Consumer medicine information

Valaciclovir SZ

Valaciclovir

BRAND INFORMATION

Brand name

Valaciclovir SZ

Active ingredient

Valaciclovir

Schedule

S4

 

Consumer medicine information (CMI) leaflet

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

What is in this leaflet

This leaflet answers some common questions about Valaciclovir SZ.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking this medicine against the benefits they expect it will have for you.

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

Keep this leaflet with the medicine. You may need to read it again.

What Valaciclovir SZ is used for

This medicine is used to treat:

  • genital herpes infections (Herpes Simplex Virus, or HSV)
  • shingles (herpes zoster) and ophthalmic zoster (shingles affecting the eye region).

This medicine is also used to prevent cytomegalovirus (CMV) infection and disease, following solid organ transplantation. CMV is another type of herpes virus. It can cause symptoms similar to glandular fever (high temperature, sore throat and swollen glands).

It contains the active ingredient valaciclovir hydrochloride. Valaciclovir hydrochloride belongs to a group of medicines called antivirals.

It works by stopping the multiplication of the viruses which cause these infections.

For genital herpes infections:
Although Valaciclovir SZ does not cure the infection, it can reduce the length and severity of an outbreak of herpes, the duration of pain and shorten the time to healing. It also helps blisters to heal more quickly. If you start taking them as soon as you feel an outbreak starting, you may prevent the blisters from developing.

Valaciclovir SZ tablets can be taken long term to prevent the HSV infection coming back. It can also reduce the risk of transmitting the virus that causes genital herpes in patients who are taking it continuously to prevent or reduce recurrent outbreaks.

This medicine (or any other antiviral) does not cure genital herpes or completely eliminates the risk of transmission. Genital herpes is a sexually transmitted disease. Therefore, in addition to therapy with this medicine, it is recommended that you should minimize having intercourse when you have an outbreak of herpes or show any symptoms. Condoms should always be used. This will reduce the risk of spreading herpes to your partner.

For shingles affecting the body and eye region:
This medicine can reduce the length and severity of an outbreak of shingles and the duration of pain associated with shingles. It is important the treatment is started within the first three days of the shingles attack.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

This medicine is not addictive.

Valaciclovir SZ is available only with a doctor's prescription.

There is not enough information to recommend the use of this medicine for children under the age of 12 years.

Before you take Valaciclovir SZ

When you must not take it

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

  • valaciclovir hydrochloride, the active ingredient, or to any of the other ingredients listed at the end of this leaflet under Product description.
  • any other similar medicines (such as aciclovir).

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

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

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

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

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

  • kidney condition
  • liver condition.

Tell your doctor if you are pregnant or plan to become pregnant or are breastfeeding. Your doctor can discuss with you the risks and benefits involved.

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

Taking other medicines

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

Some medicines and Valaciclovir SZ may interfere with each other. These include:

  • aminoglycosides, organoplatinum compounds, iodinated contrast media, methotrexate, pentamidine, foscarnet, ciclosporin, and tacrolimus.
  • cimetidine, a medicine used to treat heartburn or peptic ulcers
  • probenecid, a medicine used to treat gout
  • immunosuppressant medicines such as mycophenolate mofetil, cyclosporin and tacrolimus. These medicines are commonly taken by transplant patients and require close attention.

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

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

How to take Valaciclovir SZ

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

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

How much to take

For acute (short term) treatment of genital herpes:
If you have had a herpes infection before, you should start to take Valaciclovir SZ as early as possible if you think you are about to have another recurrence (attack). This medicine should ideally be taken just before or straight after the first signs of HSV infection appear.

The usual dose to take is one 500mg tablet with water twice daily.

For suppressive (long term) treatment of genital herpes:
The usual dose to take to prevent the herpes infection appearing again is 500mg once daily.

If you previously have had more than 10 recurrences (attacks) in one year, your doctor may recommend that you take 1000mg (two 500mg tablets) of Valaciclovir SZ once daily to prevent recurrences.

To treat shingles affecting the body and eye region:
The usual dose to take is 1000mg (two 500mg tablets) with water three times a day.

To prevent CMV infection and disease:
The usual dose for adults and children over 12 years of age is 2000mg (four 500mg tablets) with water four times a day.

If you have a kidney disease your doctor may reduce your dose.

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

Follow the instructions they give you. If you take the wrong dose, Valaciclovir SZ may not work as well.

How to take it

Swallow the tablets whole with a full glass of water.

You should drink plenty of fluids while taking this medicine, especially if you are elderly.

Do not chew them.

When to take Valaciclovir SZ

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

For genital herpes infections:
The usual times to take the tablets are in the morning and evening.

For shingles affecting the body and eye region:
The usual times to take the tablets are in the morning, afternoon and evening.

To prevent CMV infection and disease:
The tablets should be taken four times a day (i.e. morning, noon, afternoon and evening).

How long to take Valaciclovir SZ

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

For the prevention of herpes infections, you should continue to take this medicine every day as prescribed by your doctor.

For shingles affecting the body and eye region:
The usual course of treatment is seven days.

To prevent CMV infection and disease:
The usual course of treatment is 90 days.

Do not stop taking your medicine before the course of treatment is finished because you feel better, unless otherwise advised by your doctor.

If you forget to take it

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

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

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

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

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

If you take too much (overdose)

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

Symptoms of an overdose may include:

  • agitation
  • confusion or imagining sights or sounds (hallucinations)
  • drowsiness
  • nausea and vomiting.

While you are taking Valaciclovir SZ

Things you must do

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

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

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 water while you are taking Valaciclovir SZ.

Tell your doctor if your symptoms are not improving or are worsening while you are taking Valaciclovir SZ.

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.

Things you must not do

Do not take Valaciclovir SZ to treat any other complaints unless your doctor tells you to.

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

Do not stop taking Valaciclovir SZ, or change the dose, without first checking with your doctor.

Things to be careful of

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

Valaciclovir should be discontinued if central nervous system adverse reactions occur.

Side effects

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

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

If you are over 65 years of age you may have an increased chance of getting certain side effects.

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

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

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

  • headache
  • gastrointestinal discomfort (vomiting, nausea, diarrhoea, constipation, abdominal pain, indigestion)
  • dry mouth
  • fever and chills
  • difficulty sleeping
  • back pain
  • nervousness
  • skin rash which may be itchy
  • weakness
  • sensitivity to UV light, such as development of a rash like sunburn even after short exposure to UV light.

For patients taking Valaciclovir SZ for the prevention of CMV infection and disease, you should report the above side effects to the doctor or pharmacist if they are severe or become troublesome.

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

  • dizziness
  • confusion or imagining sights or sounds (hallucinations)
  • drowsiness.
  • Decreased consciousness

These side effects are more common in patients with kidney disease or in those taking high doses of Valaciclovir SZ (for the prevention of CMV infection and disease).

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

  • damage to the kidneys, which gets better when Valaciclovir SZ is stopped. Symptoms of severe damage to the kidneys includes lower back pain (kidney pain), little or no urine, drowsiness, nausea, vomiting or breathlessness.
  • Coma
  • Agitation
  • Tremor
  • Psychotic episode
  • Convulsions
  • Brain injury
  • Uncoordinated muscle movements and speech

The above is a serious side effect that may require medical attention. Serious side effects are rare.

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

  • unusual bruising or bleeding, which may indicate that your blood is not clotting properly
  • allergic reaction. 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.

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

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

Some side effects (for example hypertension (high blood pressure), damage to the liver or kidneys) can only be found when your doctor does tests from time to time to check your progress.

After taking Valaciclovir SZ

Storage

Keep your tablets in the original container.

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

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

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

Heat and dampness can destroy some medicines.

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

Disposal

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

Product description

What it looks like

Valaciclovir SZ 500mg film-coated tablets - white to off-white capsule shaped film coated tablets with '500' debossed on one side and plain on other side.

Available in blister packs of 30 film-coated tablets.

Ingredients

Active ingredients:

  • Valaciclovir SZ 500mg - 556.275mg valaciclovir hydrochloride (equivalent to 500 mg of valaciclovir)

Inactive ingredients:

  • microcrystalline cellulose
  • crospovidone
  • povidone
  • magnesium stearate
  • Opadry White 13B58802.

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Supplier

Sandoz Pty Ltd
ABN 60 075 449 553
54 Waterloo Road
Macquarie Park
NSW 2113
Australia
Tel: 1800 726 369

This leaflet was revised in February 2019.

Australian Register Number(s)

Valaciclovir SZ 500mg film-coated tablets: AUST R 154460.

Published by MIMS March 2019

BRAND INFORMATION

Brand name

Valaciclovir SZ

Active ingredient

Valaciclovir

Schedule

S4

 

1 Name of Medicine

Valaciclovir hydrochloride.

2 Qualitative and Quantitative Composition

Valaciclovir SZ tablets contain the active ingredient valaciclovir hydrochloride.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Valaciclovir SZ 500 mg capsule shaped film coated tablets.

White to off-white capsule shaped film coated tablets with '500; debossed on one side and plain on other side.

Valaciclovir SZ 1000 mg capsule shaped film coated tablets*.

White to off-white, capsule shaped film coated tablets with '1000' debossed on one side and plain on other side.
*Not currently marketed in Australia.

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.
Reduction of transmission of genital herpes in patients suffering from recurrent genital herpes. In addition to therapy with 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.

Adults.

Herpes zoster.

1000 mg of valaciclovir three times a day for seven days.

Genital herpes.

First clinical presentation, 500 mg of 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.

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 (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 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.

The dosage in adults and adolescents (from 12 years of age) 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 adjustment, Renal impairment).

Method of administration.

No special instructions for use.

Dosage adjustment.

Renal impairment.

Caution is advised when administering valaciclovir tablets to patients with impaired renal function. Adequate hydration should be maintained.

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.
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 tablets 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.

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.

Infants and children.

No data are available.

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 adjustment, Renal impairment). Adequate hydration should be maintained.

Special patient groups.

No dosage recommendations.

Monitoring advice.

No special monitoring necessary.

4.3 Contraindications

Valaciclovir SZ 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

HIV disease.

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.

Immunocompromised patients.

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.

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.

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 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.

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.

Teratogenesis.

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/day PO), rabbit (50 mg/kg/day SC and IV) or rat (50 mg/kg/day 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.

Central nervous system effects.

Reversible neurological reactions including 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.

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.

Use in renal impairment.

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 Pharmacological 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)).
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. In the event of acute renal failure and anuria, the patient may benefit from haemodialysis until renal function is restored (see Section 4.2 Dose and Method of Administration).

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.
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. cyclosporin, 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 acyclovir.
(Category B3)
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 1,246 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, i.e. 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 tablets should only be used in pregnancy if the potential benefit outweighs the potential risk.
Australian Pregnancy Categorisation - Category B3. Drugs which have been taken by only a limited number of pregnant women and women of childbearing age without an increase in the frequency of malformation or other direct or indirect harmful effects on the human foetus having been observed. Studies in animals have shown evidence of an increased occurrence of foetal damage, the significance of which is considered uncertain in humans.
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 (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 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 can not 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 the Tables 6 and 7.

Postmarketing experience.

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

Gastrointestinal tract.

Common - nausea, abdominal discomfort, vomiting and diarrhoea.

Blood and lymphatic system disorders.

Rare - thrombocytopenia.
Very rare - leukopenia*, thrombotic microangiopathy (TMA) (see Section 4.4 Special Warnings and Precautions for Use).
*Leukopenia is mainly reported in immunocompromised patients.

Hypersensitivity, skin and subcutaneous tissue disorders.

Uncommon - rashes including photosensitivity.
Rare - pruritus, dyspnoea and anaphylaxis.
Very rare - urticaria, angioedema.

Immune system disorders.

Very rare - anaphylaxis.

Renal and urinary disorders.

Rare - renal impairment.
Very rare - reports of acute renal failure, renal pain.
Renal pain may be associated with renal failure.

Hepato-biliary disorders.

Rare - reversible increases in liver function tests, occasionally described as hepatitis.

Psychiatric and nervous system disorders.

Common - headache.
Uncommon - dizziness*, confusion* and hallucinations*.
Rare - decreased consciousness*.
Very rare - coma*, agitation*, tremor*, ataxia*, dysarthria*, psychotic symptoms*, convulsions*, encephalopathy*.
*The above events are generally reversible and usually 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.

Respiratory, thoracic and mediastinal disorders.

Uncommon - dyspnoea.

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

4.9 Overdose

Symptoms.

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.

Treatment.

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

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.

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 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 patient 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.

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 tablets (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. See Table 9.
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 10.

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. Administration of a single dose of 500 mg valaciclovir to healthy subjects under fasting conditions achieved a mean peak plasma concentration of aciclovir of 3.1 microgram/mL within approximately 1.69 hours. 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 (Tmax) is 1.7 hours for 1 x 500 mg tablet, 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. The valaciclovir and aciclovir pharmacokinetic profiles are similar after single and repeat dosing.

Distribution.

Binding of aciclovir to plasma proteins is very low (9 to 33%).

Metabolism.

After oral administration, valaciclovir is rapidly and almost completely converted to aciclovir and 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. an enzyme isolated from human liver. 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. In patients with end-stage renal disease, the average elimination half-life of aciclovir after valaciclovir administration is approximately 14 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 tablets.

End-stage renal disease (ESRD).

Following administration of valaciclovir to volunteers with ESRD, the average aciclovir half-life is approximately 14 hours. During haemodialysis, the aciclovir half-life is approximately 4 hours. Approximately one third of aciclovir in the body is removed by dialysis during a 4-hour haemodialysis session. Apparent plasma clearance of aciclovir in dialysis patients was 86.3 ± 21.3 mL/min/1.73 m2, compared to 679.16 ± 162.76 mL/min/1.73 m2 in healthy volunteers.
Reduction in dosage is recommended in patients with renal impairment.

Microbiology.

Resistance development.

Resistance of HSV and VZV to aciclovir can result from qualitative and quantitative changes in the viral (thymidine kinase) TK and/or DNA polymerase. Clinical isolates of VZV with reduced susceptibility to aciclovir have been recovered from patients with AIDS. In these cases, TK-deficient mutants of VZV have been recovered.
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.

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 g valaciclovir given orally three times a day to treat herpes zoster (HZV) or with 2 g 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

The tablets also contain microcrystalline cellulose, crospovidone, povidone, magnesium stearate, and Opadry White 13B58802.

6.2 Incompatibilities

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

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

Valaciclovir SZ 500 mg capsule shaped film coated tablets are available in blister packs of 10*, 20*, 30, 42* and 100* film-coated tablets.
Valaciclovir SZ 1000 mg capsule shaped film coated tablets* are available in blister packs of 21 and 50 film-coated tablets.
*Not currently 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

Valaciclovir is the L-valine ester of aciclovir. Aciclovir is a purine nucleoside analogue.
Its chemical name is 2-[(2-amino-1,6- dihydro-6-oxo-9H-purin-9-yl) methoxy]ethyl L-valinate hydrochloride. Its empirical formula is C13H20N6O4.HCl (MW: 360.8).

Chemical structure.

Its chemical structure is:

CAS number.

124832-27-5.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes