Consumer medicine information

Valganciclovir Sandoz

Valganciclovir

BRAND INFORMATION

Brand name

Valganciclovir Sandoz

Active ingredient

Valganciclovir

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Valganciclovir Sandoz.

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about Valganciclovir Sandoz.

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 taking this medicine against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine.

WHAT IS USED FOR

This medicine is used to treat:

  • CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS)
  • Prophylaxis of CMV infection and disease following solid organ transplantation in patients at risk of CMV disease.

It contains the active ingredient valganciclovir hydrochloride.
Valganciclovir belongs to a group of medicines used to prevent the growth of viruses.

It works by acting against a virus called cytomegalovirus or CMV (a type of herpes virus). It prevents this virus from growing and multiplying in the body. In people with poor immunity, CMV can cause infections. Poor immunity can be caused by: HIV/AIDS or by medicines taken after an organ transplant.

Valganciclovir is also used to:

  • CMV eye infections in AIDS patients, which if left untreated may cause blindness. It is not a cure for CMV eye infections
  • Prevent CMV infection in patients following organ transplantation.

Valganciclovir Sandoz is not effective against any underlying HIV infection

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is available only with a doctor's prescription.

BEFORE YOU TAKE VALGANCICLOVIR SANDOZ

Animal and other laboratory studies have shown Valganciclovir causes infertility, birth defects and cancer. It is possible that these effects may also occur in humans.

When you must not take it

Do not take this medicine if you have an allergy to:

  • valganciclovir hydrochloride , the active ingredient(s), or to any of the other ingredient(s) listed at the end of this leaflet under Product Description
  • Ganciclovir, valaciclovir or aciclovir or any other similar medicines
  • If you have very low blood counts for platelets (which help clotting), neutrophils (a type of white blood cell which defends against infection) or low haemoglobin (oxygen carrying substance in the blood).

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

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Use in children

There is limited information on the safety and effectiveness of the use of Valganciclovir in children. Your doctor will advise you whether Valganciclovir is suitable for your child.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes. Especially any medicine which you have taken previously to treat your current condition.

Tell your doctor if you have or have had any of the following medical conditions:

  • history of low blood counts for platelets (thrombocytopenia), neutrophils (neutropenia) or anaemia
  • you have or previously have had poor kidney function

Tell your doctor if you are pregnant or plan to become pregnant or are breastfeeding. Valganciclovir Sandoz is not recommended for use during pregnancy. It may affect your developing baby if you take it during pregnancy. Your doctor can discuss with you the risks and benefits involved.

Tell your doctor if you are breast feeding or intend to breast feed. It is not known whether Valganciclovir Sandoz passes into breast milk. Breast feeding is not recommended during treatment with Valganciclovir Sandoz.

You are a woman who could become pregnant and you are not using contraception.

You must use a reliable form of contraception during Valganciclovir therapy, and for at least 30 days after stopping Valganciclovir, unless you are not sexually active. You are a sexually active man.

You should use condoms during and for at least 90 days following treatment with Valganciclovir unless it is certain that your female partner is not at risk of pregnancy.

Information is limited on the safety and effective of Valganciclovir Sandoz in children. Your doctor will advise.

If you have not told your doctor about any of the above, tell him/her before you start taking Valganciclovir Sandoz.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Valganciclovir Sandoz may interfere with other medicines.

These include:

  • medicines used to treat gout such as probenecid
  • medicines used to treat HIV infection, such as zidovudine (AZT) and didanosine(ddI)
  • a combination of medicines used to treat some infections, such as imipenem/cilastatin
  • medicine used to prevent organ rejection after a transplant such as mycophenolate mofetil, ciclosporin,
  • medicines for the treatment of cancer such as vincristine, adriamycin and hydroxyurea
  • anti-infective medications such as dapsone, pentamidine, flucytosine and amphotericin B
  • other medications for the treatment of HIV or HIV related infections such as nucleoside analogues
  • (lamivudine, also known as 3TC; stavudine, also known as D4T; zalcitabine also known as ddc; abacavir; lamivudine / zidovudine or; abacavir / lamivudine /zidovudine combinations).

These medicines may be affected by Valganciclovir Sandoz or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist will have more information on medicines to be careful with or avoid while taking this medicine.

HOW TO TAKE VALGANCICLOVIR SANDOZ

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions, ask your doctor or pharmacist for help.

How much to take

Valganciclovir Sandoz needs to be taken exactly as prescribed.

Your doctor will tell you how many Valganciclovir Sandoz tablets to take each day.

For Treatment of CMV Retinitis in AIDS

  • Induction Treatment (for active CMV retinitis)
    The usual dose is 900mg (two 450mg tablets) twice daily with food for 21 days
  • Maintenance Treatment (after induction treatment or for inactive CMV retinitis)
    The usual dose is 900mg (two 450mg tablets) once daily with food.

Prevention of CMV Disease in Transplantation

The usual dose is 900mg (two 450mg tablets) once daily with food, starting within 10 days of your organ transplant until 100 days after the transplant.

If you have received a kidney transplant, the same daily dose is required until 200 days after the transplant. Your dose may have to be reduced or stopped if you have or develop low blood counts, have kidney disease or if you are older than 65 years.

Ask your doctor or pharmacist if you are unsure of the correct dose for you. They will tell you exactly how much to take.

Follow the instructions they give you. If you take the wrong dose, Valganciclovir Sandoz may not work as well and your problem may not improve.

How to take it

Swallow the tablets whole with a full glass of water. Tablets must be taken with food.

When to take Valganciclovir Sandoz

Take your medicine at about the same time each day. Take during or immediately after a meal. If you take it on an empty stomach, it may not work as well. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

How long to take Valganciclovir Sandoz

Continue taking your medicine for as long as your doctor tells you. This medicine helps to control your condition, but does not cure it. It is important to keep taking your medicine even if you feel well.

Continue taking your medicine until your doctor tells you to stop.

If you forget to take it

Take your dose as soon as you remember, and continue to take it as you would normally.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone Australia 13 11 26 or New Zealand 0800 POISON or 0800 764766) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much Valganciclovir Sandoz. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

WHILE YOU ARE TAKING VALGANCICLOVIR SANDOZ

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking VALGANCICLOVIR SANDOZ.

A barrier contraceptive should be used while taking VALGANCICLOVIR SANDOZ and for 90 days after stopping treatment. Tell your doctor if you become pregnant while taking VALGANCICLOVIR SANDOZ. Condoms should be used by sexually active men while taking Valganciclovir and for 90 days after stopping treatment.

Women who are of childbearing potential should use contraception during and for at least 30 days after stopping Valganciclovir.

Tell any other doctors, dentists and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. It may affect other medicines used during surgery.

If you become pregnant while taking this medicine, tell your doctor immediately.

If you are about to have any blood tests, tell your doctor that you are taking this medicine. It may interfere with the results of some tests.

Your doctor may do some tests (blood cell counts) from time to time to make sure the medicine is working and to prevent unwanted side effects. 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 of 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). If you have not taken your medicine exactly as prescribed, you must tell your doctor. Otherwise, your doctor may think it was not effective and change your treatment unnecessarily.

Keep all of your doctor's appointments so that your progress can be checked.

Things you must not do

Do not take Valganciclovir Sandoz to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine without checking with your doctor.

Do not let yourself run out of medicine over the weekend or on holidays. Do not break or crush the tablets.

Things to be careful of

Be careful driving or operating machinery until you know how Valganciclovir Sandoz affects you. This medicine may cause dizziness, confusion, seizures, drowsiness in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

SIDE EFFECTS

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Valganciclovir Sandoz.

Valganciclovir helps most people with CMV infections but it may have unwanted side effects in a few people.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • Dizziness
  • Looking pale
  • Diarrhoea
  • Nausea
  • Fever
  • Vomiting
  • Headache

These are mild side effects of the medicine and are short-lived.

Tell your doctor as soon as possible if you notice any of the following:

  • skin rash
  • abdominal pain
  • cough
  • fatigue (tiredness)
  • oral thrush (sore, creamy yellow raised patches in the mouth)
  • insomnia (inability to sleep)
  • worsening of your eyesight

The above list includes serious side effects that may require medical attention. Serious side effects are rare

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • swelling of the tongue, lips or throat
  • any sign of infection such as fever, chills, sore throat or mouth ulcers
  • unexplained bruising or bleeding
  • thinking, hearing or seeing things that are not real
  • confusion
  • agitation
  • fits

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation. These side effects are very rare.

Tell your doctor or pharmacist if you notice anything else that is making you feel unwell. Other side effects not listed above may also occur in some people.

AFTER TAKING VALGANCICLOVIR SANDOZ

Storage

Keep your medicine in the original container.

If you take it out of its original container it may not keep well.

Keep your medicine in a cool dry place where the temperature stays below 25°C.

Do not store Valganciclovir Sandoz or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car.

Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

PRODUCT DESCRIPTION

What it looks like

Valganciclovir Sandoz 450mg - pink, convex oral tablets with 'J' on one side and '156' on the other side.

Available in blisters of 60 tablets

Ingredients

Active ingredients:

  • Each Valganciclovir Sandoz tablet contains 450mg of valganciclovir (as hydrochloride).

Inactive ingredients:

  • microcrystalline cellulose
  • crospovidone
  • stearic acid
  • povidone
  • hypromellose
  • titanium dioxide
  • macrogol 400
  • iron oxide red
  • polysorbate 80

This medicine does not contain lactose, sucrose, gluten and tartrazine,

Supplier

Sandoz Pty Ltd
ABN 60 075 449 553
54 Waterloo Road
Macquarie Park
Australia
Tel: 1800 726 369

This leaflet was prepared in January 2019.

Australian Registration Numbers

450mg Tablet: AUST R 227605

Published by MIMS March 2019

BRAND INFORMATION

Brand name

Valganciclovir Sandoz

Active ingredient

Valganciclovir

Schedule

S4

 

1 Name of Medicine

Valganciclovir hydrochloride.

6.7 Physicochemical Properties

Valganciclovir hydrochloride (valganciclovir HCl) is the hydrochloride salt of the L-valyl ester of ganciclovir. Ganciclovir is a synthetic nucleoside analogue of guanine.
Valganciclovir HCl is a white to off white crystalline powder.
Valganciclovir HCl is a polar hydrophilic compound with a solubility of 70 mg/mL in water at 25°C at a pH of 7.0 and an n-octanol/water partition coefficient of 0.0095 at pH 7.0. The pKa for valganciclovir is 7.6.
The chemical name of valganciclovir hydrochloride is L-valine, 2-[(2-amino-1,6 dihydro-6-oxo-9H-purin-9-yl)methoxy]-3-hydroxypropyl ester, monohydrochloride. The molecular formula is C14H22N6O5.HCl (MW: 390.83).

Chemical structure.

Its chemical structure is:

CAS number.

175865-59-5.

2 Qualitative and Quantitative Composition

Each tablet contains valganciclovir 450 mg (as valganciclovir hydrochloride 496 mg).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Valganciclovir Sandoz (valganciclovir HCl) is available as 450 mg pink convex oval tablets with "J" on one side and "156" on the other side. Each tablet contains 450 mg valganciclovir.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: antivirals for systemic use, nucleosides and nucleotides excl. reverse transcriptase inhibitors, ATC code: J05A B14.

Mechanism of action.

Valganciclovir is an L-valyl ester salt (prodrug) of ganciclovir which, after oral administration, is rapidly converted to ganciclovir by intestinal and hepatic esterases. Ganciclovir is a synthetic analogue of 2'-deoxyguanosine, which inhibits replication of herpes viruses in vitro and in vivo. Sensitive human viruses include human cytomegalovirus (HCMV), herpes-simplex virus-1 and 2 (HSV-1 and HSV-2), human 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.
In cytomegalovirus (CMV)-infected cells, ganciclovir is initially phosphorylated to ganciclovir monophosphate by the viral protein kinase, UL97. Further phosphorylation occurs by cellular kinases to produce ganciclovir triphosphate, which is then slowly metabolised intracellularly. This has been shown to occur in CMV-infected cells (half-life 18 hours) and HSV-infected cells (half-life between 6 and 24 hours) after removal of extracellular ganciclovir. As the phosphorylation is largely dependent on the viral kinase, phosphorylation of ganciclovir occurs preferentially in virus-infected cells.
The virustatic activity of ganciclovir is due to inhibition of viral DNA synthesis by: (a) competitive inhibition of incorporation of deoxyguanosine-triphosphate into DNA by viral DNA polymerase, and (b) incorporation of ganciclovir triphosphate into viral DNA causing termination of, or very limited, further viral DNA elongation. Typical anti-viral IC50 against CMV in vitro is in the range 0.08 micromolar (0.02 microgram/mL) to 14.32 micromolar (3.58 microgram/mL).
Valganciclovir allows systemic exposure of ganciclovir comparable to that achieved with recommended doses of intravenous (IV) ganciclovir, which has been shown to be efficacious in the treatment of CMV.
The clinical antiviral effect of valganciclovir has been demonstrated in the treatment of AIDS patients with newly diagnosed CMV retinitis (study WV15376). CMV shedding was decreased in urine from 46% (32/69) of patients at study entry to 7% (4/55) of patients following four weeks of valganciclovir treatment.

Viral resistance.

Viral resistance to ganciclovir can arise after chronic dosing with valganciclovir by selection of mutations in either the viral kinase gene (UL97) responsible for ganciclovir monophosphorylation or the viral polymerase gene (UL54). Virus containing mutations in the UL97 gene is resistant to ganciclovir alone, whereas virus with mutations in the UL54 gene may show cross-resistance to other antivirals targeting the viral polymerase and vice versa.

Treatment of CMV retinitis in AIDS.

A genotypic analysis of CMV in polymorphonuclear leucocytes (PMNL) isolates from 148 patients enrolled in one clinical study has shown that 2.2% (3/137), 6.5% (8/123), 12.8% (13/101) and 15.3% (13/85) contain UL97 mutations after 3, 6, 12 and 18 months, respectively, of valganciclovir treatment (using the number of patients still on treatment at the assessment time as the denominator). Phenotypic resistance was not identified, but very few CMV culture isolates were available for analysis.

Prevention of CMV disease in transplantation.

Resistance was studied by genotypic analysis of CMV in PMNL samples collected i) on day 100 (end of study drug prophylaxis) and ii) in cases of suspected CMV disease up to 6 months after transplantation. From the 245 patients randomised to receive valganciclovir, 198 day 100 samples were available for testing and no ganciclovir resistance mutations were observed. This compares with 2 ganciclovir resistance mutations detected in the 103 samples tested (1.9%) for patients in the oral ganciclovir comparator arm.
Of the 245 patients randomised to receive valganciclovir, samples from 50 patients with suspected CMV disease were tested and no resistance mutations were observed. Of the 127 patients randomised on the ganciclovir comparator arm, samples from the 29 patients with suspected CMV disease were tested, from which two resistance mutations were observed, giving an incidence of resistance of 6.9%.

Clinical trials.

Study WV15376: treatment of CMV retinitis in AIDS.

In a randomised, controlled study, 160 patients with AIDS and newly diagnosed CMV retinitis were randomised to receive treatment with either valganciclovir tablets (900 mg twice daily for 21 days, then 900 mg daily for 7 days) or with IV ganciclovir solution (5 mg/kg twice daily for 21 days, then 5 mg/kg daily for 7 days). Participants in the two treatment arms were comparable with respect to age, sex, weight, height and race. The mean age in the valganciclovir treatment arm was 39.6 years compared with 37.7 years in the ganciclovir arm. There was a higher proportion of males in each treatment group; 90% in the valganciclovir arm and 91% in the ganciclovir arm. The median CD4+ T-cell count at screening was 20.0 cells/microL for patients on the valganciclovir arm, and 26.0 cells/microL for patients on the ganciclovir arm; and the median HIV viral load was 4.8 log10 copies/mL in the valganciclovir arm and 4.9 log10 copies/mL in the ganciclovir arm.
In the final analysis of CMV retinitis progression by week 4 based on masked assessment of fundus photographs, 146 of 160 patients were included (73 in the valganciclovir tablets group and 73 in the IV ganciclovir group). The proportion of patients with retinitis progression at week 4 was the same in both treatment groups: 0.099 for the valganciclovir treatment group and 0.1 for the ganciclovir treatment group. The difference in progression proportions (IV ganciclovir minus valganciclovir tablets) was 0.001, with a 95% confidence interval of -0.097 to 0.100.
After week 4, all patients in this study were allowed to continue to receive treatment with valganciclovir tablets given at the dosage of 900 mg once daily. The mean (median) time from randomisation to progression of CMV retinitis in the group receiving induction and maintenance treatment with valganciclovir tablets (n = 80) was 226 (160) days and in the group receiving induction treatment with IV ganciclovir and maintenance treatment with valganciclovir tablets (n = 80) was 219 (125) days.
Satisfactory induction was achieved at week 4 in 47/61 (77%) patients given ganciclovir and 46/64 (72%) patients given valganciclovir. Satisfactory induction was defined as no progression, no increase in lesion activity and a reduction in retinitis border activity. Response was reassessed at 6 weeks when 39/62 (63%) patients given ganciclovir and 39/56 (70%) patients given valganciclovir maintained a satisfactory response to induction therapy. Three (8%) patients in each group had active retinitis at the week 6 assessment.

Study PV16000: prevention of CMV disease in solid organ transplantation.

A double-blind, double-dummy clinical active comparator study has been conducted in 372 heart, liver and kidney transplant patients at high-risk for CMV disease (donor seropositive/ recipient seronegative [(D+/R-)]). The study was designed to test for non-inferiority between the 2 treatment arms. Patients were randomised (2 valganciclovir: 1 oral ganciclovir) to receive either valganciclovir (900 mg once daily) or oral ganciclovir (1000 mg three times daily) starting within 10 days of transplantation until day 100 post-transplant.
The primary analysis of the primary endpoint, the proportion of patients who developed CMV disease, including CMV syndrome and/or tissue invasive disease during the first 6 months post-transplant was 12.1% in the valganciclovir arm (n = 239) compared with 15.2% in the oral ganciclovir arm (n = 125) as assessed by a blinded Endpoint Committee. The study achieved its objective and it was concluded that valganciclovir was non-inferior to oral ganciclovir for the prevention of CMV disease in solid organ transplant patients.
The majority of cases of CMV disease occurred following cessation of prophylaxis (post-day 100) with cases in the valganciclovir arm occurring on average later than those in the oral ganciclovir arm. The incidence of acute rejection in the first 6 months was 29.7% in patients randomised to valganciclovir compared with 36.0% in the oral ganciclovir arm. For a summary of PV16000 see Table 7.
For study PV16000 a population pharmacokinetics analysis was conducted using plasma samples taken from 160/245 patients in the valganciclovir arm and 82/127 patients in the oral ganciclovir arm, and from this analysis it was estimated that the median exposure to ganciclovir from valganciclovir was 1.74 times higher than seen with oral ganciclovir (AUC0-24h 44.3 vs. 25.4 microgram.h/mL).

IMPACT study (study NT18435): prevention of CMV disease in kidney transplant patients.

A double-blind, placebo controlled study has been conducted in 326 kidney transplant patients at high risk of CMV disease (D+/R-) to assess the efficacy and safety of extending valganciclovir CMV prophylaxis from 100 to 200 days post-transplant.
The inclusion criteria in this study required the patients to have adequate haematological (absolute neutrophil count > 1000 cells/microL, platelets > 25,000/microL, haemoglobin > 8 g/dL) and renal function (creatinine clearance > 15 mL/min and improving) in the immediate post-transplant period. The mean age of the patients who participated in this trial was about 48 years.
Patients were randomised (1:1) to receive valganciclovir tablets (900 mg once daily) within 10 days of transplantation until day 200 post-transplant or until day 100 post-transplant followed by 100 days placebo.
The proportion of patients who developed CMV disease during the first 12 months post-transplant is shown in Table 8.
The graft survival rate at 12 months post-transplant was 98.1% (160/163) for the 100-day dosing regimen and 98.2% (152/155) for the 200-day dosing regimen. The incidence of biopsy proven acute rejection at 12 months post-transplant was 17.2% (28/163) for the 100-day dosing regimen and 11.0% (17/155) for the 200-day dosing regimen.
No clinical trials have been conducted in patients following haematological or lung transplants.

Paediatric studies.

The safety and efficacy of valganciclovir in paediatric patients have not been established in adequate and well-controlled clinical studies.
The pharmacokinetics and safety of valganciclovir powder for oral solution in paediatric patients were studied in four phase I/II open-label, multi-centre clinical trials. Three studies enrolled 109 paediatric solid organ transplant recipients (heart: 12; kidney: 59; kidney + liver: 1; liver: 37) requiring anti-CMV prophylaxis, and the fourth study enrolled 24 neonates with symptomatic congenital CMV disease. Patients ranging in age from 8 days to 16 years received single or multiple doses of valganciclovir. Patients enrolled in the multiple dose studies could have received up to 100 days of therapy.
One study enrolled 20 liver transplant patients with a median age of 2 years (6 months to 16 years) who received a single daily dose of valganciclovir on 2 consecutive days. A second study enrolled 26 kidney patients with a median age of 12 years (1 to 16 years) who received multiple doses of valganciclovir on 2 consecutive days. For these two studies, the most commonly reported adverse events were related to the gastrointestinal system, particularly vomiting (liver and kidney patients), diarrhoea (kidney patients) and nausea (kidney patients).
The third solid organ transplant study enrolled 63 kidney, liver or heart patients with a median age of 9 years (4 months to 16 years) who received multiple doses of valganciclovir for up to 100 days. Common adverse events in this study were diarrhoea, pyrexia, hypertension, upper respiratory tract infection, vomiting, anaemia, neutropenia, constipation, nausea, and transplant rejection. There was no CMV disease reported during the study. However, CMV events were reported in 7 patients during the study, but none of these events fulfilled the definition of CMV disease.
In the neonate study, 24 neonates with a median age of 16.5 days (8 to 34 days) received 6 weeks of antiviral therapy. Common adverse events in this study were neutropenia and anaemia.

5.2 Pharmacokinetic Properties

The pharmacokinetic properties of valganciclovir have been evaluated in HIV- and CMV-seropositive patients, patients with AIDS and CMV retinitis and in solid organ transplant patients.
The parameters which control the exposure of ganciclovir from valganciclovir are the oral absorption of valganciclovir and the renal excretion of ganciclovir.

Absorption.

Valganciclovir is a prodrug of ganciclovir, which is well absorbed from the gastrointestinal tract and rapidly metabolised in the intestinal wall and liver to ganciclovir. The absolute bioavailability of ganciclovir from valganciclovir is approximately 60%. Systemic exposure to valganciclovir is transient and low. AUC0-24h and Cmax values are approximately 1% and 3% of those of ganciclovir, respectively.
Dose proportionality with respect to ganciclovir AUC following administration of valganciclovir in the dose range 450 to 2625 mg was demonstrated only under fed conditions. When valganciclovir is given with food mean ganciclovir AUC0-24h increased by 24% to 56% depending on the dose. When valganciclovir was given with food at a dose of 875 mg, increases were seen in both mean ganciclovir AUC0-24h (approximately 30%) and mean ganciclovir Cmax values (approximately 14%). Therefore, it is recommended that valganciclovir be administered with food (see Section 4.2 Dose and Method of Administration).
For ganciclovir, average AUC0-24h has been shown to correlate with time to progression of CMV retinitis.
The bioavailability of ganciclovir from valganciclovir is comparable across all the patient populations studied. The systemic exposure of ganciclovir to heart, kidney and liver transplant recipients was similar after oral administration of valganciclovir according to the renal function dosing algorithm.

Distribution.

Due to the rapid conversion of valganciclovir to ganciclovir, protein binding of valganciclovir was not determined. Plasma protein binding of ganciclovir was 1% to 2%. The steady state volume of distribution of ganciclovir after IV administration was 0.680 ± 0.161 L/kg.

Metabolism.

Valganciclovir is rapidly hydrolysed to ganciclovir; no other metabolites have been detected. No metabolite of orally-administered radiolabelled ganciclovir (1000 mg single dose) accounted for more than 1% to 2% of the radioactivity recovered in the faeces or urine.

Excretion.

Following dosing with valganciclovir, renal excretion as ganciclovir by glomerular filtration and active tubular secretion is the major route of elimination of valganciclovir. Renal clearance accounts for 81.5% ± 22% of the systemic clearance of ganciclovir.
The terminal half-life (t½) of ganciclovir following oral administration of valganciclovir to either healthy or HIV- and CMV-positive subjects was 4.18 ± 0.80 hours (n = 244), and that following administration of IV ganciclovir was 3.85 ± 0.74 hours (n = 87).
In patients undergoing haemodialysis, approximately half of the ganciclovir present at the start of a dialysis session is removed during dialysis. The mean intra-dialysis half-life and the mean inter-dialysis half-life was estimated to be 3.47 hours and 51.0 hours, respectively.

Special populations.

Patients with renal impairment.

Decreased renal function resulted in decreased clearance of ganciclovir from valganciclovir, and a corresponding increase in terminal half-life. Therefore, dosage adjustment is required for renally impaired patients (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

Patients with hepatic impairment.

The pharmacokinetics of valganciclovir in stable liver transplant recipients were investigated in one open label 4-part cross-over study (n = 28). The absolute bioavailability of ganciclovir from valganciclovir following a single dose of 900 mg valganciclovir under fed conditions was approximately 60%, in agreement with the estimates obtained in other patient populations. Ganciclovir AUC0-24h was comparable to that achieved by 5 mg/kg IV ganciclovir in liver transplant recipients.

Paediatric patients.

The pharmacokinetics of ganciclovir were evaluated following the administration of valganciclovir in three studies which enrolled a total of 109 paediatric solid organ transplant patients aged 4 months to 16 years (106 of the 109 were evaluable for pharmacokinetics). In these studies, patients received daily intravenous doses of ganciclovir to produce exposure equivalent to an adult 5 mg/kg intravenous dose (70 kg reference body weight) and/or received oral doses of valganciclovir to produce exposure equivalent to an adult 900 mg dose.
The pharmacokinetics was similar across organ type and age range. Population pharmacokinetic modelling suggested that bioavailability was approximately 60%. Clearance was positively influenced by both body surface area and renal function. The mean total clearance was 5.3 L/h (88.3 mL/min) for a patient with creatinine clearance of 70.4 mL/min. The mean Cmax and AUC by age and organ type are listed in Table 9.
Ganciclovir pharmacokinetics were also evaluated in 24 neonates aged 8 to 34 days with symptomatic congenital CMV disease. All patients received 6 mg/kg intravenous ganciclovir twice daily. Patients were then treated with oral valganciclovir, where the dose of valganciclovir powder for oral solution ranged from 14 mg/kg to 20 mg/kg twice daily. A dose of 16 mg/kg twice daily of valganciclovir powder for oral solution provided comparable ganciclovir exposure as 6 mg/kg intravenous ganciclovir twice daily in neonates, and also achieved ganciclovir exposure similar to the effective adult 5 mg/kg intravenous dose.
The pharmacokinetic modelling suggested that the typical value of clearance (L/h), volume of distribution (L), and bioavailability of ganciclovir in neonates were 0.146 x weight1.68, 1.15 x weight, and 54%, respectively.

5.3 Preclinical Safety Data

Genotoxicity.

Valganciclovir increased mutations in mouse lymphoma cells and was clastogenic in the mouse micronucleus assay. Valganciclovir was not mutagenic in the Ames Salmonella assay.
Ganciclovir increased mutations in mouse lymphoma cells and DNA damage in human lymphocytes in vitro. Ganciclovir was clastogenic in the mouse micronucleus assay. Ganciclovir was not mutagenic in the Ames Salmonella assay.

Carcinogenicity.

Ganciclovir was genotoxic and carcinogenic in animal studies. Valganciclovir should be considered a potential carcinogen in humans with the potential to cause cancers. No long-term carcinogenicity studies have been conducted with valganciclovir. However, upon oral administration, valganciclovir is rapidly and extensively converted to ganciclovir.
Toxicity in mice, dogs and rats was primarily characterised by testicular atrophy. Male infertility occurred at doses of 2 mg/kg/day and above which was consistent with the infertility and testicular atrophy seen in toxicity studies with doses between 2 and 10 mg/kg/day. In females, a more complex range of effects were induced which were characterised by embryo-foetal abnormalities and embryo-foetal losses in mice and rabbits and in multi-dose studies, by toxic and eventually carcinogenic changes to the reproductive system in mice.
Ganciclovir was carcinogenic in the mouse after oral doses of 20 mg/kg/day for 18 months and 1000 mg/kg/day for 15 months. All ganciclovir-induced tumours were of haematopoietic epithelial or vascular origin. Epithelial tumours involved a wide variety of tissues, including the female reproductive organs, pancreas, gastrointestinal tract and skin, as well as rodent specific glands (perputial, clitoral and Harderian). Vascular tumours were observed in females, mainly in the reproductive organs, but also in the mesenteric lymph nodes and liver. No carcinogenic effects occurred at 1 mg/kg/day. Based on data on plasma drug concentrations, exposure of humans to ganciclovir would be similar to or greater than the exposure of mice in the above study at 1000 mg/kg/day. This potential is likely to be markedly greater in children, as cell division occurs more rapidly in children.

4 Clinical Particulars

4.1 Therapeutic Indications

Valganciclovir is indicated for the treatment of cytomegalovirus (CMV) retinitis in adult patients with acquired immunodeficiency syndrome (AIDS).
Valganciclovir is indicated for the prophylaxis of CMV disease in adult solid organ transplantation (SOT) patients who are at risk.

4.3 Contraindications

Valganciclovir Sandoz is contraindicated in patients with known hypersensitivity to valganciclovir, ganciclovir or to any component of the product.
Due to the similarity of the chemical structure of valganciclovir and that of aciclovir and valaciclovir, a cross-hypersensitivity reaction between these medicines is possible.
Valganciclovir should not be administered if the absolute neutrophil count is less than 500 cells/microL, the platelet count is less than 25,000/microL, or the haemoglobin is less than 8 g/dL.

4.4 Special Warnings and Precautions for Use

Clinical toxicities of valganciclovir, which is metabolised to ganciclovir, include leucopenia and thrombocytopenia. Concomitant administration of valganciclovir and other medicines that are known to be myelosuppressive or associated with renal impairment may result in added toxicity (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
In animal studies, ganciclovir was found to be mutagenic, clastogenic, aspermatogenic, teratogenic and carcinogenic and to impair fertility; therefore, it should be considered a potential teratogen and carcinogen in humans with potential to cause birth defects and cancers. Prior to initiation of valganciclovir treatment, patients should be advised of the potential risks to the foetus and to use contraceptive measures (see Section 4.6 Fertility, Pregnancy and Lactation). Based on clinical and nonclinical studies, valganciclovir causes temporary or permanent inhibition of spermatogenesis in males (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use; Section 5.3 Preclinical Safety Data, Carcinogenicity, Genotoxicity; Section 6.6 Special Precautions for Disposal). Valganciclovir is indicated in those patients as outlined, see Section 4.1 Therapeutic Indications where the potential benefits to the patient outweighs the risks stated herein.
The diagnosis of CMV retinitis should be made by indirect ophthalmoscopy. Other conditions in the differential diagnosis of CMV retinitis include candidiasis, toxoplasmosis, histoplasmosis, retinal scars and 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.

Haematologic.

Severe leucopenia, neutropenia, anaemia, thrombocytopenia, pancytopenia, bone marrow depression and aplastic anaemia have been observed in patients treated with valganciclovir (and ganciclovir) (see Section 4.8 Adverse Effects (Undesirable Effects); Section 4.2 Dose and Method of Administration).
Therapy should not be initiated if the absolute neutrophil count is less than 500 cells/microL; or platelet count is less than 25,000/microL; or the haemoglobin is less than 8 g/dL. It is recommended that complete blood counts and platelet counts be monitored in all patients frequently during therapy; especially in patients with renal impairment in neonates and infants, in patients in whom ganciclovir or other nucleoside analogues have previously resulted in leucopenia, or in whom neutrophil counts are less than 1000 cells/microL at the beginning of treatment.
Valganciclovir 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. In patients with severe leucopenia, neutropenia, anaemia and/or thrombocytopenia, it is recommended that treatment with haematopoietic growth factors and/or dose interruption be considered. Cell counts usually begin to recover within 3 to 7 days of discontinuing medication. Colony-stimulating factors have been shown to increase neutrophil counts in patients receiving ganciclovir for treatment of CMV retinitis.

Use in hepatic impairment.

The safety and efficacy of valganciclovir have not been established in patients with hepatic impairment (see Section 5.2 Pharmacokinetic Properties, Special populations, Patients with hepatic impairment).

Use in renal impairment.

In patients with impaired renal function, dosage adjustments based on creatinine clearance are required.
Increased serum creatinine levels have been observed in trials evaluating valganciclovir tablets. Patients should have serum creatinine or creatinine clearance values monitored carefully to allow for dosage adjustments in renally impaired patients (see Section 4.2 Dose and Method of Administration, Dosage adjustment, Renal impairment).

Use in the elderly.

The pharmacokinetic profiles of valganciclovir in elderly patients have not been established. Since elderly individuals frequently have a reduced glomerular filtration rate, particular attention should be paid to assessing renal function before and during administration of valganciclovir.
Clinical studies of valganciclovir did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other therapy. Valganciclovir is known to be substantially excreted by the kidney, and the risk of toxic reactions to this medicine may be greater in patients with impaired renal function. Since elderly patients are more likely to have decreased renal function, care should be taken in dose selection. In addition, renal function should be monitored and dosage adjustments should be made accordingly (see Section 4.2 Dose and Method of Administration, Dosage adjustment, Renal impairment; Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment).

Paediatric use.

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 valganciclovir in children warrants extreme caution. Valganciclovir should be considered a potential carcinogen in humans. This potential to cause cancers is greater in infants and children than in adults. Valganciclovir is likely to cause temporary or permanent inhibition of spermatogenesis. This could result in permanent male infertility. 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 (see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects); Section 5.1 Pharmacodynamic Properties, Clinical trials).

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

In a rat in situ model of intestinal permeability, there was no interaction of valaciclovir, didanosine, nelfinavir, cyclosporin, omeprazole and mycophenolate mofetil with valganciclovir.
Valganciclovir is rapidly and extensively converted to ganciclovir; therefore, interactions associated with ganciclovir are expected for valganciclovir.
Binding of ganciclovir to plasma proteins is only about 1% to 2%, and medicine interactions involving binding site displacement are not anticipated.

Imipenem-cilastatin.

Convulsions have been reported in patients taking ganciclovir and imipenem-cilastatin concomitantly and a pharmacodynamic interaction between these two drugs cannot be discounted. Valganciclovir should not be administered concomitantly with imipenem-cilastatin unless the potential benefits outweigh the potential risks (see Section 4.4 Special Warnings and Precautions for Use).

Probenecid.

Probenecid given with oral ganciclovir resulted in statistically significantly decreased renal clearance of ganciclovir (20%) leading to statistically significantly increased exposure (40%). These changes were consistent with a mechanism of interaction involving competition for renal tubular excretion. Therefore patients taking probenecid and valganciclovir concomitantly should be closely monitored for ganciclovir toxicity.

Zidovudine.

When zidovudine was given in the presence of oral ganciclovir there was a small (17%), but statistically significant, increase in the AUC of zidovudine. There was also a trend towards lower ganciclovir concentrations when administered with zidovudine although this was not statistically significant. Both zidovudine and valganciclovir have the potential to cause neutropenia and anaemia. A pharmacodynamic interaction may occur during concomitant administration of these drugs and some patients may not tolerate concomitant therapy at full dosage.

Didanosine.

Didanosine plasma concentrations were found to be consistently raised when given with ganciclovir (both IV and oral). At ganciclovir oral doses of 3 g/day and 6 g/day, an increase in the AUC of didanosine ranging from 84% to 124% has been observed, and likewise at IV doses of 5 mg/kg/day and 10 mg/kg/day, and increase in the AUC of didanosine ranging from 38% to 67% has been observed confirming a pharmacokinetic interaction during the administration of these drugs. There was no significant effect on ganciclovir concentrations. Patients should be closely monitored for didanosine toxicity (e.g. pancreatitis). This increase cannot be explained by competition for renal tubular secretion, as there was an increase in the percentage of didanosine dose excreted. This increase could arise from either increased bioavailability or decreased metabolism. There was no clinically significant effect on ganciclovir concentrations. However, given the increase in didanosine plasma concentrations in the presence of ganciclovir, patients should be closely monitored for didanosine toxicity.

Mycophenolate mofetil.

Based on the results of a single dose administration study of recommended doses of oral mycophenolate mofetil (MMF) and IV ganciclovir and the known effects of renal impairment on the pharmacokinetics of MMF and ganciclovir, it is anticipated that co-administration of these medicines (which have the potential to compete for renal tubular secretion) will result in increases in phenolic glucuronide of mycophenolic acid (MPAG) and ganciclovir concentration. No substantial alteration of mycophenolic acid (MPA) pharmacokinetics is anticipated and MMF dose adjustment is not required. In patients with renal impairment in which MMF and ganciclovir are co-administered, the dose recommendation of ganciclovir should be observed and patients monitored carefully.

Zalcitabine.

Zalcitabine increased the AUC0-8h of oral ganciclovir by 13%. There were no statistically significant changes in any of the other pharmacokinetic parameters assessed. Additionally, there were no clinically relevant changes in zalcitabine pharmacokinetics in the presence of oral ganciclovir although a small increase in the elimination rate constant was observed.

Stavudine.

No statistically significant pharmacokinetic interaction was observed when stavudine and oral ganciclovir were given in combination.

Trimethoprim.

Trimethoprim statistically significantly decreased the renal clearance of oral ganciclovir by 16.3% and this was associated with a statistically significant decrease in the terminal elimination rate and corresponding increase in half-life by 15%. However, these changes are unlikely to be clinically significant, as AUC0-8h and Cmax were unaffected. The only statistically significant change in trimethoprim pharmacokinetic parameters when co-administered with ganciclovir was an increase in Cmin by 12%. However, this is unlikely to be of clinical significance and no dose adjustment is recommended.

Cyclosporin.

There was no evidence that introduction of ganciclovir affects the pharmacokinetics of cyclosporin based on the comparison of cyclosporin trough concentrations. However, there was some evidence of increases in the maximum serum creatinine value observed following initiation of ganciclovir therapy.

Other potential medicine interactions.

Toxicity may be enhanced when ganciclovir is co-administered with other medicines known to be myelosuppressive or associated with renal impairment (such as dapsone, pentamidine, flucytosine, vincristine, vinblastine, adriamycin, amphotericin B, nucleoside analogues and hydroxyurea). Therefore, these medicines should be considered for concomitant use with ganciclovir only if the potential benefits outweigh the potential risks.

Paediatric population.

Interaction studies have only been performed in adults.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

In animal studies, ganciclovir was found to be aspermatogenic. It is therefore considered likely that valganciclovir causes temporary or permanent inhibition of spermatogenesis.
Reproductive toxicity studies have not been conducted with valganciclovir. Valganciclovir is rapidly and extensively converted to ganciclovir and therefore is expected to have similar reproductive toxicity effects as ganciclovir. Animal data indicate that the administration of ganciclovir causes inhibition of spermatogenesis and subsequent infertility. These effects were reversible at lower doses and irreversible at higher doses. It is considered probable that in humans, valganciclovir at the recommended doses may cause temporary or permanent inhibition of spermatogenesis. Ganciclovir caused decreased mating behaviour, decreased fertility, and an increased incidence of embryolethality in female mice following IV doses of 90 mg/kg/day (approximately 2.1 times the mean drug exposure to ganciclovir in humans following the maximum recommended dose of valganciclovir, 900 mg twice daily, based on AUC comparisons).
Ganciclovir caused decreased fertility in male mice and hypospermatogenesis in mice and dogs following daily oral or IV administration of doses ranging from 0.2 to 10 mg/kg/day. Systemic drug exposure (AUC) at the lowest dose showing toxicity in each species ranged from 0.02 to 0.1 times the AUC of ganciclovir in humans following the maximum recommended dose of valganciclovir. Valganciclovir caused similar effects on spermatogenesis in mice, rats and dogs. It is considered likely that valganciclovir could cause inhibition of human spermatogenesis.
Prior to initiation of ganciclovir treatment, patients should be advised of the potential risks to the foetus and to use contraceptive measures.
(Category D)
The safety of valganciclovir for use in pregnant women has not been established however, ganciclovir readily diffuses across the human placenta. Valganciclovir should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
Women of childbearing potential should be advised to use effective contraception during and for at least 30 days after treatment with valganciclovir because of the mutagenic and teratogenic potential of ganciclovir. Sexually active men should be advised to use condoms during, and for at least 90 days following, treatment with valganciclovir, unless it is certain that the female partner is not at risk of pregnancy.
The safe use of valganciclovir during labour has not been established.
Valganciclovir is expected to have reproductive toxicity effects similar to ganciclovir. 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 at 60 mg/kg/day IV and mice at 108 mg/kg/day (2.7 times the mean drug exposure to ganciclovir in humans following the maximum recommended dose of valganciclovir, 900 mg twice daily, based on AUC comparisons). Effects observed in rabbits included: foetal growth retardation, embryolethality, teratogenicity and/or maternal toxicity. Teratogenic changes included cleft palate, anophthalmia/microphthalmia, aplastic organs (kidney and pancreas), hydrocephaly and brachygnathia. In mice, effects observed were foetal toxicity and embryolethality.
Daily intravenous doses 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 the month-old male 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 2.1 times the human AUC.
Valganciclovir may be teratogenic or embryotoxic at dose levels recommended for human use. In addition, the effect on the future fertility of boys is unknown. There are no adequate and well-controlled studies in pregnant women.
Many medicines are excreted in human milk and, because carcinogenic and teratogenic effects occurred in animals treated with ganciclovir, the possibility of serious adverse reactions from ganciclovir in breastfed infants is considered likely. Human data are not available but animal data indicates that ganciclovir is excreted in the milk of lactating rats. Therefore, valganciclovir should not be given to breastfeeding mothers or breastfeeding should be discontinued. The minimum time interval before breastfeeding can safely be resumed after the last dose of valganciclovir is unknown.

4.8 Adverse Effects (Undesirable Effects)

Clinical trials.

Experience with valganciclovir.

Valganciclovir, a prodrug of ganciclovir, is rapidly converted to ganciclovir after oral administration. The undesirable effects known to be associated with ganciclovir usage can therefore be expected to occur with valganciclovir. All of the adverse events observed in clinical studies with valganciclovir have been previously observed with ganciclovir.

Adult patients. Treatment of CMV retinitis in AIDS.

The safety profiles of valganciclovir and IV ganciclovir during 28 days of randomised study phase (21 days induction dose and 7 days maintenance dose) in 158 patients were comparable. The most frequently reported events were diarrhoea, neutropenia and pyrexia. More patients reported diarrhoea, oral candidiasis, headache and fatigue in the oral valganciclovir arm, and nausea and injection site-related events in the IV ganciclovir arm (see Table 2).
Based on two clinical trials (n = 370) where patients with CMV retinitis received valganciclovir at a dosage of 900 mg twice daily or once daily, corresponding to the induction or maintenance regimen, respectively, the adverse events with an incidence of ≥ 5%, regardless of seriousness and drug relationship is shown in Table 3. Approximately 65% of these patients received valganciclovir for more than nine months (maximum duration was 30 months).
The most frequently reported adverse events (% of patients), regardless of seriousness and drug relationship reported from these two clinical trials (n = 370) in patients taking valganciclovir were diarrhoea (38%), pyrexia (26%), nausea (25%), neutropenia (24%) and anaemia (22%). The majority of the adverse events were of mild or moderate intensity. The most frequently reported adverse event (% of patients), regardless of seriousness, that were considered related (remotely, possibly or probably) to valganciclovir by the investigator were neutropenia, anaemia (14%), diarrhoea (13%) and nausea (9%).

Prevention of CMV disease in transplantation.

Table 3 shows the adverse events (up to 28 days after study treatment) regardless of seriousness and drug relationship with an incidence of ≥ 5% from a clinical trial, PV16000 where solid organ transplant patients received valganciclovir (n = 244) or oral ganciclovir (n = 126) starting within 10 days of transplantation until day 100 post-transplant. The most frequently reported adverse events (% of patients), regardless of seriousness and drug relationship in patients taking valganciclovir reported in this clinical trial (n = 244) were diarrhoea (30%), tremors (28%), graft rejection (24%), nausea (23%), headache (22%), lower limb oedema (21%), constipation (20%), back pain (20%), insomnia (20%), hypertension (18%), and vomiting (16%). These events were also seen with oral ganciclovir at a comparable incidence. The majority of the adverse events were of mild or moderate intensity.
Events seen in the solid organ transplant clinical trial (100 day dosing regime) not seen in CMV retinitis clinical trials at a frequency ≥ 2% included hypertension (18%), raised blood creatinine (10%), metabolism disorders e.g. hyperkalaemia (14%) and abnormal hepatic function (9%). These events occurred at a similar rate with oral ganciclovir and could be considered a reflection of the underlying disease process.
The most frequently reported adverse reactions (% of patients), regardless of seriousness, that were considered related (remotely, possibly or probably) to valganciclovir by the investigator in solid organ transplant patients treated until day 100 post-transplant were leukopenia (9%), diarrhoea (7%), nausea (6%), neutropenia (5%) and vomiting (5%) and were leukopenia, neutropenia, anaemia and diarrhoea in kidney transplant patients treated until day 200 post-transplant. The most frequently reported adverse reactions (% of patients), regardless of seriousness, that were considered related (remotely, possibly or probably) to ganciclovir by the investigator in solid organ transplant patients were leucopenia (4%), diarrhoea (6%), nausea (3%), vomiting (3%), thrombocytopenia (3%) and renal impairment (3%).
Serious adverse events for valganciclovir from these three clinical trials (n = 614) with a frequency of less than 5% and which are not mentioned in Tables 2 and 3, are listed below.

Blood and lymphatic system disorders.

Pancytopenia, bone marrow depression, aplastic anaemia, febrile neutropenia.

Renal and urinary disorders.

Decreased renal creatinine clearance.

Infections and infestations.

Local and systemic infections and sepsis.

Bleeding complications.

Potentially life-threatening bleeding associated with thrombocytopenia.

Nervous system disorders.

Convulsion, psychotic disorder, hallucinations, confusion, agitation.

General disorder and administration site conditions.

Valganciclovir hypersensitivity.
Severe neutropenia (ANC < 500/microL) is seen more frequently in CMV retinitis patients (16%) undergoing treatment with valganciclovir than in solid organ transplant patients receiving valganciclovir (5%) or oral ganciclovir (3%) until day 100 post-transplant or valganciclovir (10%) until day 200 post-transplant. There was a greater increase in serum creatinine seen in solid organ transplant patients treated until day 100 or day 200 post-transplant with both valganciclovir and oral ganciclovir when compared to CMV retinitis patients. Impaired renal function is a feature common to solid organ transplantation patients.
The overall safety profile of valganciclovir did not change with the extension of prophylaxis up to 200 days in high risk kidney transplant patients. Leucopenia was reported with a slightly higher incidence in the 200 days arm while the incidence of neutropenia, anaemia and thrombocytopenia were similar in both arms. The incidence of adverse events in this patient population from the IMPACT study is shown in Table 4 and Table 5. Table 4 shows adverse events occurring in the first 100 days of the study when all patients were receiving valganciclovir prophylaxis. While, Table 5 shows adverse events occurring after day 100 of the study when only patients in the 200 days arm were receiving valganciclovir (patients in the 100 day arm were receiving placebo).

Experience with ganciclovir.

Valganciclovir is rapidly converted to ganciclovir. Adverse events reported with ganciclovir, and not mentioned above, are listed below.

Gastrointestinal disorders.

Abdominal distension, cholangitis, dyspepsia, dysphagia, eructation, oesophagitis, faecal incontinence, flatulence, gastritis, gastrointestinal disorder, gastrointestinal haemorrhage, mouth ulceration, pancreatitis, tongue disorder.

General disorders and administration site conditions.

Ascites, asthenia, bacterial, fungal and viral infections, haemorrhage, malaise, mucous membrane disorder, pain, photosensitivity reaction, rigors, sepsis, taste disturbance, decreased libido.

Hepatobiliary disorders.

Hepatitis, jaundice.

Skin and subcutaneous tissue disorders.

Acne, alopecia, exfoliative dermatitis, dry skin, increased sweating, urticaria.

Nervous system disorders.

Abnormal dreams, amnesia, anxiety, ataxia, coma, dry mouth, emotional disturbance, hyperkinetic syndrome, hypertonia, myoclonic jerks, nervousness, somnolence, tremor.

Psychiatric disorder.

Abnormal thinking.

Musculoskeletal and connective tissue disorders.

Musculoskeletal pain, myasthenic syndrome.

Renal and urinary disorders.

Haematuria present, impotence, renal failure, urinary frequency.

Metabolic and nutritional disorders.

Increased blood alkaline phosphatase, increased blood creatine phosphokinase, decreased blood glucose, increased blood lactic dehydrogenase, decreased blood magnesium, diabetes mellitus, oedema, abnormal hepatic function, hypocalcaemia, hypokalaemia, hypoproteinaemia.

Eye disorders.

Amblyopia, blindness, eye haemorrhage, eye pain, glaucoma, abnormal vision, vitreous disorder.

Ear and labyrinth disorders.

Earache, deafness, tinnitus.

Blood and lymphatic system disorders.

Eosinophilia, leucocytosis, lymphadenopathy, splenomegaly.

Cardiac disorders.

Arrhythmia (including ventricular arrhythmia), deep thrombophlebitis, hypertension, hypotension, migraine, phlebitis, tachycardia, vasodilatation.

Respiratory, thoracic and mediastinal disorders.

Pleural effusion, sinus congestion.

Laboratory abnormalities.

Laboratory abnormalities reported in adult CMV retinitis and SOT patients receiving with valganciclovir tablets until day 100 post-transplant are listed in Table 6.

Post-marketing experience.

Experience with ganciclovir and valganciclovir.

Adverse events from post-marketing spontaneous reports with intravenous and oral ganciclovir not mentioned in any section above, and for which a causal relationship cannot be excluded are listed below. As valganciclovir is rapidly and extensively converted to ganciclovir, such adverse events might also occur with valganciclovir.
Anaphylaxis.
Decreased fertility in males.
Agranulocytosis.
Granulocytopenia.
Adverse events that have been reported during the post-marketing period are consistent with those seen in clinical trials with valganciclovir and ganciclovir (see Section 4.8 Adverse Effects (Undesirable Effects); Section 5.1 Pharmacodynamic Properties, Clinical trials).

Reporting suspected adverse effects.

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 http://www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Dosage.

Caution.

Strict adherence to dosage recommendations is essential to avoid overdose.
Valganciclovir is rapidly and extensively converted to the active ingredient ganciclovir. The bioavailability of ganciclovir from valganciclovir is up to 10-fold higher than from oral ganciclovir, therefore the dosage and administration of valganciclovir tablets or powder for oral solution as described below should be closely followed (see Section 4.4 Special Warnings and Precautions for Use; Section 4.9 Overdose).

Treatment of CMV retinitis.

Adult patients.

Induction treatment.

For patients with active CMV retinitis, the recommended dosage is 900 mg twice daily for 21 days with food. Prolonged induction treatment may increase the risk of bone marrow toxicity (see Section 4.4 Special Warnings and Precautions for Use, Haematologic).

Maintenance treatment.

Following induction treatment, or in patients with inactive CMV retinitis the recommended dose is 900 mg once daily with food. Patients whose retinitis worsens may repeat induction treatment (see Induction treatment).

Prevention of CMV disease in transplantation.

Adult patients.

Kidney transplant.

For kidney transplant patients, the recommended dose is 900 mg once daily with food, starting within 10 days of transplantation until 200 days post-transplantation [see Section 5.1 Pharmacodynamic Properties, Clinical trials, IMPACT study (study NT18435)].

Solid organ transplant other than kidney.

For all other solid organ transplant patients, the recommended dose is 900 mg once daily with food, starting within 10 days of transplantation until 100 days post-transplantation (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Study PV16000).

Method of administration.

Valganciclovir is administered orally, and should be taken with food (see Section 5.1 Pharmacodynamic Properties; Section 5.2 Pharmacokinetic Properties, Absorption).

Dosage adjustment.

Renal impairment.

Serum creatinine or creatinine clearance levels should be monitored carefully. Dosage adjustment is required based on creatinine clearance as shown in Table 1 (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties, Special populations).
Creatinine clearance can be calculated from serum creatinine by the following formula:

Patients with severe leucopenia, neutropenia, anaemia, thrombocytopenia and/or pancytopenia.

Severe leucopenia, neutropenia, anaemia, thrombocytopenia, pancytopenia, bone marrow depression and aplastic anaemia have been observed in patients treated with valganciclovir (and ganciclovir). Therapy should not be initiated if the absolute neutrophil count is less than 500 cells/microL or the platelet count is less than 25,000/microL or the haemoglobin is less than 8 g/100 mL (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).

Paediatric patients.

(Powder for oral solution can be available from other brand/s.)
The safety and efficacy of valganciclovir in paediatric patients have not been established in adequate and well-controlled clinical studies.
In paediatric solid organ transplant patients (paediatric heart transplant patients from 4 weeks and paediatric kidney transplant patients from 4 months (see Section 5.1 Pharmacodynamic Properties, Clinical trials), who are at risk of developing CMV disease, the recommended once daily dose of valganciclovir is based on body surface area (BSA) and creatinine clearance (CrCl) derived from Schwartz formula, and is calculated using the equation below.
Paediatric dose (mg) = 7 x BSA x CrCl (calculated using the Schwartz formula). If the calculated Schwartz creatinine clearance exceeds 150 mL/min/1.73 m2, then a maximum value of 150 mL/min/1.73 m2 should be used in the equation.
All calculated doses should be rounded to the nearest 25 mg increment for the actual deliverable dose. If the calculated dose exceeds 900 mg, a maximum dose of 900 mg should be administered. The oral solution is the preferred formulation since it provides the ability to administer a dose calculated according to the formula above; however, valganciclovir tablets may be used if the calculated doses are within 10% of available tablet doses and the patient is able to swallow tablets. For example, if the calculated dose is between 405 mg and 495 mg, one 450 mg tablet may be taken.
It is recommended to monitor serum creatinine levels regularly and consider changes in height and body weight and adapt the dose as appropriate during prophylaxis period.

4.7 Effects on Ability to Drive and Use Machines

Convulsions, sedation, dizziness, ataxia and/or confusion have been reported with the use of valganciclovir and/or ganciclovir. If they occur, such effects may affect tasks requiring alertness including the patient's ability to drive and operate machinery.

4.9 Overdose

Overdose experience with valganciclovir tablets.

One adult developed fatal bone marrow depression (medullary aplasia) after several days of dosing that was at least 10-fold greater than recommended for the patient's estimated degree of renal impairment (decreased creatinine clearance).
It is expected that an overdose of valganciclovir could also possibly result in increased renal toxicity (see Section 4.2 Dose and Method of Administration, Dosage adjustment, Renal impairment; Section 4.4 Special Warnings and Precautions for Use).
Haemodialysis and hydration may be of benefit in reducing blood plasma levels in patients who receive an overdose of valganciclovir (see Section 5.2 Pharmacokinetic Properties, Special populations).

Overdose experience with intravenous ganciclovir.

Toxic manifestations seen in animals given very high single intravenous doses of ganciclovir (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 intravenous 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.

Pancytopenia, bone marrow depression, medullary aplasia, leucopenia, neutropenia, granulocytopenia.

Hepatotoxicity.

Hepatitis, liver function disorder.

Renal toxicity.

Worsening of haematuria in a patient with pre-existing renal impairment, acute renal failure, and elevated creatinine.

Gastrointestinal toxicity.

Abdominal pain, diarrhoea, vomiting.

Neurotoxicity.

Generalised tremor, convulsion.
Treatment of overdose should consist of general supportive measures.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

The excipients are microcrystalline cellulose, crospovidone, stearic acid and povidone. The film coat applied to the tablets contains Opadry Pink 15B24005 which consists of hypromellose, titanium dioxide, macrogol 400, iron oxide red and polysorbate 80.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
For information on interactions with other medicines and other forms of interactions, see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

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

Valganciclovir Sandoz tablets should be stored at below 25°C.
Protect from light.

6.5 Nature and Contents of Container

Valganciclovir Sandoz is supplied in blister packs (Al/Al) of 60 tablets.

6.6 Special Precautions for Disposal

Caution should be exercised in the handling of valganciclovir tablets. Valganciclovir tablets should not be broken or crushed. Since valganciclovir is considered a potential teratogen and carcinogen in humans and inhibits spermatogenesis, caution should be observed in handling valganciclovir tablets. Avoid direct contact of broken or crushed tablets with skin or mucous membranes. If such contact occurs, wash thoroughly with soap and water, and rinse eyes thoroughly with sterile water, or plain water if sterile water is unavailable.
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. Unused or expired medicine should be returned to a pharmacy for disposal.
In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes