Consumer medicine information

Valganciclovir AN

Valganciclovir

BRAND INFORMATION

Brand name

Valganciclovir AN Tablets

Active ingredient

Valganciclovir

Schedule

S4

 

Consumer medicine information (CMI) leaflet

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

What is in this leaflet

This leaflet answers some common questions about VALGANCICLOVIR AN tablets.

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 VALGANCICLOVIR AN 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.

You may need to read it again.

What VALGANCICLOVIR AN is used for

VALGANCICLOVIR AN contains the active ingredient valganciclovir. In the body valganciclovir rapidly changes to ganciclovir.

VALGANCICLOVIR AN belongs to a class of medicines used to prevent the growth of viruses.

VALGANCICLOVIR AN acts against a virus called cytomegalovirus or CMV (a type of herpes virus). It prevents this virus from growing and multiplying in the body. CMV causes infections, mainly in people with poor immunity. Poor immunity can be caused by HIV/AIDS or by medications taken after an organ transplant.

VALGANCICLOVIR AN is used to treat CMV eye infections (known as CMV retinitis) in AIDS patients, which, if left untreated can cause blindness. It is not a cure for CMV eye infections.

VALGANCICLOVIR AN is not effective against any underlying HIV infection.

VALGANCICLOVIR AN is also used to prevent CMV infection in patients following organ transplantation.

Your doctor, however, may have prescribed VALGANCICLOVIR AN for another purpose.

Ask your doctor if you have any questions about why VALGANCICLOVIR AN has been prescribed for you.

VALGANCICLOVIR AN is not addictive.

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

Before you take VALGANCICLOVIR AN

Animal and other laboratory studies have shown VALGANCICLOVIR AN 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 VALGANCICLOVIR AN if

  1. you have had an allergic reaction to VALGANCICLOVIR AN, ganciclovir, valaciclovir or aciclovir or any ingredients listed at the end of this leaflet

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), neutrophils (a type of white blood cell which defends against infection) or low haemoglobin (oxygen carrying substance in the blood)
  2. the package is torn or shows signs of tampering
  3. 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 taking VALGANCICLOVIR AN, talk to your doctor.

Use in children

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

Before you start to take 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
  2. you have any other health problems, especially the following:
  • you have a history of low blood counts for platelets (thrombocytopenia), neutrophils (neutropenia) or anaemia
  • you have, or previously have had, poor kidney function
  1. you are pregnant or intend to become pregnant
    VALGANCICLOVIR AN is not recommended for use during pregnancy.
    VALGANCICLOVIR AN may affect your developing baby if you take it during pregnancy. Your doctor will discuss the risks and benefits of using VALGANCICLOVIR AN if you are pregnant.
  2. you are breast-feeding or intend to breast-feed
    It is not known whether VALGANCICLOVIR AN passes into breast milk. Breast-feeding is not recommended during therapy with VALGANCICLOVIR AN.

If you have not told your doctor about any of the above, tell them before you start taking VALGANCICLOVIR AN.

Taking other medicines

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

Some medicines may interfere with VALGANCICLOVIR AN. These medicines include:

  • probenecid, a medicine used to treat gout
  • zidovudine (AZT) a medicine, used to treat HIV infection
  • imipenem/cilastatin combination of medicines used totreat some infections
  • didanosine (ddI), a medicine used to treat HIV infection
  • mycophenolate mofetil, a medicine used to prevent organ rejection after a transplant
  • medicines for the treatment of cancer such as vincristine, adriamycin, hydroxyurea
  • anti-infective agents such as dapsone, pentamidine, flucytosine, pegylated interferons plus ribavirin and amphotericin B
  • other medicines 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 AN, or may affect how well it works. You may need to use different amounts of your medicine, or you may need to take different medicines. Your doctor will advise you.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking VALGANCICLOVIR AN.

Ask your doctor or pharmacist if you are not sure about this list of medicines.

How to take VALGANCICLOVIR AN

Follow all directions given to you by your doctor or pharmacist carefully.

They may differ from the information contained in this leaflet.

How much to take

Take VALGANCICLOVIR AN

Take VALGANCICLOVIR AN exactly as your doctor has prescribed.

Your doctor will tell you how many VALGANCICLOVIR AN tablets to take each day.

Treatment of CMV Retinitis in AIDS for adults

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

Prevention of CMV Disease in Transplantation for adults
The usual dose is 900 mg (two 450 mg 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.

Prevention of CMV Disease in Transplantation for children
Your doctor will let you know how many VALGANCICLOVIR AN tablets you should give your child each day.

How to take it

Swallow tablets whole with a glass of water. VALGANCICLOVIR AN must be taken with food.

When to take it

Take VALGANCICLOVIR AN during or immediately after a meal.

If you take VALGANCICLOVIR AN on an empty stomach, it may not work as well.

Take VALGANCICLOVIR AN at about the same time each day.

Taking your medicine at the same time each day will have the best effect. It will also help you remember when to take VALGANCICLOVIR AN.

How long to take it

Continue taking VALGANCICLOVIR AN until your doctor tells you to stop.

If you forget to take it

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

Otherwise, take it as soon as you remember and then go back to taking it as you would normally.

Do not take a double dose to make up for the dose you missed.

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

If you have trouble remembering your dose, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor, or the Poisons Information Centre (telephone 13 11 26), or go to Accident and Emergency at your nearest hospital, if you think you or anyone else may have taken too much VALGANCICLOVIR AN. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

Keep telephone numbers for these places handy.

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

While you are taking VALGANCICLOVIR AN

Things you must do

Tell all doctors, dentists and pharmacists who are treating you that you are taking VALGANCICLOVIR AN.

A barrier contraceptive should be used while taking VALGANCICLOVIR AN and for 90 days after stopping treatment.

Tell your doctor if you become pregnant while taking VALGANCICLOVIR AN.

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, for any reason, you have not taken your medicine exactly as prescribed.

Otherwise, your doctor may think that it was not effective and change your treatment unnecessarily.

Be sure to keep all of your appointments with your doctor so that your progress can be checked.

Things you must not do

Do not stop taking VALGANCICLOVIR AN or change the dose without first checking with your doctor.

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

Do not take any other medicines whether they require a prescription or not without first telling your doctor or consulting a pharmacist.

Do not give VALGANCICLOVIR AN to anyone else even if they have the same condition as you.

Be careful when handling VALGANCICLOVIR AN tablets. Do not break or crush them. If you accidentally touch broken or crushed tablets, wash your hands thoroughly with soap and water. If any powder from the tablet gets in your eyes, rinse your eyes thoroughly with water.

Things to be careful of

Be careful driving or operating machinery until you know how VALGANCICLOVIR AN affects you.

VALGANCICLOVIR AN may cause drowsiness, dizziness, confusion or seizures (fits) in some people and therefore may affect alertness. Make sure you know how you react to VALGANCICLOVIR AN 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 while you are taking VALGANCICLOVIR AN.

VALGANCICLOVIR AN 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. Your doctor has weighed the risks of using this medicine against the benefits they expect it will have for you.

Do not be alarmed by this list of possible side effects.

You may not experience any of them.

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

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

  • dizziness
  • looking pale
  • diarrhoea
  • nausea
  • fever
  • vomiting
  • headache

These are more common side effects of VALGANCICLOVIR AN and are usually short- lived.

Tell your doctor immediately 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

These side effects may be serious. You may require medical attention.

Tell your doctor immediately, or go to Accident and Emergency at your nearest hospital, if you notice any of the following:

  • 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

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 taking VALGANCICLOVIR AN

Storage

Keep your tablets in the bottle until it is time to take them.

If you take the tablets out of the bottle they may not keep well.

Keep VALGANCICLOVIR AN in a cool dry place where the temperature stays below 25°C.

Do not store it, or any other medicine, in a bathroom or near a sink.

Do not leave it in the car or on window sills.

Heat and dampness can destroy some medicines.

Keep VALGANCICLOVIR AN where young 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 VALGANCICLOVIR AN, or the tablets have passed their expiry date, ask your pharmacist what to do with any tablets that are left over.

Product description

Availability

VALGANCICLOVIR AN comes in 450 mg film- coated tablets.

VALGANCICLOVIR AN comes in bottles containing 60 tablets.

What VALGANCICLOVIR AN looks like

VALGANCICLOVIR AN 450 mg tablets are pink convex oval tablets plain on one side and "450" on the other side.

Ingredients

Active ingredient - valganciclovir

  • each VALGANCICLOVIR AN tablet contains 450 mg of valganciclovir

Inactive ingredients -

VALGANCICLOVIR AN film-coated tablets also contain

  • microcrystalline cellulose (460)
  • povidone K-30
  • crospovidone
  • stearic acid (570)
  • hypromellose
  • titanium dioxide (171)
  • macrogol 400
  • polysorbate 80 (433)
  • FD&C red.

VALGANCICLOVIR AN tablets are lactose and gluten free.

Sponsor

Juno Pharmaceuticals Pty Ltd
Level 2, 6 Bond St
South Yarra VIC 3141
AUSTRALIA

Australian Registration Number
AUST R 262931

This leaflet was prepared in December 2017

BRAND INFORMATION

Brand name

Valganciclovir AN Tablets

Active ingredient

Valganciclovir

Schedule

S4

 

Name of the medicine

Valganciclovir hydrochloride.

Excipients.

Microcrystalline cellulose, povidone, crospovidone, and stearic acid. The film-coat applied to the tablets contains Opadry Pink which consists of hypromellose, titanium dioxide, macrogol 400, and Allura Red AC aluminium lake.

Description

CAS: 175865-59-5. The chemical name for 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 and molecular weight is 390.83.
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.
Valganciclovir AN is available as a 450 mg tablet for oral administration. Each tablet contains 496.3 mg valganciclovir HCl (corresponding to 450 mg valganciclovir), and inactive ingredients: microcrystalline cellulose, povidone, crospovidone, and stearic acid. The film-coat applied to the tablets contains Opadry Pink which consists of hypromellose, titanium dioxide, macrogol 400, and Allura Red AC aluminium lake.

Pharmacology

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 microM (0.02 microgram/mL) to 14.32 microM (3.58 microgram/mL).

Pharmacodynamics.

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). 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).

Adult patients.

Treatment of CMV retinitis in AIDS.

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%.
Resistance was evaluated in a study that extended valganciclovir CMV prophylaxis from 100 days to 200 days post-transplant in adult kidney transplant patients at high risk for CMV disease (D+/R-) (see Clinical Trials). Five subjects from the 100 day group and four subjects from the 200 day group meeting the resistance analysis criteria had known ganciclovir resistance-associated amino acid substitutions detected. In six subjects, the following resistance associated amino acid substitutions were detected within pUL97: 100 day group: A440V, M460V, C592G; 200 day group: M460V, C603W. In three subjects, the following resistance-associated amino acid substitutions were detected within pUL54: 100 day group: E315D, 200 day group: E315D, P522S. Overall, the detection of known ganciclovir resistance-associated amino acid substitutions was observed more frequently in patients during prophylaxis therapy than after the completion of prophylaxis therapy (during therapy: 5/12 [42%] versus after therapy: 4/58 [7%]). The possibility of viral resistance should be considered in patients who show poor clinical response or experience persistent viral excretion during therapy.

Pharmacokinetics.

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 and bioavailability.

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 valganiclovir is transient and low. AUC0-24 h 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 AUC0-24 h 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 AUC0-24 h (approximately 30%) and mean ganciclovir Cmax values (approximately 14%). Therefore, it is recommended that valganciclovir tablets be administered with food (see Dosage and Administration).
For ganciclovir, average AUC0-24 h 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 (adult and paediatric). 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 and paediatric dosing algorithm (see Dosage and Administration).

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 (t1/2) 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.

Pharmacokinetics in 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 Precautions and Dosage and Administration).

Patients with hepatic impairment.

The pharmacokinetics of ganciclovir from 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 AUC0-24 h was comparable to that achieved by 5 mg/kg IV ganciclovir in liver transplant recipients.

Paediatric patients.

Prevention of CMV disease in transplantation.

The pharmacokinetics of ganciclovir following the administration of valganciclovir were characterised using a population PK model based on data from four studies in paediatric solid organ transplant patients aged 3 weeks to 16 years. PK data were evaluable from 119 of the 123 patients enrolled. 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 model indicated that clearance is influenced by body weight and creatinine clearance while the central and peripheral volumes of distribution were influenced by body weight (see Dosage and Administration).
The mean ganciclovir Cmax, AUC and half-life by age and organ type in studies using the paediatric dosing algorithm are listed in Table 1 and are consistent with estimates obtained in adult solid organ transplant patients.

Congenital CMV.

Ganciclovir pharmacokinetics following valganciclovir administration were also evaluated in 133 neonates aged 2 to 31 days with symptomatic congenital CMV disease in two studies. In the first study, 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 solution1 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. In the second study, all patients received valganciclovir powder for oral solution at a dose of 16 mg/kg twice daily for 6 weeks and subsequently 96 out of 109 enrolled patients were randomised to continue receiving valganciclovir or placebo for 6 months.
The mean ganciclovir AUC0-12 hr after oral dose administration of valganciclovir was approximately 23.2 microgram.h/mL (equivalent to 46.4 microgram.h/mL in AUC0-24 hr) in the first study. Similar exposure was also observed in the second study.
1Valganciclovir powder for oral solution is unavailable in this brand.

Clinical Trials

Valganciclovir powder for oral solution is unavailable in this brand. Clinical trial information obtained using valganciclovir powder for oral solution has been included in the following sub-sections for completion and for prescriber information.

Adult patients.

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 2.
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 (AUC0-24 h 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 3.
The graft survival rate at 12 months post-transplant was 98.2% (160/163) for the 100-day dosing regimen and 98.1% (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 patients.

Prevention of CMV disease in transplantation.

Valganciclovir powder for oral solution has been studied in five open-label, multi-centre clinical trials in paediatric solid transplant (SOT) patients.
Three of these studies assessed only the pharmacokinetics and safety of oral valganciclovir in SOT patients aged from 4 weeks to 16 years of age who were requiring CMV prophylaxis (see Pharmacology, Pharmacokinetics in special populations).
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. The third study enrolled 14 heart transplant patients with a median age of 13 weeks (4 weeks to 125 days) who received a single daily dose of valganciclovir on 2 consecutive days. The other two studies assessed the development of CMV disease, as a measure of efficacy, following prophylaxis of valganciclovir for up to 100 days and 200 days post-transplant using the described paediatric dosing algorithm (see Dosage and Administration).
One solid organ transplant study enrolled 63 paediatric kidney, liver or heart patients with a median age of 9 years (4 months to 16 years) who received daily doses of valganciclovir for up to 100 days. There was no CMV event reported during the study that would fulfil the definition of CMV disease. CMV events were reported in 7 patients during the study of which 3 did not require adjustment to the study drug or were not treated and, therefore, were not considered clinically significant (see Adverse Effects, Clinical Trials and Pharmacology, Pharmacokinetics). The second study in solid organ transplant enrolled 57 paediatric kidney patients with a median age of 12 years (1 to 16 years) who received daily doses of valganciclovir for up to 200 days. There was no CMV event reported during the study that would fulfill the definition of CMV disease. While 4 patients reported CMV events, one could not be confirmed by the central laboratory and of the 3 remaining events one did not require treatment and, therefore, was not considered clinically significant (see Adverse Effects, Clinical trials).

Congenital CMV.

The efficacy and safety of ganciclovir and/or valganciclovir were studied in neonates and infants with congenital symptomatic CMV infection in two studies, with patients receiving up to 6 weeks or 6 months of treatment. The dose of valganciclovir that was determined in the first study and carried forward to the second study was twice daily doses of valganciclovir oral solution based on body weight using the following equation: Dose (mg) = 16 mg per kg of body weight.
Efficacy was evaluated using relevant endpoints such as hearing outcomes, neurodevelopmental outcomes and correlations of CMV blood viral load with ganciclovir plasma concentrations and hearing (see Adverse Effects, Clinical trials).

Indications

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

Contraindications

Valganciclovir AN 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 AN 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.

Precautions

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 Precautions and Interactions with Other Medicines).
In animal studies ganciclovir was found to be mutagenic, clastogenic, aspermatogenic, teratogenic and carcinogenic; therefore it should be considered a potential teratogen and carcinogen in humans with potential to cause birth defects and cancers. It is also considered likely that valganciclovir causes temporary or permanent inhibition of spermatogenesis (see Precautions, Carcinogenicity and Genotoxicity). Valganciclovir is indicated in those patients as outlined under the Indications section 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 Adverse Effects and Dosage and 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 frequently during therapy; especially 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.

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 Dosage and Administration, Special patient groups).

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.

Use in pregnancy.

(Category D)
Women of childbearing potential should be advised to use effective contraception during treatment with valganciclovir because of the mutagenic and teratogenic potential of ganciclovir. Men should be advised to practise barrier contraception during, and for at least 90 days following, treatment with valganciclovir.
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. The safety of valganciclovir for use in human pregnancy has not been established. Valganciclovir should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Use in lactation.

It is not known whether ganciclovir is excreted in human or animal milk. However, 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. Therefore Valganciclovir AN 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 AN is unknown.

Paediatric use.

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 Clinical Trials, Dosage and Administration, Adverse Effects).

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 Precautions, Renal impairment and Dosage and Administration, Patients with renal impairment).

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.

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.

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.

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 will be 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. Valganciclovir should not be administered concomitantly with imipenem-cilastatin unless the potential benefits outweigh the potential risks (see Precautions).

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. However, since both zidovudine and valganciclovir have the potential to cause neutropenia and anaemia, 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. 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 AUC0-8 h 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 AUC0-8 h 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.

Since ganciclovir is excreted through the kidney via glomerular filtration and active tubular secretion (see Pharmacology, Pharmacokinetics, Excretion), co-administration of valganciclovir with antiretroviral drugs that share the tubular secretion pathway, such as nucleos(t)ide reverse transcriptase inhibitors, may change the plasma concentrations of valganciclovir and/or the coadministered drug.
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, hydroxyurea and pegylated interferons/ribavirin). Therefore, these medicines should be considered for concomitant use with ganciclovir only if the potential benefits outweigh the potential risks.

Adverse 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 oral 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 4).
Based on two clinical trials (n = 370) where patients with CMV retinitis received oral 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 5. Approximately 65% of these patients received valganciclovir for more than nine months (maximum duration was 30 months).
The most frequently reported adverse reactions regardless of seriousness, that were considered related (remotely, possibly or probably) to valganciclovir by the investigator were neutropenia, anaemia, diarrhoea and nausea.

Prevention of CMV disease in transplantation.

Table 5 also 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, where solid organ transplant patients received valganciclovir or oral ganciclovir starting within 10 days post-transplantation until Day 100 post-transplant.
The most frequently reported adverse reactions, 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, diarrhoea, nausea and neutropenia and were leukopenia, neutropenia, anaemia and diarrhoea in kidney transplant patients treated until Day 200 post-transplant.
Serious adverse events for valganciclovir from these three clinical trials (n = 934) with a frequency of less than 5% and which are not mentioned in Tables 4 and 5, 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 Tables 6 and 7. Table 6 shows adverse events occurring in the first 100 days of the study when all patients were receiving valganciclovir prophylaxis. While, Table 7 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.

Cholangitis, dysphagia, eructation, oesophagitis, faecal incontinence, flatulence, gastritis, gastrointestinal disorder, gastrointestinal haemorrhage, mouth ulceration, pancreatitis, tongue disorder.

General disorders and administration site conditions.

Asthenia, bacterial, fungal and viral infections, haemorrhage, malaise, mucous membrane disorder, 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.

Paediatric patients.

Valganciclovir has been studied in 179 paediatric solid organ transplant patients who are at risk of developing CMV disease (aged 3 weeks to 16 years) and in 133 neonates with symptomatic congenital CMV disease (aged 2 to 31 days), with duration of ganciclovir exposure ranging from 2 to 200 days (see Clinical Trials).

Prevention of CMV disease in solid organ transplant (SOT).

Table 8 shows the adverse events (up to 28 days after completion of study treatment) regardless of seriousness and relationship with an incidence of ≥ 10% from two clinical trials where solid organ transplant paediatric patients received valganciclovir starting within 10 days post-transplantation until Day 100 post-transplant and where kidney transplant paediatric patients received valganciclovir once daily starting within 10 days post transplantation until Day 200 post-transplant.
The overall safety profile was similar in paediatric patients as compared to adults. However, the rates of certain adverse events, such as, but not limited to, upper respiratory tract infection, pyrexia, abdominal pain and dysuria, that may be characteristic of the paediatric population, were reported in somewhat higher incidence in paediatrics than in adults. Neutropenia was also reported with slightly higher incidence in the two paediatric studies as compared to adults but neutropenia and infectious adverse events were generally not correlated in the paediatric populations.

Congenital CMV.

The safety profile of valganciclovir and ganciclovir for up to 6 months of treatment was assessed in 133 neonates or infants with symptomatic congenital CMV infection aged from 2 days to 31 days in two studies. Although this data is limited, no safety issues have been identified and safety appears consistent with the known safety profile of valganciclovir/ganciclovir.
In the first study, the primary toxicity associated with ganciclovir was neutropenia with 9 out of 24 subjects (38%) developing Grade 3 or 4 neutropenia while on therapy. Only one subject had to permanently discontinue antiviral treatment, due to neutropenia. Most events were manageable with continuation of antiviral therapy in this study. Growth (head circumference, weight and height) of all neonates, who had growth measurements recorded, increased over time in this non-comparative study.
In the second study, the most frequent treatment-related AEs associated with oral valganciclovir were neutropenia, anaemia, liver function abnormality and diarrhoea, all seen more frequently in the placebo group. The only treatment-related SAEs were neutropenia and anaemia, both seen more frequently in the placebo arm. No statistically or clinically significant differences were observed in the rate of growth (average head circumference, weight and length) over time at each time point between the two treatment groups.

Laboratory abnormalities.

Laboratory abnormalities reported in adult patients receiving valganciclovir until Day 100 post-transplant are listed in Table 9. The incidence of laboratory abnormalities was comparable with the extension of prophylaxis up to 200 days in high risk kidney transplant patients.
Laboratory abnormalities reported in paediatric SOT patients are listed in Table 10. The incidence of severe neutropenia (ANC < 500/microL) was higher in paediatric kidney patients treated until Day 200 as compared to paediatric patients treated until Day 100 and as compared to adults kidney transplant patients treated until Day 100 or Day 200.

Post-marketing experience.

Experience with ganciclovir and valganciclovir.

As valganciclovir is rapidly and extensively converted to ganciclovir, any adverse events associated with ganciclovir might also occur with 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.
Anaphylaxis;
decreased fertility in males.
Adverse events that have been reported during the post-marketing period are consistent with those seen in clinical trials with valganciclovir and ganciclovir.

Dosage and Administration

Caution.

Strict adherence to dosage recommendations is essential to avoid overdose.
Valganciclovir AN tablet is administered orally, and should be taken with food (see Pharmacology, Pharmacokinetics, Absorption and bioavailability).
Valganciclovir is rapidly and extensively converted to the active ingredient ganciclovir. The bioavailability of ganciclovir from oral valganciclovir is up to 10-fold higher than from oral ganciclovir, therefore the dosage and administration of Valganciclovir AN tablets as described below should be closely followed (see Precautions and Overdosage).
The ganciclovir systemic exposure following administration of 900 mg valganciclovir hydrochloride powder for oral solution is equivalent to 900 mg valganciclovir hydrochloride dose administered as two 450 mg tablets.

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 Precautions, 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).

Paediatric patients.

The safety and efficacy of valganciclovir in paediatric patients have not been established in adequate and well-controlled clinical studies.

Prevention of CMV disease in transplantation.

Adult patients.

For kidney transplant patients, the recommended dose is 900 mg once daily with food, starting within 10 days post-transplantation and continuing until 200 days post-transplantation [see Clinical Trials, IMPACT study (study NT18435)].
For all other solid organ transplant patients, the recommended dose is 900 mg once daily with food, starting within 10 days post-transplantation and continuing until 100 days post-transplantation (see Clinical Trials, Study PV16000).

Paediatric patients.

Valganciclovir powder for oral solution is unavailable in this brand. Valganciclovir tablets should not be broken or crushed (see Handling and disposal section). Where accurate and safe dosing using the valganciclovir oral tablet is not possible, valganciclovir powder for oral solution from other suppliers should be used.
In paediatric solid organ transplant patients, (paediatric heart transplant patients from 4 weeks and paediatric kidney transplant patients from 4 months (see 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 (CrCLS), and is calculated using the equation below.
Paediatric Dose (mg) = 7 x BSA x CrCLS (see Equations 1 and 2, Mosteller BSA formula and Schwartz Creatinine Clearance). 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.
Refer to adult dosing for patients older than 16 years.
The k values provided are based on the Jaffe method of measuring serum creatinine, and may require correction when enzymatic methods are used.
*A lowering of k value may also be necessary for appropriate sub-populations.
For paediatric kidney transplant patients, the recommended once daily mg dose (7 x BSA x CrCLS) should start within 10 days post-transplantation and continue until 200 days post-transplantation.
For paediatric patients who have received a solid organ transplant other than kidney, the recommended once daily mg dose (7 x BSA x CrCLS) should start within 10 days post transplantation and continue until 100 days post-transplantation.
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 AN 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.

Special patient groups.

Renal impairment.

Adult patients.

Serum creatinine or creatinine clearance levels should be monitored carefully. Dosage adjustment is required based on creatinine clearance as shown in Table 11 (see Pharmacology, Pharmacokinetics in special populations and Precautions).
Creatinine clearance can be calculated from serum creatinine by the following formula (see Equation 3).
Serum creatinine or creatinine clearance levels should be monitored carefully.

Paediatric patients.

Dosing of paediatric solid organ transplant patients is individualised based on a patient’s renal function and size (see Dosage and Administration).

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

Severe leukopenia, 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 Contraindications, Precautions and Adverse Effects).

Handling and disposal.

Caution should be exercised in the handling of Valganciclovir AN tablets. Valganciclovir AN 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 AN tablets. Avoid direct contact of broken or crushed tablets, powder or reconstituted solution 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.

Overdosage

Overdose experience with oral valganciclovir.

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 Precautions and Dosage and Administration, Patients with renal impairment).
Haemodialysis and hydration may be of benefit in reducing blood plasma levels in patients who receive an overdose of valganciclovir (see Pharmacology, Pharmacokinetics in 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 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, leukopenia, 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 Poisons Information Centre on 131 126 (Australia).

Presentation

Valganciclovir AN tablets.

Valganciclovir AN (valganciclovir HCl) is available as 450 mg pink oval tablets plain on one side and "450" on the other side. Each tablet contains 496.3 mg of valganciclovir hydrochloride equivalent to 450 mg valganciclovir.
Valganciclovir AN is supplied in bottles (HDPE bottle with a polypropylene child-resistant screw cap) of 60 tablets.

Storage

Valganciclovir AN tablets should be stored below 25°C.

Poison Schedule

S4.