Consumer medicine information

APX-Valaciclovir

Valaciclovir

BRAND INFORMATION

Brand name

APX-Valaciclovir

Active ingredient

Valaciclovir

Schedule

SUMMARY CMI

APX-VALACICLOVIR

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 APX-Valaciclovir?

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

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

2. What should I know before I use APX-Valaciclovir?

Do not use if you have ever had an allergic reaction to valaciclovir or aciclovir 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 APX-Valaciclovir? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with APX-Valaciclovir 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 APX-Valaciclovir?

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.

More instructions can be found in Section 4. How do I use APX-Valaciclovir? in the full CMI.

5. What should I know while using APX-Valaciclovir?

Things you should do	Remind any doctor, dentist or pharmacist you visit that you are using APX-Valaciclovir Drink plenty of fluids while you are taking this medicine.
Things you should not do	Do not stop using this medicine suddenly Do not use this medicine to treat any other complaints unless your doctor says to.
Driving or using machines	Be careful before you drive or use any machines or tools until you know how APX-Valaciclovir affects you.
Drinking alcohol	Tell your doctor if you drink alcohol.
Looking after your medicine	Keep APX-Valaciclovir tablets in a cool, dry place where it stays below 30°C. Heat and dampness can destroy some medicines. Keep your tablets in their pack until it is time to take them. If you take the tablets out of their pack, they may not keep well.

For more information, see Section 5. What should I know while using APX-Valaciclovir? 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

APX-VALACICLOVIR

Active ingredient(s): valaciclovir hydrochloride

Consumer Medicine Information (CMI)

This leaflet provides important information about using APX-Valaciclovir. 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 APX-Valaciclovir.

Where to find information in this leaflet:

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

1. Why am I using APX-Valaciclovir?

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

APX-Valaciclovir tablets work by stopping the multiplication of the virus which causes herpes, shingles and cold sores. It can reduce the length and severity of an outbreak and duration of pain, and shorten the healing time of crusts, associated with herpes, shingles and cold sores. APX-Valaciclovir 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 cold sores, the tablets should be taken at the earliest symptom of a cold sore (e.g. tingling, itching, or burning).

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.

APX-Valaciclovir 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.

APX-Valaciclovir tablets are more effective in patients 50 years of age and older.

Ask your doctor if you have any questions about why APX-Valaciclovir tablets have been prescribed for you.

APX-Valaciclovir tablets are available only with a doctor's prescription.

APX-Valaciclovir tablets are not addictive

Use in children

There is not enough information to recommend the use of APX-Valaciclovir in children.

2. What should I know before I use APX-Valaciclovir?

Warnings

Do not use APX-Valaciclovir if you have ever had an allergic reaction to:

valaciclovir or aciclovir
any of the 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

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 any of the following medical conditions:

kidney or liver conditions
are anaemic (reduced red blood cells or iron stores)

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

previous skin reactions with valaciclovir which may include a rash, fever, facial swelling or blistering/peeling skin

If you have not told your doctor about any of the above, please do so before you take APX-Valaciclovir.

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.

3. What if I am taking other medicines?

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 APX-Valaciclovir 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.

Do not take APX-Valaciclovir tablets after the expiry date (EXP) printed on the pack.

If you take it after the expiry date has passed, it may not work as well. who are at risk of dehydration, such as the elderly.

Do not take APX-Valaciclovir tablets if the packaging is torn or shows signs of tampering.

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

4. How do I use APX-Valaciclovir?

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

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.

For the 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 a kidney disease your doctor may reduce your dose.

For the treatment of shingles

500 mg tablets: The normal dose to take is two tablets with water three times a day.

For the treatment of cold sores

500 mg tablets: The normal dose to take for the one-day regimen is four tablets with water twice a day, with the second dose taken about 12 hours after the first dose.

For the treatment of acute (short term) genital herpes:

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

500 mg tablets: For the treatment of HSV infection, the usual dose to take is one tablet with water twice daily.

For suppressive (long term) treatment of genital herpes:

500mg tablets: To prevent the herpes infection appearing again, the usual dose to take is 500 mg once daily. Your doctor may recommend that you take this as a divided dose (i.e. 250 mg twice daily).

If you previously have had more than 10 recurrences (attacks) in one year, your doctor may recommend that you take 1000 mg of APX-Valaciclovir once daily to prevent recurrences.

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

When to take APX-Valaciclovir

It does not matter if you take this medicine before or after food.

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 cold sores
The tablets should be taken at the earliest symptom of a cold sore (e.g. tingling, itching, or burning).
Treatment for cold sores should not exceed 1 day (2 doses) and the doses should be taken 12 hours apart.
The shingles and cold sore packs are designed to help you to remember to take the tablets at the correct times.

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 APX-Valaciclovir

Swallow the tablets with a glass of water.
You should drink plenty of fluids while taking APX-Valaciclovir tablets, especially if you are elderly

How long to take them

For the prevention of CMV infection and disease

The usual course of treatment is 90 days.

For the treatment of shingles

The usual course of treatment is 7 days

Do not stop taking APX-Valaciclovir tablets before the course of treatment is finished just because you feel better. The shingles may not be completely over.

For the treatment of cold sores

The course of treatment should not exceed 1 day (2 doses) and the doses should be taken 12 hours apart.

For the treatment of herpes simplex (genital herpes)

For the treatment of 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 the prevention of herpes infections

You should continue to take this medicine every day as prescribed by your doctor.

Do not stop taking APX-Valaciclovir tablets just because you feel better. The herpes outbreak may not be completely over.

If you forget to use APX-Valaciclovir

APX-Valaciclovir should be used regularly at the same time each day.

For prevention of CMV infection and disease, the treatment of shingles or the treatment of herpes simplex (genital herpes)

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.

For the treatment of cold sores

Take the second dose as soon as possible once 12 hours have passed.

If you miss more than one dose, or you are not sure what to do ask your doctor or pharmacist.

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

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

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

If you use too much APX-Valaciclovir

If you think that you have used too much APX-Valaciclovir, 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 APX-Valaciclovir?

Things you should do

Drink plenty of fluids while you are taking this medicine.

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

Call your doctor straight away 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.
become pregnant or are trying to become pregnant or intend to breastfeed while you are taking this medicine.
for any reason you have not taken your medicine exactly as prescribed.

Remind any doctor, dentist or pharmacist you visit that you are using APX-Valaciclovir. 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 APX-Valaciclovir 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.

APX-Valaciclovir 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 using this medicine suddenly 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 this medicine to treat any other complaints unless your doctor says to.

Driving or using machines

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

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

Keep APX-Valaciclovir tablets in a cool, dry place where it stays below 30°C.
A locked cupboard at least one-and-a half metres above the ground is a good place to store medicines.
Heat and dampness can destroy some medicines.
Keep your tablets in their pack until it is time to take them. If you take the tablets out of their pack, they may not keep well.

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

Store it in a cool dry place away from moisture, heat or sunlight; for example, 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.

When to discard your medicine (as relevant)

If your doctor tells you to stop taking APX-Valaciclovir, 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 effects	What to do
headache gastrointestinal discomfort (vomiting, nausea, diarrhoea, constipation, abdominal pain, indigestion) 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 effects

What to do

Some of these side effects are more common in patients with kidney disease or in those taking high doses of APX-Valaciclovir:

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

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

damage to the kidney, which gets better when APX-Valaciclovir 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

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.

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 APX-Valaciclovir 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.

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

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

What APX-Valaciclovir contains

Active ingredient (main ingredient)	APX-Valaciclovir tablets contain the active ingredient valaciclovir hydrochloride
Other ingredients (inactive ingredients)	microcrystalline cellulose crospovidone povidone colloidal anhydrous silica carnauba wax magnesium stearate Opadry YS-19043 (white colour concentrate)

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

What APX-Valaciclovir looks like:

APX-Valaciclovir 500mg: White, film coated tablet, white to off-white core, biconvex, elongated, unscored engraved with “500” on one side and plain on the other. AUST R 335725 (bottle pack) & AUST R 335726 (blister pack).
APX-Valaciclovir 1000mg tablets: White, film coated tablet, white to off-white core, biconvex, elongated, with a partial score bar on both sides, engraved with "1000" on one side and plain on the other. AUST R 335727

Available in a pack size of 2 (starter pack), 4, 6, 10, 20, 21, 30, 42,60, 80,90,100, 240, 480, 500, 8x500, 4x1000 tablets*

*Not all pack sizes may be available or marketed

Who distributes APX-Valaciclovir

Arrotex Pharmaceuticals Pty Ltd
15-17 Chapel Street
Cremorne VIC 3121
www.arrotex.com.au

This leaflet was prepared in September 2024

Published by MIMS October 2024

BRAND INFORMATION

Brand name

APX-Valaciclovir

Active ingredient

Valaciclovir

Schedule

1 Name of Medicine

Valaciclovir as hydrochloride.

2 Qualitative and Quantitative Composition

APX-Valaciclovir tablets 500 mg contain 500 mg of valaciclovir as hydrochloride.
APX-Valaciclovir tablets 1000 mg contain 1000 mg of valaciclovir as hydrochloride.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

APX-Valaciclovir tablets 500 mg.

White, film coated tablet, white to off-white core, biconvex, elongated, unscored engraved with "500" on one side and plain on the other.

APX-Valaciclovir tablets 1000 mg.

White, film coated tablet, white to off-white core, biconvex, elongated, unscored engraved with "1000" on one side and plain on the other.

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 recurrent herpes labialis (cold sores).
For the treatment of clinical episodes of genital herpes simplex infections.
For the prevention of recurrent genital herpes.
Reduction of transmission of genital herpes in patients suffering from recurrent genital herpes. In addition to therapy with APX-Valaciclovir, it is recommended that patients use safer sex practices (see Section 4.4 Special Warnings and Precautions for Use).
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 the treatment of herpes zoster, 1000 mg of APX-Valaciclovir three times a day for seven days.
For the treatment of herpes labialis (cold sores). The recommended dosage of APX-Valaciclovir for the treatment of cold sores is 2000 mg twice daily for 1 day with the second dose taken about 12 hours (no sooner than 6 hours) after the first dose. Therapy should be initiated at the earliest symptom of a cold sore (e.g. tingling, itching, or burning).
Genital herpes.

For the treatment of genital herpes.

For treatment of first clinical presentation of genital herpes, 500 mg of APX-Valaciclovir twice a day for 5 to 10 days. For recurrent episodes of genital herpes, 500 mg 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.

For the prevention of genital herpes in patients with a history of fewer than 10 recurrences each year, 500 mg of valaciclovir once daily, either as a single dose or a divided dose (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
For the prevention of genital herpes in patients with a history of 10 or more recurrences each year when not taking suppressive therapy, 1000 mg of valaciclovir once daily.
For immunocompromised patients, 500 mg 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 APX-Valaciclovir 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 infection (CMV) and disease.

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

The dosage of APX-Valaciclovir is 2 g 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 APX-Valaciclovir to patients with impaired renal function. Adequate hydration should be maintained.

Dose reduction in the treatment of herpes zoster and genital herpes simplex.

The dose of APX-Valaciclovir should be modified as follows in patients with significantly impaired renal function (see Table 1).

Dose reduction in the treatment of herpes labialis.

The dose of APX-Valaciclovir should be modified as follows in patients with significantly impaired renal function (see Table 2).

In patients on haemodialysis the APX-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 APX-Valaciclovir should be adjusted in patients with impaired renal function as shown in Table 3.

The creatinine clearance should be monitored frequently, especially during periods when renal function is changing rapidly e.g. immediately after transplantation or engraftment. The APX-Valaciclovir dosage should be adjusted accordingly.

Dosage in hepatic impairment.

Studies with a 1 g unit dose of APX-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

APX-Valaciclovir 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 grams 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 higher 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.

Use in cold sores (herpes labialis).

Patients should be advised to initiate treatment at the earliest symptom of a cold sore (e.g. tingling, itching, or burning). There are no data on the effectiveness of treatment initiated after the development of clinical signs of a cold sore (e.g. papule, vesicle, or ulcer). Patients should be instructed that treatment for cold sores should not exceed 1 day (2 doses) and that their doses should be taken 12 hours apart. Patients should be informed that valaciclovir is not a cure for cold sores (herpes labialis).

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 APX-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 APX-Valaciclovir on transmission of sexually transmitted infections other than herpes (including HIV, gonorrhoea, syphilis and Chlamydia) is unknown.
The efficacy of APX-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 practises.

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 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 co-administered. 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 Zovirax 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 post dose. 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 post dose, 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 (C_max) 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 had been detected in breast milk at concentrations ranging from 0.6 to 4.1 times the corresponding aciclovir plasma concentration.
Caution is therefore advised if valaciclovir is to be administered to a breast-feeding mother. Valaciclovir should only be administered to breast-feeding 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 4 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 5.

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 6.

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 7 and 8.

Cold sores (herpes labialis).

In clinical studies for the treatment of cold sores, the adverse events reported by patients receiving valaciclovir (n = 609) or placebo (n = 609) included headache (valaciclovir 14%, placebo 10%) and dizziness (valaciclovir 2%, placebo 1%). The frequencies of abnormal ALT (> 2 x ULN) were 1.8% for patients receiving valaciclovir compared with 0.8% for placebo. Other laboratory abnormalities (haemoglobin, white blood cells, alkaline phosphatase and serum creatinine) occurred with similar frequencies in the 2 groups.

Post marketing experience.

The following adverse events have been observed during post-approval use of 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, hallucinations, coma, agitation, tremor, ataxia, dysarthria, psychotic symptoms, convulsions, encephalopathy, aggressive behaviour, delirium.
Neurological disorders, sometimes severe, may be linked to encephalopathy and include confusion, agitation, convulsions, hallucinations, coma. These events are generally reversible and usually seen 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 (8000 mg daily) of Valtrex for CMV prophylaxis, neurological reactions occurred more frequently compared with lower doses used for other indications.

Respiratory, thoracic and mediastinal disorders.

Dyspnoea.

Gastrointestinal tract.

Abdominal discomfort, vomiting, diarrhoea, nausea.

Hepato-biliary disorders.

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

Skin and subcutaneous tissue disorders.

Rashes including photosensitivity, pruritus, urticarial, angioedema, 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 Precaution for Use). Elevated blood creatine 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 13 11 26 (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 post-herpetic neuralgia) and in the duration of post-herpetic neuralgia when compared with aciclovir. There was no statistically significant difference between the three treatments for the resolution of rash. See Table 9.

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 associated with these beneficial effects.

Cold sores (herpes labialis).

Two double-blind, placebo-controlled clinical trials were conducted in 1,856 healthy immunocompetent adults and adolescents (≥ 12 years old) with a history of recurrent cold sores. Patients self-initiated therapy at the earliest symptoms and prior to any signs of a cold sore. The majority of patients initiated treatment within 2 hours of onset of symptoms.
The two trials investigated the clinician based duration of episode and prevention/blockage of cold sore lesion development as diametrically opposed primary and secondary endpoints.
Patients were randomised in to 3 groups: valaciclovir 2 grams twice daily for one day or valaciclovir 2 grams twice daily for one day, followed by 1 gram twice daily on day 2, or placebo on both days.
An integrated analysis of both trials showed a statistically significant prevention/blockage of onset of lesions in 44% of patients on one day therapy compared to 37% receiving placebo. The mean duration of cold sores in the integrated analysis showed a significant reduction in duration of approximately 1 day when compared to placebo. The ITT population showed the mean duration of episodes was 6.2 days in the placebo group, and 5.2 days in the 1 day group giving a treatment difference of -1.0 day (CI -1.4, -0.6).
The single study results showed the mean duration of cold sore episodes was approximately 1 day shorter in treated subjects when compared to placebo. For the ITT population, when tested as the primary endpoint, the mean duration of episodes was 6.1 days in the placebo group and 5.0 days in the 1 day group, giving a treatment difference of -1.1 days (CI -1.6, -0.6). When tested as the secondary endpoint, For the ITT population, the mean duration of episodes was 6.3 days in the placebo group and 5.3 days in the 1 day group, giving a treatment difference of -1.0 days (CI -1.5, -0.5).
The onset of lesions was prevented in the 43 - 44% of patients on one day valaciclovir therapy compared with 35-38% placebo treated patients. No significant difference was observed between subjects receiving valaciclovir or Placebo in the prevention of progression of cold sore lesions beyond the papular stage when tested as the primary or secondary endpoint.
There are no data on the effectiveness of treatment initiated after the development of clinical signs of a cold sore i.e. papule, vesicle or ulcer. The 2 day regimen did not offer additional benefit over the 1-day regimen.
The data are based on treatment of a single episode of herpes labialis.

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 Zovirax (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 end-points 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.

Three large, multicentre, double-blind, randomised trials were conducted to investigate the efficacy of valaciclovir for the prevention of recurrent genital HSV infection. Two studies evaluated the disease in immunocompetent individuals, while the third evaluated an immunocompromised (HIV-infected) population.

Immunocompetent patients.

The two trials conducted in immunocompetent patients included a total of 1861 patients, of which 1366 received valaciclovir for up to 52 weeks. The primary endpoint in both trials was defined as the first clinical recurrence of HSV infection, and the proportion recurrence free at the end of 12 months was another endpoint. In Study BQRT/95/0026, 500 mg once daily treatment with valaciclovir was compared with placebo in patients with a history of at least 8 recurrences per year. Clinical recurrence was defined as lesions reaching the papule/vesicle stage, and valaciclovir delayed or prevented 85% of the recurrences compared with placebo.
Study BQRT/96/0001 was a double blind study comparing a variety of valaciclovir doses and aciclovir with placebo. Clinical recurrence was defined as lesions at the macule/papule stage. As HSV infection had been identified as a strong prognostic factor in previous genital herpes studies, subgroup analyses was conducted according to recurrence history. The results from the proportional hazards analyses (hazard ratios and 95% CI) for the active treatment comparisons with placebo obtained within each subgroup are presented in Table 10.

Results show that 250 mg twice daily offered the best clinical efficacy for suppression of genital herpes recurrences in this group of patients. However, the same total daily dose given as single daily dose (i.e. 500 mg once daily) was also very effective, as confirmed with Study BQRT/95/0026.
Although 1000 mg daily was more effective than 500 mg once daily in the first study, the marginal difference between the two did not justify long term exposure to double the daily dose. The hazard ratio comparing valaciclovir 1000 mg once daily and 500 mg once daily indicated an increase in efficacy of only approximately 12% (hazard ratio 0.879, 95% CI 0.637, 1.211).

Immunocompromised patients.

A third 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.

Study HS2AB3009 was 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. 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, non-herpes 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 11.

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 post dose. The time to peak (T_max) 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 post dose, and are at or below the limit of quantification 3 hours after dosing.
Aciclovir maximum concentration (C_max) 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 C_max (± 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 C_max 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 C_max (± 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 Pharmacokinetics 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-hydroxy-aciclovir (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 aciclovir is reduced, and the aciclovir 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 aciclovir was 3.11 ± 0.51 hours, compared with 2.54 ± 0.33 hours in healthy younger adult volunteers. The pharmacokinetics of aciclovir 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

APX-Valaciclovir tablets contain microcrystalline cellulose, crospovidone, povidone, colloidal anhydrous silica, carnauba wax, magnesium stearate and Opadry YS-19043 (white colour concentrate).

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 30°C.

6.5 Nature and Contents of Container

APX-Valaciclovir 500 mg tablets are available in PVC/Al blister packs of 4, 6, 8, 10, 20, 30, 42, 60, 80, 90, 100, 240 and 480 and HDPE bottles of 240, 480 and 500.
APX-Valaciclovir 1000 mg tablets are available in PVC/Al blister packs of 3, 4 and 21.
Not all strengths, pack sizes or container types may be distributed 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

Valaciclovir is the L-valine ester of aciclovir. Its chemical name is 2 [(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl l-valinate hydrochloride. Aciclovir is a purine nucleoside analogue.

Chemical structure.

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

CAS number.

124832-27-5.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

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APX-Valaciclovir 500 mg Tablets