary fibrosis.

Central nervous system.

Rare: encephalopathy, hallucinations. Very rare: dysphasia, myelopathy, extrapyramidal reaction, facial palsy, irritability.

Skin and appendages.

Very rare: exfoliative dermatitis.

Special senses.

Very rare: cataracts, loss of sense of smell, dry eyes.

Metabolic and nutritional disorders.

Rare: acidosis. Very rare: hyponatremia, elevated triglyceride levels.

Cardiovascular system.

Rare: cardiac arrest. Very rare: stroke, intracranial hypertension, vasculitis, peripheral ischaemia, ventricular tachycardia, cardiac conduction abnormality, Torsades de Pointes.

Urogenital system.

Very rare: infertility, testicular hypotrophy.

Musculoskeletal system.

Very rare: arthritis.

Laboratory abnormalities.

Very rare: syndrome of inappropriate antidiuretic hormone secretion.

Laboratory abnormalities in HIV-infected patients.

Laboratory abnormalities reported from three clinical trials in HIV-infected patients receiving IV ganciclovir as maintenance treatment for CMV retinitis are listed in Table 4. One hundred seventy-nine patients were eligible for the laboratory abnormality analysis.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Reconstituted Cymevene sterile powder is for IV administration only.

Intravenous administration.

Cymevene must be reconstituted and diluted under the supervision of a healthcare professional and administered as an intravenous infusion (see Section 6.6 Special Precautions for Disposal).
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.
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 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.
5 mg/kg given as an IV infusion over one hour, once daily on 7 days per week or 6 mg/kg given once daily on 5 days per week.
The duration of maintenance therapy 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 prevention of CMV disease in transplant recipients.

Dosage 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, 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 Table 1.
The following recommended dosages in renal impairment are not based on experience in patients with AIDS.
As dosage modifications are recommended in patients with renal impairment, serum creatinine or estimated creatinine clearance levels should be monitored carefully.
To calculate an estimated creatinine clearance:

Hepatic impairment.

The safety and efficacy of Cymevene has not been studied in patients with hepatic impairment (see Section 4.8 Adverse Effects (Undesirable Effects)).

Reduction of dosage.

Severe neutropenia (absolute neutrophil count < 0.5 x 109/L) or thrombocytopenia (platelets < 2.5 x 1010/L) requires a dose interruption until some evidence of marrow recovery is observed (absolute neutrophil count > 0.75 x 109/L, platelets > 5 x 1010/L).
Dose reductions should also be considered for anaemia and leukopenia.
Caution should be exercised in the handling and preparation of Cymevene products in a manner similar to that for cytotoxic medicines since Cymevene is considered a potential teratogen and carcinogen in humans (see Section 5.3 Preclinical Safety Data).
Avoid ingestion, inhalation, or direct contact with the skin and mucous membranes with either Cymevene solution or powder. It is advised that latex gloves and safety glasses be used to handle the preparation of Cymevene solution and when wiping the outer surface of the bottle/cap and the table after reconstitution.
If ganciclovir contacts the skin or mucous membranes, wash thoroughly with soap and water for at least 15 minutes. For eye exposure rinse thoroughly with plain water. Cymevene IV solutions are alkaline (pH approximately 11).

Method of administration.

Preparation of intravenous solution.

Each 10 mL clear glass vial contains the equivalent of 500 mg of the ganciclovir free base. The contents of the vial should be prepared for administration as follows (see Section 4.2 Dose and Method of Administration; Section 6.6 Special Precautions for Disposal).
1. The freeze dried powder should be reconstituted by injecting 10 mL of sterile water for injection into the vial.
Do not use bacteriostatic water for injection containing para-hydroxybenzoates, since these are incompatible with Cymevene sterile powder and may cause precipitation.
2. The vial should be shaken to dissolve the medicine.
3. Reconstituted solution should be inspected for particulate matter prior to proceeding with admixture preparation.

Administration of infusion solution.

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.
Cymevene should not be mixed with other IV products.
Cymevene vials should be administered within 24 hours of reconstitution to reduce microbiological hazard. If required, it may be diluted with the infusion solutions named above and held at 2-8°C for 24 hours after reconstitution (do not freeze).
Cymevene vials are for one dose in one patient only. Discard any remaining contents of the vial.
Compounding centres which are licensed by the Australian Therapeutic Goods Administration to reconstitute and/or further dilute cytotoxic medicines, and have validated aseptic procedures and regular monitoring of aseptic technique, may apply a shelf life of 15 days at 2-8°C (refrigerate, do not freeze) to Cymevene infusions reconstituted with water and further diluted with 0.9% sodium chloride or glucose (dextrose) 5%. These further diluted solutions have been shown to be chemically stable for this period. The extended shelf life does not apply to reconstituted injections diluted with Ringer's injection and Ringer-Lactate solution for injection.

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. Adverse reactions, for example seizures, dizziness, ataxia, 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.

4.9 Overdose

Toxic manifestations seen in animals given very high single IV doses of Cymevene (500 mg/kg) included emesis, hypersalivation, anorexia, bloody diarrhoea, inactivity, cytopenia, elevated liver function test results, elevated serum urea, testicular atrophy and death.
Reports of overdoses with IV ganciclovir, some with fatal outcomes, have been received from clinical trials and during post-marketing experience. In some of these cases no adverse events were reported. The majority of patients experienced one or more of the following adverse events.

Haematological toxicity.

Myelosuppression including pancytopenia, bone marrow failure, leukopenia, 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, seizure.
In patients who have received an overdose of Cymevene, dialysis and hydration may be of benefit in reducing drug plasma levels. The use of haematopoietic growth factors should be considered.
Treatment of overdose should consist of general supportive measures.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

None.

6.2 Incompatibilities

The following infusion fluids are compatible with Cymevene: normal saline, glucose 5% in water, Ringer's Injection, Ringer-Lactate Solution for Injection.
Cymevene should not be mixed with other IV products.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Unopened vials.

Store below 30°C.

Reconstituted vials.

Cymevene vials should be administered within 24 hours of reconstitution to reduce microbiological hazard. If required, it may be diluted with the infusion solutions named above and held at 2-8°C for 24 hours after reconstitution (do not freeze).
Cymevene vials are for one dose in one patient only. Discard any remaining contents of the vial.

Compounding centres.

1. Which are licensed by the Australian Therapeutic Goods Administration to reconstitute and/or further dilute cytotoxic medicines; and
2. Have validated aseptic procedures and regular monitoring of aseptic technique may apply a shelf-life of 15 days at 2-8°C (refrigerate, do not freeze) to Cymevene infusions reconstituted with water and further diluted with 0.9% sodium chloride or glucose (dextrose) 5%. These further diluted solutions have been shown to be chemically stable for this period. The extended shelf-life does not apply to reconstituted injections diluted with Ringer's Injection and Ringer-Lactate Solution for Injection.

6.5 Nature and Contents of Container

Cymevene for IV infusion is available in 10 mL clear glass vials containing sterile freeze-dried ganciclovir sodium 543 mg equivalent to ganciclovir 500 mg.
Each carton contains 5 vials.

6.6 Special Precautions for Disposal

The release of medicines into the environment should be minimised. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided.
In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes