Consumer medicine information

Valaciclovir RBX

Valaciclovir

BRAND INFORMATION

Brand name

Valaciclovir RBX

Active ingredient

Valaciclovir

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Valaciclovir RBX.

SUMMARY CMI

Valaciclovir RBX

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using Valaciclovir RBX?

Valaciclovir RBX contains the active ingredient valaciclovir hydrochloride. Valaciclovir RBX tablets belong to a group of medicines called antivirals. They are used for the treatment of genital herpes, herpes zoster (shingles) and ophthalmic zoster (shingles affecting the eye region)

For more information, see Section 1. Why am I using Valaciclovir RBX? in the full CMI.

2. What should I know before I use Valaciclovir RBX?

Do not use if you have ever had an allergic reaction to Valaciclovir hydrochloride or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use Valaciclovir RBX? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Valaciclovir RBX medicine name and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Valaciclovir RBX?

  • Your doctor will tell you how many tablets, how many doses and when to take your doses each day.
  • Swallow the tablets whole with a glass of water and take Valaciclovir RBX at about the same time each day.

More instructions can be found in Section 4. How do I use Valaciclovir RBX medicine name? in the full CMI.

5. What should I know while using Valaciclovir RBX?

Things you should do
  • Remind any doctor, dentist, pharmacist or other healthcare professionals you visit that you are using Valaciclovir RBX.
  • If you become pregnant, or are trying to become pregnant, or intend to breastfeed while taking this medicine, tell your doctor immediately.
  • Drink plenty of fluids while you are taking Valaciclovir RBX tablets.
Things you should not do
  • Do not stop using this medicine suddenly, or change the dose, without first checking with your doctor.
  • Do not give your medicine to anyone else, even if they have the same condition as you.
Driving or using machines
  • Be careful driving or operating machinery until you know how Valaciclovir RBX affects you.
Drinking alcohol
  • Tell your doctor if you drink alcohol.
Looking after your medicine
  • Keep Valaciclovir RBX tablets in a cool dry place where the temperature stays below 25°C.
  • Keep your tablets in the packaging until it is time to take them.

For more information, see Section 5. What should I know while using Valaciclovir RBX? in the full CMI.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

Valaciclovir RBX

Active ingredient(s): Valaciclovir hydrochloride

Consumer Medicine Information (CMI)

This leaflet provides important information about using Valaciclovir RBX. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Valaciclovir RBX.

Where to find information in this leaflet:

1. Why am I using Valaciclovir RBX?
2. What should I know before I use Valaciclovir RBX?
3. What if I am taking other medicines?
4. How do I use Valaciclovir RBX?
5. What should I know while using Valaciclovir RBX?
6. Are there any side effects?
7. Product details

1. Why am I using Valaciclovir RBX?

Valaciclovir RBX Tablets contains the active ingredient valaciclovir hydrochloride and belong to a group of medicines called antivirals.

Valaciclovir RBX tablets are used for the treatment of genital herpes, shingles (herpes zoster), ophthalmic zoster (shingles affecting the eye region). It also used to prevent cytomegalovirus (CMV) infection and disease following solid organ transplantation. CMV is another type of herpes virus that can cause symptoms similar to glandular fever (high temperature, sore throat and swollen glands).

Valaciclovir RBX tablets work by stopping the multiplication of the virus which causes herpes and shingles. It can reduce the length and severity of an outbreak and duration of pain, and shorten the healing time of crusts, associated with herpes and shingles. Valaciclovir RBX does not eliminate the herpes virus (Herpes Simplex Virus or HSV) from the body.

It is important the treatment for shingles is started within the first three days of the shingles attack.

For the treatment of herpes simplex, start taking the tablets as soon as you feel an outbreak starting, as you may prevent the blisters from developing, or help the blisters to heal more quickly.

Valtrex tablets can also be taken long term to help prevent or reduce recurrent outbreaks of HSV and reduce the risk of transmitting the virus that causes genital herpes but does not cure or completely eliminate the risk of transmission.

Valtrex tablets are more effective in patients 50 years of age and older.

Ask your doctor if you have any questions about why Valtrex tablets have been prescribed for you.

Valtrex tablets are available only with a doctor's prescription.

Valtrex tablets are not addictive

Use in children

There is not enough information to recommend the use of Valtrex in children.

2. What should I know before I use Valaciclovir RBX?

Warnings

Do not use Valaciclovir RBX if:

  • you are allergic to Valaciclovir, or aciclovir or any of the ingredients listed at the end of this leaflet.
  • always check the ingredients to make sure you can use this medicine.
    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.
  • you are pregnant, trying to become pregnant, or breastfeeding.
  • the expiry date (EXP) printed on the pack has passed.
  • the packaging is torn or shows signs of tampering.

Check with your doctor if you:

  • have any other medical conditions
  • allergies to any other medicines, foods, preservatives or dyes.
  • take any medicines for any other condition
  • are pregnant, trying to become pregnant or breastfeeding unless your doctor says you should.

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

  • kidney or liver problem.
  • anaemic (reduced red blood cells or iron stores).
  • skin reactions with valaciclovir which may include a rash, fever, facial swelling or blistering/peeling skin.

Care should be taken to ensure adequate fluid intake in patients who are at risk of dehydration, such as the elderly.

Immunocompromised patients with ophthalmic zoster or those with a high risk for disease dissemination and visceral organ involvement should be treated with intravenous antiviral therapy

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.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Your doctor can discuss with you the risks and benefits involved.

3. What if I am taking other medicines?

Some medicines may interfere with Valaciclovir RBX and affect how it works.

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

Tell your doctor if you are taking any of the following medicines:

  • mycophenolate mofetil
  • cyclosporin
  • tacrolimus
  • aminoglycosides
  • organoplatinum compounds
  • iodinated contrast media
  • methotrexate
  • pentamidine
  • foscarnet

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

Some of the medicines above are commonly taken by transplant patients and require close attention.

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

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Valaciclovir RBX.

4. How do I use Valaciclovir RBX?

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

They may differ from the information contained in this leaflet.

Your doctor or pharmacist will tell you:

  • how many tablets to take at each dose
  • how many doses to take each day
  • when to take your doses each day.

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

How much to take Valaciclovir RBX

Your doctor will decide what dose you should take and how often you should take Valaciclovir RBX tablets. The dosage may vary depending on your medical history.

Treatment of Herpes Zoster (shingles)

The usual dose is 2 Valaciclovir RBX tablets (each containing 500 mg of valaciclovir) three times a day.

Treatment of genital herpes

If you are suffering from genital herpes infection for the first time, the dose usually given is one Valaciclovir RBX tablet (containing 500 mg of valaciclovir) two times a day.

If you have had a herpes infection before, the dose usually given is one Valaciclovir RBX tablet (containing 500 mg of valaciclovir) two times a day.

You should start to take Valaciclovir RBX tablets as early as possible if you think you are about to have a recurrence (attack) of genital herpes. Dosing should ideally start just before, or straight after the first signs of genital herpes infection appear.

Prevention of genital herpes in immunocompromised patients

To prevent the herpes infection appearing again, the usual dose to take is one Valaciclovir RBX tablet (containing 500 mg of valaciclovir) two times a day.

Reduction of risk of transmission of genital herpes

In adults with normal immune function with less than 10 recurrences of genital herpes infection per year, the usual dose for the infected partner is one Valaciclovir RBX tablet (containing 500 mg of valaciclovir) taken once daily.

Prevention of CMV infection and disease

The usual dose for adults and children over 12 years of age is four 500 mg tablets four times a day for 90 days.

If you have liver or kidney problems: Your dosage would be different if you have liver or kidney problems and your doctor will decide the dose and duration of treatment for you

If you are elderly: your dose may be adjusted by your doctor according to your kidney function.

If you think you have been advised to take a different dose, talk to your doctor or pharmacist.

When to take Valaciclovir RBX

Take your Valaciclovir RBX tablets at about the same time each day. Taking your tablets at the same time each day will have the best effect. It will also help you to remember when to take the tablets.

For the prevention of CMV infection and disease

The tablets should be taken four times a day (i.e. morning, noon, afternoon and evening).

For the treatment of shingles

The usual times to take the tablets are in the morning, afternoon and evening.

For the treatment of herpes simplex infections (genital herpes)

The usual times to take the tablets are in the morning and evening.

How to take Valaciclovir RBX

Valaciclovir RBX tablets are to be taken orally. Swallow the tablet whole with a full glass of water.

You should drink plenty of fluids while on treatment with Valaciclovir RBX, especially if you are elderly.

How long to take Valaciclovir RBX

For the treatment of shingles: The usual course of treatment is 7 days.

For the treatment of genital herpes infections, The usual course of treatment is 5 days. However in some instances your doctor may want you to take your tablets for 10 days.

For prevention of genital herpes infections in immunocompromised patients with moderate to normal kidney function and reduction of risk of transmission of the genital herpes infection: You should continue to take this medicine as long as prescribed by your doctor.

For the prevention of CMV infection and disease: The usual course of treatment is 90 days.

Continue taking the medicine as long as the Doctor has told you to. Do not stop taking the Valaciclovir RBX tablets before the course of treatment is finished just because you feel better. If you stop too soon, the infection may start again.

If you forget to take Valaciclovir RBX

Valaciclovir RBX should be taken regularly at the same time each day. If you miss your dose at the usual time and 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, then go back to taking it as you would normally.

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

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

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

If you use too much Valaciclovir RBX

If you think that you have used too much Valaciclovir RBX, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using Valaciclovir RBX?

Things you should do

  • Tell your doctor, dentist or pharmacist that you are taking Valaciclovir RBX tablets if you are about to be started on any new medicines.
  • 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.
  • Tell your doctor if you become pregnant or are trying to become pregnant or intend to breast-feed while you are taking Valacicclovir RBX tablets.
  • Drink plenty of fluids while you are taking Valaciclovir RBX tablets.
  • 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.
  • 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.
  • Keep all your doctor's appointments so that your progress can be checked.

Your doctor may do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects.

It is recommended that patients using Valaciclovir RBX continuously to prevent or reduce recurrent outbreaks, or to reduce the risk of transmitting the virus that causes genital herpes, also avoid contact when symptoms are present and always use condoms.

Valaciclovir RBX does not cure genital herpes or completely eliminate the risk of transmission. Because genital herpes is a sexually transmitted disease, you should minimise having intercourse when you have an outbreak of herpes or show any symptoms. This will avoid the risk of spreading herpes to your partner.

Things you should not do

  • Do not stop taking VAlaciclovir RBX tablets, or alter the dose, without first checking with your doctor.
  • Do not give this medicine to anyone else, even if their symptoms seem similar to yours.
  • Do not use VALACICLOVIR RBX tablets to treat any other complaints unless your doctor tells you to.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Valaciclovir RBX affects you.

Drinking alcohol

Tell your doctor if you drink alcohol

Looking after your medicine

Follow the instructions in the carton on how to take care of your medicine properly.

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

Store it in a cool dry place. away from moisture, heat or sunlight where it stays below 25°C

Heat and dampness can destroy some medicines.

Do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

A locked cupboard at least one-and-a-half meters above the ground is a good place to store medicines.

When to discard your medicine (as relevant)

If your doctor tells you to stop taking Valtrex, or the tablets have passed their expiry date, ask your pharmacist what to do with any tablets left over.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

Check with your doctor as soon as possible if you have any problems while taking this medicine, even if you do not think the problems relate to the medicine or are not listed in this leaflet.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
  • headache
  • gastrointestinal discomfort (vomiting, nausea, diarrhoea, constipation, abdominal pain, indigestion, flatulence)
  • dry mouth
  • fever
  • difficulty sleeping
  • chills
  • back pain
  • nervousness
  • skin rash which may be itchy
  • weakness
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Some of these side effects are more common in patients with kidney disease or in those taking high doses of Valtrex:
  • sensitivity to UV light, which may include development of a rash-like sunburn even after short period of exposure to UV or sunlight
  • dizziness, confusion, imagining sights or sounds (hallucinations), difficulty in thinking
  • drowsiness or decreased consciousness
  • tiredness, dizziness, or being short of breath when exercising (signs of anaemia)
  • high blood pressure
  • damage to the kidney, which gets better when Valaciclovir RBX treatment is stopped
  • unusual bruising or bleeding. Tell your doctor immediately if you notice any bruising or bleeding, as it may indicate that the number of platelets (a type of blood cell responsible for blood clotting) in your blood are reduced
  • skin reactions which may include a rash, fever, facial swelling or blistering or peeling skin
  • renal pain, acute renal failure and tubulointerstitial nephritis (elderly population)
  • damage to the liver, which gets better when Valaciclovir RBX treatment is stopped.
  • agitation or tremor
  • uncoordinated eye and muscle movements and speech or difficulty speaking
  • psychotic episodes
  • convulsions or seizures or coma
  • brain injury
  • symptoms of an allergic reaction including cough, shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; rash, itching or hives on the skin
  • some other side effects may occur in some people, for example changes in kidney or liver function, can only be found when your doctor does tests from time to time to check your progress.
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell, even if it is not on this list

Other side effects not listed here may occur in some people.

Ask your doctor or pharmacist any questions you may have.

Do not be alarmed by this list of possible side-effects. You may not experience any of them

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What Valaciclovir RBX contains

Active ingredient
(main ingredient)		valaciclovir hydrochloride
Other ingredients
(inactive ingredients)
  • microcrystalline cellulose
  • magnesium stearate
  • crospovidone
  • povidone (K 30)
  • povidone (K 90D)
  • indigo carmine aluminum lake (11-14%)
  • Opadry 02C50740 Blue which consists of hypromellose, titanium dioxide, macrogol 400, macrogol 6000, polysorbate 80 and indigo carmine aluminum lake (30-36%)

Do not take this medicine if you are allergic to any of these ingredients.

What Valaciclovir RBX looks like

Valaciclovir RBX tablets are available as blue coloured, capsule-shaped, biconvex, film-coated tablets, debossed with ‘V’ and ‘5’ on either side of the break line on one side, notched on either side along with the break line and plain on the other side containing valaciclovir (as hydrochloride) 500 mg.

Valaciclovir RBX tablets are available in blister packs containing 30, 42 or 100 tablets (Aust R 142803).

Who distributes Valaciclovir RBX

Sun Pharma ANZ Pty Ltd.
12 waterloo Road,
Macquarie Park
NSW 2113, Australia
Email: [email protected]
Tel: 1800 726 229

This leaflet was prepared in Nov 2024

Published by MIMS December 2024

BRAND INFORMATION

Brand name

Valaciclovir RBX

Active ingredient

Valaciclovir

Schedule

S4

 

1 Name of Medicine

Valaciclovir.

2 Qualitative and Quantitative Composition

Valaciclovir RBX film-coated tablet contains 500 mg valaciclovir (as hydrochloride).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Blue coloured, capsule shaped, biconvex, film coated tablets, debossed with 'V' and '5' on either side of the breakline on one side, notched on either side along with the breakline and plain on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

For the treatment of herpes zoster (shingles) in adult patients who commence therapy within 72 hours of the onset of rash.
For the treatment of ophthalmic zoster.
For the treatment of clinical episodes of genital herpes simplex infections.
For the prevention of recurrent genital herpes in immunocompromised patients with creatinine clearance of > 15 mL/min.
For reduction of transmission of genital herpes in patients suffering from recurrent genital herpes. In addition to therapy with Valaciclovir RBX (valaciclovir), it is recommended that patients use safer sex practices (see Section 4.4 Special Warnings and Precautions for Use).
For prophylaxis of cytomegalovirus (CMV) infection and disease following solid organ transplantation in patients at risk of CMV disease.

4.2 Dose and Method of Administration

Dosage in adults.

For the treatment of herpes zoster (shingles). For treatment of herpes zoster, 1000 mg of valaciclovir (2 tablets of Valaciclovir RBX) three times a day for seven days.
For the treatment of genital herpes. For treatment of first clinical presentation of genital herpes, 500 mg of valaciclovir (1 tablet of Valaciclovir RBX) twice a day for 5 to 10 days.
For recurrent episodes of genital herpes, 500 mg of valaciclovir (1 tablet of Valaciclovir RBX) twice daily for 5 days.
Dosing should begin as early as possible. For recurrent episodes of genital herpes, this should ideally be during the prodromal period or immediately following the appearance of the first signs or symptoms.
For the prevention of genital herpes in immunocompromised patients. For the prevention of genital herpes in immunocompromised patients, 500 mg of valaciclovir (1 tablet of Valaciclovir RBX) twice daily.
Reduction of transmission of genital herpes. In immunocompetent heterosexual adults with less than 10 recurrences per year and with the susceptible partner discordant for HSV-2 antibodies, 500 mg of valaciclovir (1 tablet of Valaciclovir RBX) to be taken once daily by the infected partner.
There are no data on the reduction of transmission in other patient populations.
For the prophylaxis of cytomegalovirus (CMV) infection and disease.

Dosage in adults and adolescents (from 12 years of age).

The dosage of valaciclovir is 2 g (4 tablets of Valaciclovir RBX) four times a day for 90 days, to be initiated as early as possible post-transplant. This dose should be reduced according to creatinine clearance (see Section 4.2 Dose and Method of Administration, Dosage in renal impairment).

Dosage in renal impairment.

Caution is advised when administering valaciclovir to patients with impaired renal function. Adequate hydration should be maintained (see Section 4.4 Special Warnings and Precautions for Use).

Herpes zoster treatment and herpes simplex treatment, suppression and reduction of transmission of genital herpes.

The dose of valaciclovir should be modified as follows in patients with significantly impaired renal function (see Table 1).
For the prevention of herpes simplex in immunocompromised patients with creatinine clearance of > 15 mL/min, no dose modification is required.
In patients on haemodialysis the valaciclovir dose recommended for patients with a creatinine clearance of less than 15 mL/min should be used, but the dose should be administered after the haemodialysis has been performed.

CMV prophylaxis.

The dosage of valaciclovir should be adjusted in patients with impaired renal function as shown in Table 2.
The creatinine clearance should be monitored frequently, especially during periods when renal function is changing rapidly e.g. immediately after transplantation or engraftment. The valaciclovir dosage should be adjusted accordingly.

Dosage in hepatic impairment.

Studies with a 1 g unit dose of valaciclovir show that dose modification is not required in patients with mild or moderate cirrhosis (hepatic synthetic function maintained). Pharmacokinetic data in patients with advanced cirrhosis (impaired hepatic synthetic function and evidence of portal systemic shunting) do not indicate the need for dosage adjustment; however clinical experience is limited. For higher doses recommended for CMV prophylaxis (see Section 4.4 Special Warnings and Precautions for Use).

Dosage in children.

No data are available.

Dosage in the elderly.

The possibility of renal impairment in the elderly must be considered and the dosage should be adjusted accordingly (see Section 4.2 Dose and Method of Administration, Dosage in renal impairment). Adequate hydration should be maintained.

4.3 Contraindications

Valaciclovir RBX is contraindicated in patients known to be hypersensitive to valaciclovir, aciclovir or any component of the formulation.

4.4 Special Warnings and Precautions for Use

Thrombotic thrombocytopenic purpura or haemolytic uraemic syndrome (TTP/HUS), in some cases resulting in death, has occurred in patients with advanced HIV disease who were treated with valaciclovir for prolonged periods and also in allogenic bone marrow transplant and renal transplant recipients who were treated with valaciclovir while participating in clinical trials at doses of 8 gram per day. Treatment with valaciclovir should be stopped immediately if clinical signs, symptoms, and laboratory abnormalities consistent with TTP/HUS occur.
Similar signs have been observed in patients with the same underlying or concurrent conditions who were not treated with valaciclovir.
Use of valaciclovir at doses of 1000 mg/day in immunocompromised patients with CD4+ counts > 100 x 106 L has not been associated with occurrences of thrombotic microangiopathy (TMA). However use in severely immunocompromised patients (CD4+ counts < 100 x 106 L) has not been examined at this low dosage.

Drug reaction with eosinophilia and systemic symptoms (DRESS).

DRESS, which can be life-threatening or fatal, has been reported in association with valaciclovir treatment. At the time of prescribing patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of DRESS appear, valaciclovir should be withdrawn immediately and an alternative treatment considered (as appropriate). If the patient has developed DRESS with the use of valaciclovir, treatment with valaciclovir must not be restarted in this patient at any time.

Use of high dose valaciclovir in hepatic impairment and liver transplantation.

There are no data available on the use of high doses of valaciclovir (4000 mg or more per day) in patients with liver disease. Specific studies of valaciclovir have not been conducted in liver transplantation, and hence caution should be exercised when administering daily doses greater than 4000 mg to these patients (see Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment).

Use for zoster treatment.

Clinical response should be closely monitored, particularly in immunocompromised patients. Consideration should be given to intravenous antiviral therapy when response to oral therapy is considered insufficient.
Patients with complicated herpes zoster, i.e. those with visceral involvement, disseminated zoster, motor neuropathies, encephalitis and cerebrovascular complications should be treated with intravenous antiviral therapy.
Moreover, immunocompromised patients with ophthalmic zoster or those with a high risk for disease dissemination and visceral organ involvement should be treated with intravenous antiviral therapy.

Hydration status.

Care should be taken to ensure adequate fluid intake in patients who are at risk of dehydration, particularly the elderly.
Patients without adequate hydration. Precipitation of aciclovir in renal tubules may occur when the solubility (2.5 mg/mL) is exceeded in the intratubular fluid. Adequate hydration should be maintained for all patients.

Information for patients.

Patients should be informed that valaciclovir (or any other antiviral) is not a cure for genital herpes. Because genital herpes is a sexually transmitted disease, patients should avoid contact with lesions, damaged skin/mucosa or intercourse when lesions and/or symptoms are present to avoid infecting partners. Genital herpes can also be transmitted in the absence of symptoms through asymptomatic viral shedding.

Use in genital herpes.

Patients should be advised to avoid intercourse when symptoms are present even if treatment with an antiviral has been initiated. Continuous therapy with valaciclovir in patients with recurrent genital herpes reduces the risk of transmitting genital herpes. It does not cure genital herpes or completely eliminate the risk of transmission. In addition to therapy with valaciclovir, it is recommended that patients use safer sex practices. As genital herpes is a sexually transmitted infection, patients should, in order to further reduce the risk of infecting partners, avoid contact with lesions, damaged skin/mucosa, and avoid intercourse when lesions and/or symptoms are present. Genital herpes is frequently transmitted in the absence of symptoms through asymptomatic viral shedding; therefore patients should be counselled to use safer sex practices. The effect of valaciclovir on transmission of sexually transmitted infections other than herpes (including HIV, gonorrhoea, syphilis and Chlamydia) is unknown.
The efficacy of valaciclovir for reducing transmission of genital herpes has not been established in individuals with multiple partners, non-heterosexual couples and couples not counselled to use safer sex practices.

Use in ocular HSV infections.

Clinical response should be closely monitored in these patients. Considerations should be given to intravenous antiviral therapy when response to oral therapy is unlikely to be sufficient.

Use in CMV infections.

Data on the efficacy of valaciclovir from transplant patients (~200) at high risk of CMV disease (e.g. donor CMV positive/recipient CMV negative or use of anti-thymocyte globulin induction therapy) indicate that valaciclovir should only be used in these patients when safety concerns preclude the use of valganciclovir or ganciclovir.
High dose valaciclovir as required for CMV prophylaxis may result in more frequent adverse events, including CNS abnormalities, than observed with lower doses administered for other indications (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients should be closely monitored for changes in renal function, and doses adjusted accordingly (see Section 4.2 Dose and Method of Administration).

Central nervous system effects.

Reversible neurological reactions including agitation, dizziness, confusion, hallucinations, rarely decreased consciousness and very rarely tremor, ataxia, dysarthria, convulsions, encephalopathy and coma have been reported. These events are usually seen in patients with renal impairment or with other predisposing factors. In organ transplant patients receiving high doses (8 g daily) of valaciclovir for CMV prophylaxis, neurological reactions occurred more frequently compared with lower doses. Valaciclovir should be discontinued if central nervous system adverse reactions occur.

Use in hepatic impairment.

For further information (see Section 5.2 Pharmacokinetic Properties, Special populations, Hepatic impairment).

Use in renal impairment.

Renal insufficiency or acute renal failure has been observed in patients taking valaciclovir at the recommended dosage and/or with no previous renal conditions and may be associated with renal pain.
The dose of valaciclovir must be reduced in patients with renal impairment (see Section 4.2 Dose and Method of Administration). Valaciclovir is converted to aciclovir which is eliminated by renal clearance (see Section 5.2 Pharmacokinetic Properties). Patients with renal impairment are at increased risk of developing neurological side effects and should be closely monitored for evidence of these effects. In the reported cases, these reactions were generally reversible on discontinuation of treatment (see Section 4.8 Adverse Effects (Undesirable Effects)).
Cases of acute renal failure have been reported in patients without adequate hydration. Precipitation of aciclovir in renal tubules may occur when the solubility (2.5 mg/mL) is exceeded in the intratubular fluid. Adequate hydration should be maintained for all patients.
Caution should be exercised when administering valaciclovir to patients with significant renal impairment or those receiving potentially nephrotoxic agents, since this may increase the risk of renal dysfunction and/or the risk of reversible central nervous system such as those that occur infrequently in patients treated with intravenous aciclovir.

Use in the elderly.

Elderly patients are likely to have reduced renal function and therefore the need for dose reduction must be considered in this group of patients. Elderly patients are at increased risk of developing neurological side effects and should be closely monitored for evidence of these effects. In the reported cases, these reactions were generally reversible on discontinuation of treatment (see Section 4.8 Adverse Effects (Undesirable Effects)).

Paediatric use.

Safety and effectiveness in children have not been established.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

The combination of valaciclovir with nephrotoxic medicinal products should be made with caution, especially in subjects with impaired renal function, and warrants regular monitoring of renal function. This applies to concomitant administration with aminoglycosides, organoplatinum compounds, iodinated contrast media, methotrexate, pentamidine, foscarnet, ciclosporin, and tacrolimus.
Aciclovir is eliminated primarily unchanged in the urine via active renal tubular secretion. Any drugs administered concurrently that compete with this mechanism may increase aciclovir plasma concentrations following valaciclovir administration.
Following 1 g valaciclovir, cimetidine and probenecid increase the AUC of aciclovir by this mechanism, and reduce aciclovir renal clearance. However, no dosage adjustment is necessary at this dose because of the wide therapeutic index of aciclovir.
In patients receiving high dose valaciclovir (8 g/day) for CMV prophylaxis, caution is required during concurrent administration with drugs which compete with aciclovir for elimination, because of the potential for increased plasma levels of one or both drugs or their metabolites. Increases in plasma AUCs of aciclovir and of the inactive metabolite of mycophenolate mofetil, an immunosuppressant agent used in transplant patients, have been shown when the drugs are coadministered. There is limited experience with the use of the combination of valaciclovir and mycophenolate mofetil.
Care is also required (with monitoring for changes in renal function) if administering high dose valaciclovir with drugs which affect other aspects of renal physiology (e.g. ciclosporin, tacrolimus).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Valaciclovir did not impair fertility or reproduction in rats at 200 mg/kg per day, corresponding to plasma levels 2.8 (HZV) and 0.3 (CMV) times human plasma concentrations (AUC). However, high parenteral doses of aciclovir caused testicular atrophy and aspermogenesis in rats (80 mg/kg/day) and dogs (100 mg/kg/day).
No human fertility studies were performed with valaciclovir, but no changes in sperm count, motility or morphology were reported in 20 aciclovir recipients, with culture confirmed genital HSV-2 and with normal baseline sperm counts after 6 months of daily treatment with 400 mg to 1 g aciclovir.
(Category B3)
Valaciclovir was not teratogenic in rats or rabbits given oral doses of 400 mg/kg (which results in exposures of 1.1 and 2.0 times (HZV) and 0.4 and 0.7 times (CMV) human exposure, respectively, based on body surface area) during the period of major organogenesis. Aciclovir was not teratogenic in the mouse (450 mg/kg PO), rabbit (50 mg/kg SC and IV) or rat (50 mg/kg SC) when dosed throughout the period of organogenesis. Plasma concentrations of aciclovir in the rat were 3.5 (HZV) and 0.8 (CMV) times human concentrations. In additional studies in which rats were given three SC doses of 100 mg/kg aciclovir on gestation day 10, foetal abnormalities, such as head and tail anomalies, were reported. Plasma concentrations of aciclovir in the rat were 19 (HZV) and 4.3 (CMV) times human concentrations.
There are no adequate and well controlled studies of valaciclovir or aciclovir in pregnant women. A prospective epidemiologic registry of aciclovir use during pregnancy has been ongoing since June 1984. Pregnancy registries have documented the pregnancy outcomes in women exposed to valaciclovir or to any formulation of aciclovir (the active metabolite of valaciclovir); 111 and 1246 outcomes (29 and 756 exposed during the first trimester of pregnancy), respectively, were obtained from women prospectively registered. Registry findings do not indicate an increased risk of major birth defects after aciclovir exposure in comparison with the general population. The accumulated case histories represent an insufficient sample for reaching reliable and definitive conclusions regarding the risk associated with aciclovir exposure during pregnancy. The daily aciclovir AUCs (area under plasma concentration time curve) following valaciclovir 1000 mg and 8000 mg daily would be approximately 2 and 9 times greater than that expected with oral aciclovir 1000 mg daily, respectively.
There are limited data on the use of valaciclovir in pregnancy. Valaciclovir should only be used in pregnancy if the potential benefit outweighs the potential risk.
 Lactating rats given a 25 mg/kg PO dose of 14C-valaciclovir showed peak milk radioactivity levels of 26 microgram/eq/g, 2 hours postdose. The milk radioactivity levels declined slower than in plasma, and were undetectable at 12 hours. Suckling pups had radioactivity in the stomach and intestinal contents up to 7 hours postdose, but not in tissues.
Limited data show that aciclovir does pass into human breast milk. In a study conducted on 5 women, following oral administration of a 500 mg dose of valaciclovir, peak aciclovir concentrations (Cmax) in breast milk ranged from 0.5 to 2.3 (median 1.4) times the corresponding maternal aciclovir serum concentrations. The aciclovir AUC was 2.2 times (range 1.4 to 2.6) higher in breast milk compared to maternal serum.
In other studies, conducted with oral aciclovir administration, aciclovir has been detected in breast milk at concentrations ranging from 0.6 to 4.1 times the corresponding aciclovir plasma concentrations.
Caution is therefore advised if valaciclovir is to be administered to a breastfeeding mother. Valaciclovir should only be administered to breastfeeding mothers if the benefits to the mother outweigh the potential risks to the baby.

4.7 Effects on Ability to Drive and Use Machines

No special precautions necessary.
A detrimental effect on driving or ability to operate machinery cannot be predicted from the pharmacological properties of valaciclovir or the active substance aciclovir. No studies to investigate the effect of valaciclovir on such activities have been conducted. However, the clinical status of the patient and the adverse event profile of valaciclovir should be borne in mind when considering a patient's ability to drive or operate machinery.

4.8 Adverse Effects (Undesirable Effects)

Valaciclovir was well tolerated when used for the treatment of herpes zoster and genital herpes in clinical trials. The most commonly reported adverse experiences were headache and nausea and these were reported in a similar proportion of patients on valaciclovir, aciclovir and placebo.

Herpes zoster infections.

Table 3 lists all adverse events reported during a six month observation period in immunocompetent patients receiving short-term treatment (7 or 14 days) with valaciclovir and reference products in controlled clinical trials.

HSV infections.

Initial and recurrent genital herpes (short-term treatment).

The adverse events reported by greater than 2% of a given treatment group in the initial and recurrent genital herpes clinical trials with valaciclovir and reference products used in the trials are listed in Table 4.

Prevention of genital herpes (long-term preventative therapy).

The adverse events reported at an incidence of 5% or greater in a given treatment group, in clinical trials for the preventative treatment of genital herpes with valaciclovir and reference products, are listed in Table 5.

Prophylaxis of cytomegalovirus (CMV) infection and disease, following organ transplantation.

Valaciclovir was well tolerated in the clinical studies of renal and heart transplant patients. The nature and frequency of adverse events were similar between placebo, aciclovir and valaciclovir treated patients, with the exception of adverse events relating to the CNS (hallucinations, confusion and thinking abnormality). These were reported more frequently in valaciclovir than placebo in renal transplant patients. The most common adverse events reported in the renal transplant patients were anaemia, hypertension and headache. Headache and myalgia were the most common adverse events reported in the heart transplant patients. All the clinical adverse events occurring at an incidence of ≥ 5% or ≥ 20% in a given treatment group, in clinical trials for CMV prophylaxis following renal and heart transplants respectively are listed in Tables 6 and 7.

Post marketing experience.

The following adverse events have been observed in clinical practice with valaciclovir:

Blood and lymphatic system disorders.

Thrombocytopenia, leukopenia*, thrombotic microangiopathy (TMA) (see Section 4.4 Special Warnings and Precautions for Use).
*Leukopenia is mainly reported in immunocompromised patients.
Aplastic anaemia, leukocytoclastic vasculitis, thrombotic thrombocytopenic purpura/ hemolytic uremic syndrome (TTP/HUS).

Immune system disorders.

Anaphylaxis, acute hypersensitivity reactions including anaphylaxis, angioedema, dyspnea, pruritus, rash and urticaria.

Psychiatric and nervous system disorders.

Headache, decreased consciousness*, dizziness*, confusion* and hallucinations*, coma*, agitation*, tremor*, ataxia*, dysarthria*, psychotic symptoms*, convulsions*, encephalopathy*, aggressive behavior*, delirium*.
*The above events are generally reversible and usually in patients with renal impairment or with other predisposing factors (see Section 4.4 Special Warnings and Precautions for Use). In organ transplant patients receiving high doses (8 gram daily) of valaciclovir for CMV prophylaxis, neurological reactions occurred more frequently compared with lower doses.
Neurological disorders, sometimes severe, may be linked with encephalopathy and include confusion, agitation, convulsions, hallucinations, coma.

Respiratory, thoracic and mediastinal disorders.

Dyspnoea.

Gastrointestinal tract.

Nausea, abdominal discomfort, vomiting and diarrhoea.

Hepatobiliary disorders.

Reversible increases in liver function tests, occasionally described as hepatitis.

Skin and subcutaneous tissue disorders.

Rashes including photosensitivity, pruritus, urticaria, angioedema and drug reaction with eosinophilia and systemic symptoms (DRESS) and erythema multiform (see Section 4.4 Special Warnings and Precautions for Use).

Renal and urinary disorders.

Renal pain, haematuria (often associated with other renal events), renal impairment, acute renal failure (especially in elderly patients or in patients with renal impairment receiving higher than the recommended doses), tubulointerstitial nephritis.
Renal pain may be associated with renal failure.
Intratubular precipitation of aciclovir crystals in the kidney has also been reported. Adequate fluid intake should be ensured during treatment (see Section 4.4 Special Warnings and Precautions for Use). Elevated blood creatin and blood urea nitrogen (BUN).

General.

Facial edema, hypertension, tachycardia.

Ophthalmologic.

Visual abnormalities.

Other.

There have been reports of renal insufficiency, microangiopathic haemolytic anaemia and thrombocytopenia (sometimes in combination) in severely immunocompromised patients, particularly those with advanced HIV disease, receiving high doses (8 g daily) of valaciclovir for prolonged periods in clinical trials. These findings have been observed in patients not treated with valaciclovir who have the same underlying or concurrent conditions.

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

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

Symptoms and signs.

Acute renal failure and neurological symptoms, including confusion, hallucinations, agitation, decreased consciousness and coma, have been reported in patients receiving overdoses of valaciclovir. Nausea and vomiting may also occur. Caution is required to prevent inadvertent overdosing. Many of the reported cases involved renally impaired and elderly patients receiving repeated overdoses, due to lack of appropriate dosage reduction.

Management.

Patients should be observed closely for signs of toxicity. Haemodialysis significantly enhances the removal of aciclovir from the blood and may, therefore, be considered a management option in the event of symptomatic overdose.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Valaciclovir is rapidly and almost completely converted in man to aciclovir probably by the enzyme valaciclovir hydrolase. Aciclovir is a specific inhibitor of the herpes viruses with in vitro activity against herpes simplex viruses (HSV) type 1 and type 2 (IC50 0.1-3.0 microM), varicella zoster virus (VZV) (IC50 1.6-5.1 microM) and human cytomegalovirus (HCMV) (IC50 10- > 200 microM). Aciclovir inhibits herpes virus DNA synthesis once it has been phosphorylated to the active triphosphate form. The first stage of phosphorylation requires the activity of a virus specific enzyme: thymidine kinase in HSV and VZV infected cells or protein kinase in HCMV infected cells. This requirement for activation of aciclovir by a virus specific enzyme largely explains its unique selectivity. The phosphorylation process is completed (conversion from mono to triphosphate) by cellular kinases. Aciclovir triphosphate competitively inhibits the virus DNA polymerase and incorporation of this nucleoside analogue results in obligate chain termination, halting virus DNA synthesis and thus blocking virus replication.

Pharmacodynamic effects.

Pharmacodynamics/resistance development.

Resistance to aciclovir is normally due to a thymidine kinase deficient phenotype. In animal models, the viral fitness and pathogenicity of this phenotype appears to be reduced. Infrequently, reduced sensitivity to aciclovir has been described as a result of subtle alterations in either the virus thymidine kinase or DNA polymerase. The virulence of these variants in animal models resembles that of the wild-type virus.
Resistance of HSV and VZV to aciclovir occurs by the same mechanisms. While most of the aciclovir resistant mutants isolated thus far from immunocompromised patients have been found to be TK deficient mutants, other mutants involving the viral TK gene (TK partial and TK altered) and DNA polymerase have also been isolated. TK negative mutants may cause severe disease in immunocompromised patients. The possibility of viral resistance to valaciclovir (and therefore, to aciclovir) should be considered in patients who show poor clinical response during therapy.

Clinical trials.

Herpes zoster infections. Two doses of valaciclovir were compared to aciclovir in a double blind randomised trial in immunocompetent patients aged 50 years and over with herpes zoster (n = 1141). All patients were treated within 72 hours of the appearance of the rash. Valaciclovir 1 g three times daily for seven days achieved statistically significant reductions in the duration of zoster associated pain (which is the sum of acute pain and postherpetic neuralgia) and in the duration of postherpetic neuralgia when compared with aciclovir. There was no statistically significant difference between the three treatments for the resolution of rash. See Table 8.
There was no significant difference to the duration of zoster associated pain when treatment was started within 48 hours or 72 hours. Patients treated within 48 hours of rash onset were found to have faster healing rates as measured by the duration of new lesion formation and time to crusting or healing of 50% or more of lesions. Thus, greater benefit is gained if the drug is started within 48 hours. See Figure 1.
In a second, placebo controlled trial in patients under 50 years of age (n = 399), demonstration of efficacy was restricted to a small decrease in mean time to cessation of new lesion formation. No significant effects were demonstrated for other outcomes of herpes zoster in this age group. Nevertheless, the occasional younger patients with severe herpes zoster may benefit from therapy with valaciclovir. Herpes zoster is usually a milder condition in younger patients.
In ophthalmic zoster oral aciclovir has been shown to reduce the incidence of stromal keratitis and both the incidence and severity of anterior uveitis but not other ocular complications or acute pain. The recommended dose of valaciclovir produces higher plasma concentrations of aciclovir than those required for these beneficial effects.
Acute treatment of initial and recurrent herpes simplex virus (HSV) infections. Four large multicentre, randomised double blind trials were conducted in adults with herpes simplex infections. These studies included a total of 3569 treated patients of whom 1941 received valaciclovir.
Initial genital herpes simplex infections. One study compared valaciclovir (1000 mg twice daily) with aciclovir (200 mg five times daily) administered for 10 days in immunocompetent patients with initial (primary or first episode) genital herpes. Patients reported to the clinic for treatment within 72 hours of the first signs or symptoms of genital herpes.
Patients were randomized to receive valaciclovir (n = 323) or aciclovir (n = 320) for 10 days. The median time to lesion healing was 9 days in each treatment group. The median time to the cessation of viral shedding was 3 days in each treatment group. Median time to cessation of pain was 5 days in each treatment group.
Recurrent genital herpes simplex infections. The other three studies enrolled immunocompetent patients with a history of recurrent genital herpes infections. These studies compared valaciclovir (1000 mg and/or 500 mg twice daily) with aciclovir (200 mg five times daily) and/or placebo, administered for 5 days. Patients self initiated therapy within 24 hours of the first sign or symptom of a recurrent genital herpes episode.
The primary efficacy endpoints in each study were: lesions healing time and pain/ discomfort; proportions of patients in whom lesions were prevented (aborted lesions); viral shedding.
In one study, patients were randomized to receive five days of treatment with either valaciclovir 500 mg bid (n = 360) or placebo (n = 259).

Duration of lesions.

The median time to lesion healing was four days in the group receiving valaciclovir 500 mg versus six days in the placebo group.

Cessation of viral shedding.

The median time to cessation of viral shedding in patients with at least one positive culture (42% of the overall study population) was two days in the group receiving valaciclovir 500 mg versus four days in the placebo group.

Cessation of pain.

The median time to cessation of pain was three days in the group receiving valaciclovir 500 mg versus four days in the placebo group. Results supporting efficacy were replicated in the other two studies.

Prevention of lesion development (aborted episodes).

Pooled analysis of the three studies also showed that the use of valaciclovir in patients who self initiated treatment in the prodrome, increased the chances of preventing lesion development (aborting episodes) by 31% to 44% compared with placebo.
Prevention of recurrent genital herpes simplex virus (HSV) infections in immunocompromised patients. A study examined a total of 1062 immunocompromised patients (HIV infected, CD4+ counts of ≥ 100/mm3 at enrolment) of whom 713 received valaciclovir (1000 mg once daily, 500 mg twice daily, 48 weeks) compared with 349 patients who received aciclovir (400 mg twice daily, 48 weeks). The primary endpoint was the time to first HSV recurrence (onset of macules/ papules). The study demonstrated that valaciclovir 500 mg twice daily is as effective as aciclovir in preventing or delaying HSV infections in immunocompromised patients. Valaciclovir 500 mg twice daily was significantly more efficacious than valaciclovir 1000 mg once daily.
Reduction of genital herpes simplex virus transmission. A randomised, double blind, placebo controlled trial evaluating valaciclovir 500 mg once daily for eight months in the prevention of HSV-2 transmission in heterosexual monogamous couples was conducted. 1484 couples received treatment with 741 source partners receiving placebo and 743 source partners receiving valaciclovir. Source partners had to be seropositive for HSV-2 and have a history of recurrent genital herpes with less than 10 recurrences per year. Susceptible partners could not be seropositive for HSV-2, but could be seropositive for HSV-1. Couples were encouraged to practice safer sex (including use of condoms). The primary endpoint of the study was the proportion of couples that developed clinical evidence of a first episode of genital herpes HSV-2 in the susceptible partner. Clinical evidence of a first episode was defined as symptomatic genital herpes confirmed by laboratory analysis.
The results of this study established that the proportion of couples with clinical symptoms of genital herpes in the susceptible partner was higher in the placebo group than in the valaciclovir group (2.2% vs. 0.5% respectively). The risk of transmission of symptomatic genital herpes was reduced by 75% (95% CI 26%, 92%, p = 0.011) in the valaciclovir group, a difference which is both clinically and statistically significant.
The results of the time to event analysis confirm those of the primary endpoint, with the time to clinical symptoms being significantly longer in the valaciclovir group compared with the placebo group (p = 0.008).
The proportion of couples with overall acquisition* of genital HSV-2 infection in the susceptible partner was 3.6% (27/741) in the placebo group and 1.9% (14/743) in the valaciclovir group (p = 0.054, approximate relative risk (95% CI): 0.52 (0.27, 0.97). These analyses show that there was a 48% reduction in the risk of acquiring HSV-2 infection in the valaciclovir group compared with the placebo group. This difference approached statistical significance for overall acquisition.
(*Overall acquisition: in which the susceptible partner acquired genital herpes HSV-2 infection, as documented by HSV-2 seroconversion only, or by seroconversion and/or detection of the virus by culture or PCR, and irrespective of the presence of clinical symptoms.)
The result of the analysis of time to overall acquisition of HSV-2 (hazard ratio: 0.52; 95% CI: 0.27, 0.99), which explicitly allows for differential length of follow-up, is statistically significant (p = 0.039).
The proportion of couples with HSV-2 seroconversion in the susceptible partner was 3.2% (24/741) in the placebo group and 1.6% (12/743) in the valaciclovir group [p = 0.060, approximate relative risk (95% CI): 0.50 (0.25, 0.99)].
The proportion of couples with asymptomatic seroconversion in the susceptible partner was 1.5% (11/741) in the placebo group and 1.3% (10/743) in the valaciclovir group (p = 0.996), approximate relative risk (95% CI): 0.91 (0.39, 2.12).
Valaciclovir was effective in reducing the risk of genital HSV-2 recurrence in source partners (the proportion of source partners with a genital HSV-2 recurrence was: placebo: 573/724, 79%; valaciclovir: 288/715, 40%), with the time to first recurrence being significantly longer in the valaciclovir group compared with the placebo group (p < 0.001; hazard ratio 0.30, 95% CI 0.26, 0.35).
The incidence of the primary endpoint was higher in the female susceptible partners than in the male susceptible partners. The proportion of female susceptible partners in whom clinical evidence of first episode genital HSV-2 infection was reported was 4.1% (10/244) in the placebo group and 0.8% (2/244) in the valaciclovir group. The proportion of male susceptible partners in whom clinical evidence of first episode genital HSV-2 infection was reported was 1.2% (6/497) in the placebo group and 0.4% (2/499) in the valaciclovir group.
The safety profile of valaciclovir in this study was similar to that of placebo, and to that demonstrated previously for this dosing regimen in a similar population.
Prophylaxis of cytomegalovirus (CMV) infection and disease, following organ transplantation. Three double blind, randomised clinical studies were conducted to investigate the efficacy and safety of valaciclovir in the prophylaxis of CMV infection and disease following renal or heart transplantation. These studies included a total of 643 patients, of whom 320 received valaciclovir, 13 received aciclovir and 310 received placebo.
The primary efficacy endpoint in renal transplant studies was the development of CMV disease and the primary endpoint in the heart transplant study was the development of CMV antigenaemia. Secondary endpoints for the studies included CMV disease (heart transplant study), CMV infection, reduced acute graft rejection, fewer opportunistic bacterial or fungal infections and reduced herpes virus disease (HSV, VZV).
Renal transplant studies. The two renal transplant studies involved a total of 616 renal transplant recipients, of which 306 received a daily dose of 2 g valaciclovir four times daily (adjusted according to creatinine clearance for renal function) and 310 received placebo for 90 days. The patients were stratified by donor and recipient CMV serostatus (seropositive recipients [R+] versus seronegative recipients of a graft from a seropositive donor [D+R-]). Patients commenced study drug within 72 hours post-transplant and continued treatment for 90 days (treatment period) receiving, following adjustment for renal function, a daily average dose of 4.7 g ([R+] subjects) and 5.3 g ([D+R-] subjects) valaciclovir. Patients were evaluated for efficacy and safety for six months post-transplant (study period).
In renal transplant recipients valaciclovir was significantly better than placebo in preventing or delaying CMV disease by 78% and 82% in the [D+R-] and [R+] strata respectively, during the six month study period. See Figure 2.
Valaciclovir was also significantly better than placebo in preventing or delaying the development of viraemia, viruria and clinical HSV disease during the study period. No valaciclovir recipient developed VZV disease, whereas 2% and 4% of placebo patients did, R+ and D+R- strata respectively. Additionally in D+R- patients, valaciclovir was shown to significantly reduce acute graft rejections (biopsy proven and clinical acute rejection by 57% and 45% respectively) and opportunistic infections (48% primarily bacterial and fungal infections). There were no significant differences in rates of chronic graft rejection. Allograft function and survival, including the proportion of patients with a functional graft at their last assessment were similar between treatment groups. Administration of valaciclovir was associated with significantly fewer hospital admissions and reduced use of ganciclovir and aciclovir for the treatment of CMV disease or other herpes virus infections, respectively.
Heart transplant study. The third study enrolled 27 heart transplant recipients. This study compared valaciclovir (n = 14, 2 g four times daily, adjusted according to creatinine clearance for renal function) with aciclovir (n = 13, 200 mg four times daily). Treatment was commenced within 3 days post-transplant and continued for 90 days. Patients were followed up until the end of the sixth month.
During the 90 day treatment period, 29% of patients on valaciclovir developed CMV antigenaemia (primary endpoint) compared to 92% of patients who received aciclovir. The time difference to CMV antigenaemia was statistically significant, with median time to CMV antigenaemia of 19 vs. 119 days in favour of valaciclovir (HR = 0.422, 95% CI: 0.179, 0.992; p = 0.049). At the end of the study period (3 months following the treatment period) the proportion of patients with CMV antigenaemia was similar in both treatment arms.
Notable but not statistically significant reductions in the rates of CMV infection (valaciclovir 43%, aciclovir 92%), symptomatic CMV infection (valaciclovir 0%, aciclovir 38%), CMV disease (valaciclovir 0%, aciclovir 23%) and HSV disease (valaciclovir 29%, aciclovir 54%), were observed during the 90 day treatment period. The incidence of other infections (bacterial, fungal, nonherpes virus) was also lower in the valaciclovir group throughout the entire study period (valaciclovir 36%, aciclovir 62%). There were no significant differences in graft rejection and survival rates between the valaciclovir and aciclovir patients at the end of the study (3 months following treatment period). See Table 9.
Bone marrow transplant studies. Two additional clinical studies have been conducted to assess the safety and efficacy of valaciclovir in the prophylaxis of CMV infection in bone marrow transplant recipients. The adverse event data from these trials is consistent with the current safety profile of valaciclovir.

5.2 Pharmacokinetic Properties

Absorption.

After oral administration valaciclovir is well absorbed and rapidly and almost completely converted to aciclovir and valine. This conversion is probably mediated by valaciclovir hydrolase, an enzyme isolated from human liver. Mean peak aciclovir concentrations are 10-37 microM (2.2-8.3 microgram/mL) following single doses of 250-2000 mg valaciclovir to healthy subjects with normal renal function and occur at a median time of 1.00-2.00 hours postdose. The time to peak (Tmax) is 1.6 hours for 2 x 500 mg tablets and 1.9 hours for a 1000 mg tablet. The bioavailability of aciclovir following a dose of 1000 mg of valaciclovir is 54% and is unaffected by food. Peak plasma concentrations of valaciclovir are only 4% of aciclovir levels, occur 30-100 minutes postdose, and are at or below the limit of quantification 3 hours after dosing.
Aciclovir maximum concentration (Cmax) and area under the aciclovir concentration-time curve (AUC) after single-dose administration of 100 mg, 250 mg, 500 mg, 750 mg, and 1 gram of valaciclovir to 8 healthy volunteers resulted in the mean Cmax (± SD) of 0.83 (± 0.14), 2.15 (± 0.50), 3.28 (± 0.83), 4.17 (± 1.14), and 5.65 (± 2.37) microgram/mL, respectively; and a mean AUC (± SD) of 2.28 (± 0.40), 5.76 (± 0.60), 11.59 (± 1.79), 14.11 (± 3.54), and 19.52 (± 6.04) hr.microgram/mL, respectively.
Similarly aciclovir Cmax and AUC after the multiple-dose administration of 250 mg, 500 mg, and 1 gram of valaciclovir administered 4 times daily for 11 days in parallel groups of 8 healthy volunteers resulted in a mean Cmax (± SD) of 2.11 (± 0.33), 3.69 (± 0.87), and 4.96 (± 0.64) microgram/mL, respectively, and a mean AUC (± SD) of 5.66 (± 1.09), 9.88 (± 2.01), and 15.70 (± 2.27) hr.microgram/mL, respectively.

Distribution.

Binding of aciclovir to plasma proteins is very low (9 to 33%). CSF penetration, determined by CSF/plasma AUC ratio, is about 25% for aciclovir and the metabolite 8-hydroxy-aciclovir (8-OH-ACV), and about 2.5% for the metabolite 9-(carboxymethoxy)methylguanine (CMMG), regardless of renal function (see Section 5.2 Pharmacokinetic Properties, Metabolism, Special populations).

Metabolism.

After oral administration, valaciclovir is converted to aciclovir and L-valine by first-pass intestinal and/or hepatic metabolism. Aciclovir is converted to a small extent to the metabolites 9-(carboxymethoxy)methylguanine (CMMG) by alcohol and aldehyde dehydrogenase and to 8-hydroxyaciclovir (8-OH-ACV) by aldehyde oxidase. Approximately 88% of the total combined plasma exposure is attributable to aciclovir, 11% to CMMG and 1% to 8-OH-ACV. Neither valaciclovir nor aciclovir is metabolised by cytochrome P450 enzymes.

Excretion.

In patients with normal renal function the plasma elimination half-life of aciclovir after both single and multiple dosing with valaciclovir is approximately 3 hours. Less than 1% of the administered dose of valaciclovir is recovered in the urine as unchanged drug. Valaciclovir is eliminated principally as aciclovir (greater than 80% of the recovered dose) and the known aciclovir metabolite, 9-(carboxymethoxy) methylguanine (CMMG), in the urine.

Characteristics in patients.

The pharmacokinetics of valaciclovir and aciclovir are not altered significantly in patients with herpes zoster and herpes simplex infections after oral administration of valaciclovir.

Special populations.

Renal impairment.

The elimination of aciclovir is correlated to renal function, and exposure to aciclovir will increase with increased renal impairment. In patients with end-stage renal disease, the average elimination half-life of aciclovir after valaciclovir administration is approximately 14 hours, compared with about 3 hours for normal renal function.
Exposure to aciclovir and its metabolites CMMG and 8-OH-ACV in plasma and cerebrospinal fluid (CSF) was evaluated at steady-state after multiple-dose valaciclovir administration in 6 subjects with normal renal function (mean creatinine clearance 111 mL/min, range 91-144 mL/min) receiving 2000 mg every 6 hours and 3 subjects with severe renal impairment (mean CLcr 26 mL/min, range 17-31 mL/min) receiving 1500 mg every 12 hours. In plasma as well as CSF, concentrations of aciclovir,
CMMG and 8-OH-ACV were on average 2, 4 and 5-6 times higher, respectively, in severe renal impairment compared with normal renal function. There was no difference in extent of CSF penetration (as determined by CSF/plasma AUC ratio) for aciclovir, CMMG or 8-OH-aciclovir between the two populations (see Section 5.2 Pharmacokinetic Properties, Distribution).

Hepatic impairment.

Administration of valaciclovir to patients with moderate (biopsy-proven cirrhosis) or severe (with and without ascites and biopsy-proven cirrhosis) liver disease indicated that the rate but not the extent of conversion of valaciclovir to acyclovir is reduced, and the acyclovir half-life is not affected. Dosage modification is not recommended for patients with cirrhosis. For higher doses [4000 mg or more per day] (see Section 4.4 Special Warnings and Precautions for Use, Use of high dose valaciclovir in hepatic impairment and liver transplantation, Use in hepatic impairment).

HIV infection.

In patients with HIV infection, the disposition and pharmacokinetic characteristics of aciclovir after oral administration of multiple doses of 1000 mg valaciclovir are unaltered compared with healthy subjects.

Elderly.

After single-dose administration of 1 gram of valaciclovir in healthy geriatric volunteers, the half-life of acyclovir was 3.11 ± 0.51 hours, compared with 2.54 ± 0.33 hours in healthy younger adult volunteers. The pharmacokinetics of acyclovir following single- and multiple-dose oral administration of valaciclovir in geriatric volunteers varied with renal function. Dose reduction may be required in geriatric patients, depending on the underlying renal status of the patient (see Section 4.2 Dose and Method of Administration).

5.3 Preclinical Safety Data

Genotoxicity.

Valaciclovir was not mutagenic in bacterial cells nor did it demonstrate any clastogenic potential in vitro in human lymphocytes or in vivo in the rat bone marrow assay. The mouse micronucleus assay was negative at 250 mg/kg but weakly positive at 500 mg/kg. Valaciclovir, at concentrations ≥ 2000 microgram/mL in the presence of S9 metabolic activation was mutagenic in the mouse lymphoma assay. The active metabolite, aciclovir, was clastogenic in Chinese hamster cells in vivo, at exposure levels also causing nephrotoxicity (500 and 1000 mg/kg parenteral dose). There was also an increase, though not statistically significant, in chromosomal damage at maximum tolerated doses (100 mg/kg) of aciclovir in rats. No activity was found in a dominant lethal study in mice or in 4 microbial assays. Positive results were obtained in 2 of 7 genetic toxicity assays using mammalian cells in vitro (positive in human lymphocytes in vitro and one locus in mouse lymphoma cells, negative at 2 other loci in mouse lymphoma cells and 3 loci in a Chinese hamster ovary cell line).
The results of these mutagenicity tests in vitro and in vivo suggest that valaciclovir and aciclovir are unlikely to pose a genetic threat to man at therapeutic dose levels.

Carcinogenicity.

The data presented below include references to the steady-state aciclovir AUC observed in humans treated with 1 gram valaciclovir given orally three times a day to treat herpes zoster (HZV) or with 2 gram valaciclovir given orally four times a day to treat cytomegalovirus (CMV). Plasma drug concentrations in animal studies are expressed as multiples of human exposure to aciclovir.
Valaciclovir was noncarcinogenic in lifetime carcinogenicity bioassays at oral doses of up to 120 mg/kg/day for mice and 100 mg/kg/day for rats. There was no significant difference in the incidence of tumours between treated and control animals, nor did valaciclovir shorten the latency of tumours. Plasma concentrations (AUC) of aciclovir were equivalent to 1.1 (HZV) and 0.1 times (CMV) human levels in the mouse bioassay and 1.3 (HZV) and 0.1 (CMV) times human concentrations in the rat bioassay.

6 Pharmaceutical Particulars

6.1 List of Excipients

Microcrystalline cellulose, magnesium stearate, crospovidone, povidone (K 30), povidone (K 90D), indigo carmine aluminium lake, and Opadry complete film coating system 02C50740 Blue (PI 12532).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

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

Store below 25°C.

6.5 Nature and Contents of Container

The tablets are available in PVC/PVDC/Al (polyvinyl chloride/polyvinylidene chloride/aluminium) blister packs containing 10, 30, 42 or 100 tablets.
Not all pack sizes are marketed in Australia.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical name: 2-[(2-amino-1,6-dihydro-6-oxo- 9H-purin-9-yl) methoxy]ethyl L-valinate hydrochloride.

Chemical structure.


Molecular formula: C13H20N6O4,HCl.
Molecular weight: 360.8.

CAS number.

124832-27-5.
Valaciclovir is the L-valine ester of aciclovir which is a purine nucleoside analogue.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes