Consumer medicine information

Shilova 500 & 1000 Tablets

Valaciclovir

BRAND INFORMATION

Brand name

Shilova Tablets

Active ingredient

Valaciclovir

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Shilova 500 & 1000 Tablets.

What is in this leaflet

This leaflet answers some common questions about SHILOVA tablets. It does not contain all of 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 SHILOVA tablets against the benefits this medicine is expected to 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 SHILOVA tablets are used for

How SHILOVA tablets work

SHILOVA tablets belong to a group of medicines called antivirals. SHILOVA tablets are used for the treatment of genital herpes infection, shingles (infection zoster), ophthalmic zosters (shingles affecting the eye region), cold sores (herpes labialis) and for the prevention of Cytomegalovirus (CMV) infection in people following an organ transplant.

SHILOVA tablets work by stopping the multiplication of the virus which causes herpes, shingles and cold sores. They can reduce the length and severity of an outbreak of herpes, shingles and cold sores and the duration of pain and shorten the time to healing of crusts associated with herpes.

Genital herpes
SHILOVA tablets do not eliminate the herpes virus from the body. The herpes virus is also known as the Herpes Simplex Virus, or HSV.

SHILOVA tablets help the blisters to heal more quickly. If you start taking them as soon as you feel an outbreak starting, you may actually prevent the blisters from developing.

SHILOVA tablets can also be taken long term to help prevent the HSV infection coming back.

SHILOVA tablets 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. It does not cure genital herpes or completely eliminate the risk of transmission. Therefore, in addition to therapy with SHILOVA, it is recommended that patients avoid contact when symptoms are present and always use condoms.

SHILOVA (or any other antiviral) is not a cure for genital herpes. 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.

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

Cold sores
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).

Cytomegalovirus (CMV)
SHILOVA is used to prevent the cytomegalovirus (CMV) infection in people following an organ transplant.

CMV is a common viral infection caused by human herpes virus. It can be spread by contact with infectious blood or body secretions (e.g. saliva, urine, cervical mucous, or semen). CMV may cause symptoms similar to glandular fever (fatigue, fever, sore throat and swollen glands).

SHILOVA tablets are more effective inpatients 50 years of age and older.

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

SHILOVA tablets are not addictive.

Before you take SHILOVA tablets

When you must not take them

  • Do not take SHILOVA tablets if you have ever had an allergic reaction to valaciclovir, aciclovir or any of the ingredients listed at the end of this leaflet.
    Refer to "Side Effects" section for some common symptoms of an allergic reaction.
  • Do not take SHILOVA tablets if you are pregnant, trying to become pregnant or breastfeeding, unless your doctor says you should.
    Your doctor will discuss the risks and benefits of using SHILOVA tablets when pregnant and during breastfeeding.
  • Do not take SHILOVA 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.
  • Do not take SHILOVA tablets if the packaging is torn or shows signs of tampering.
    If you are not sure whether you should be taking SHILOVA, talk to your doctor.

Before you start to take them

You must tell your doctor if:

  • you are allergic to foods, dyes, preservatives or any other medicines.
  • you have a kidney or liver condition.

If you have not told your doctor about any of the above, please do so before you take SHILOVA

Taking other medicines

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

Some medicines may affect the way others work. Your doctor or pharmacist will be able to tell you what to do when taking SHILOVA tablets with other medicines.

Use in children

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

How to take SHILOVA tablets

Take SHILOVA tablets exactly as your doctor has prescribed. 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.

The label on the pack will give the same information. If there is something you do not understand, ask your doctor or pharmacist.

How much to take for the treatment of genital herpes

Your doctor will decide what dose you should take, how often you should take it and what strength SHILOVA tablets you should use. The dosage may vary depending on your medical history.

Acute (short term) treatment of genital herpes:

If you have had a herpes infection before, you should start to take SHILOVA 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.

If you have been prescribed SHILOVA 500 mg tablets for, the treatment of HSV infection, the usual dose to take is one tablet with water twice daily.

Suppressive (long term) treatment of genital herpes:

If you have been prescribed SHILOVA500 mg 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.250mg twice daily).

If you previously have had more than10 recurrences (attacks) in one year, your doctor may recommend that you take 1000mg of SHILOVA once daily to prevent recurrences.

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

How much to take for the treatment of shingles

If you have been prescribed SHILOVA 500 mg tablets, the normal dose to take is two tablets with water three times a day.

If you have been prescribed SHILOVA 1000 mg tablets, the normal dose to take is one tablet with water three times a day.

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

How much to take for the treatment of cold sores

If you have been prescribed SHILOVA 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.

If you have been prescribed SHILOVA 1000 mg tablets, the normal dose to take for one day regimen is two tablets with water twice a day, with the second dose taken about 12 hours after the first dose.

How much to take for the treatment of CMV

The usual dose for adults and children over 12 years of age is 2000 mg (two 1000 mg tablets or four 500 mg tablets) taken 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.

How to take them

Swallow the tablets with a glass of water.

You should drink plenty of fluids while taking SHILOVA tablets, especially if you are elderly.

When to take them

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

Shingles
The shingles packs are designed to help you to remember to take the tablets at the correct times.

For the treatment of shingles the usual times to take the tablets are in the morning, afternoon and evening.

Cold sores
The cold sore packs are designed to help you to remember to take the tablets at the correct times.

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.

CMV
Unless your doctor tells you otherwise, take SHILOVA four times a day (i.e. morning, noon, afternoon and evening).

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.

How long to take them

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

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

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

Shingles
For shingles the usual course of treatment is seven days

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

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

CMV
Continue taking this medicine four times daily for the full course of the treatment.

The usual course of treatment is 90 days.

Do not stop taking your medicine before the course of treatment is finished unless advised by your doctor.

If you forget to take them

For treatment of genital herpes, shingles and CMV, 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.

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

If you take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone 131126) for advice, if you think you or anyone else may have taken too much SHILOVA tablets, even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Keep telephone numbers for these places handy.

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

While you are taking SHILOVA tablets

Things you must do

Tell your doctor or pharmacist that you are taking SHILOVA tablets if you are about to be started on any new medicines.

Tell your doctor if you become pregnant or are trying to become pregnant or intend to breastfeed while you are taking SHILOVA tablets.

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

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

Be careful driving or operating machinery until you know how SHILOVA tablets affect you.

Things you must not do

Do not stop taking SHILOVA tablets, or alter the dose, without first checking with your doctor.

Do not give this medicine to anyone else, even if their symptoms seem similar to yours.

Do not use SHILOVA tablets to treat any other complaints unless your doctor says to.

Side Effects

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

Like all medicines, SHILOVA tablets can cause some side effects. If they occur, they are most likely to be minor and temporary. However, some may be serious and need medical attention.

The most commonly reported side effects are:

  • headache
  • gastrointestinal discomfort (vomiting, nausea, diarrhoea, constipation, abdominal pain, indigestion)
  • sensitivity to UV light, such as the development of a rash or sunburn, even after short exposure

For patients taking SHILOVA 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.

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:

  • dry mouth
  • fever
  • difficulty sleeping
  • chills
  • back pain
  • nervousness
  • skin rash which may be itchy
  • weakness

Some people are allergic to medicines. Symptoms of an allergic reaction may be mild or severe. They usually include some or all of the following: wheezing, swelling of the lips/mouth, difficulty in breathing, hayfever, lumpy rash ("hives") or fainting.

If you think you are having an allergic reaction to SHILOVA tablets, stop taking the tablets and tell your doctor immediately or go to the casualty department at your nearest hospital.

This is not a complete list of all possible side effects. Others may occur in some people and there may be some side effects not yet known.

Some rare side effects of SHILOVA tablets include:

  • sensitivity to UV light, such as development of a rash like sunburn even after short exposure to UV light.
  • damage to the kidney, which gets better when SHILOVA 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.
  • Damage to the liver, which gets better when SHILOVA treatment is stopped.

You should contact your doctor if you experience any of the following side effects which are more common in patients with kidney disease or in those taking high doses of SHILOVA:

  • Dizziness
  • Confusion or imagining sights or sounds (hallucinations)
  • Drowsiness.

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

Ask your doctor or pharmacist if you don't understand anything in this list.

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

After taking SHILOVA tablets

Storage

Keep this medicine where young children cannot reach it.

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

Keep SHILOVA tablets in a cool, dry place where it stays below 25°C. Do not store them, or any other medicine, in a bathroom or near a sink.

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

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.

Disposal

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

Product Description

What SHILOVA tablets look like

SHILOVA 500 is presented in pack size of 10,30 &90 tablets in blister and 30, 100 & 500 in bottle.

SHILOVA 1000 is presented in pack size of 10 & 30 tablets in blister and 30, 100 & 500 in bottle.

SHILOVA 500
Blue, film-coated, capsule shaped tablets with a partial scorebar on both sides containing ‘F’ on one side and ‘9’ and ‘3’ on the other side.

SHILOVA 1000
Blue, film-coated, capsule shaped tablets with a partial scorebar on both sides containing ‘F’ on one side and ‘8’ and ‘3’ on the other side..

Ingredients

Active Ingredient:
Valaciclovir (as hydrochloride)

Each tablet contains either 500 mg or 1000 mg of valaciclovir as hydrochloride.

Other Ingredients:

  • microcrystalline cellulose
  • crospovidone
  • povidone
  • magnesium stearate
  • opadry blue 13B50578 (PI-ARTG No. 106487).

Please read this leaflet carefully before you start taking SHILOVA. You may wish to keep it to read again.

Name and Address of the Sponsor

Aurobindo Pharma Australia Pty Ltd
Unit 3 North Rydelink
277-283 Lane Cove Road
Macquarie Park NSW 2113
Australia

Date of Approval

18 October 2011

BRAND INFORMATION

Brand name

Shilova Tablets

Active ingredient

Valaciclovir

Schedule

S4

 

Name of the medicine

Valaciclovir (hydrochloride).

Excipients.

Microcrystalline cellulose, crospovidone, povidone, magnesium stearate and opadry blue 13B50578.

Description

Chemical name: 2-[(2-amino- 6-oxo- 1,6-dihydro-9H-purin- 9-yl) methoxy] ethyl-L-valinate hydrochloride. Molecular formula: C13H21ClN6O4.xH2O. MW: 360.8 (anhydrous). CAS: 124832-27-5 (anhydrous). Valaciclovir is the L-valine ester of aciclovir. Aciclovir is a purine nucleoside analogue.
Valaciclovir hydrochloride is a white or almost white powder, hygroscopic. It is freely soluble in water, very slightly soluble in anhydrous ethanol, practically insoluble in acetonitrile.
Inactive: microcrystalline cellulose, crospovidone, povidone, magnesium stearate and opadry blue 13B50578.

Pharmacology

Mode 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 micromolar), varicella zoster virus (VZV) (IC50 1.6-5.1 micromolar) and human cytomegalovirus (HCMV) (IC50 10 - > 200 micromolar). 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.

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 micromolar (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 1.6 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 (Cmax) and area under the aciclovir concentration time curve (AUC) after single dose administration of 100 mg, 250 mg, 500 mg, 750 mg, and 1 gram of valaciclovir to 8 healthy volunteers resulted in the mean Cmax (± SD) of 0.83 (± 0.14), 2.15 (± 0.50), 3.28 (± 0.83), 4.17 (± 1.14), and 5.65 (± 2.37) microgram/mL, respectively; and a mean AUC (± SD) of 2.28 (± 0.40), 5.76 (± 0.60), 11.59 (± 1.79), 14.11 (± 3.54), and 19.52 (± 6.04) hr.microgram/mL, respectively.
Similarly aciclovir Cmax and AUC after the multiple dose administration of 250 mg, 500 mg, and 1 gram of valaciclovir administered 4 times daily for 11 days in parallel groups of 8 healthy volunteers resulted in a mean Cmax (± SD) of 2.11 (± 0.33), 3.69 (± 0.87), and 4.96 (± 0.64) microgram/mL, respectively, and a mean AUC (± SD) of 5.66 (± 1.09), 9.88 (± 2.01), and 15.70 (± 2.27) hr.microgram/mL, respectively.

Distribution.

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

Elimination.

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 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 Precautions).

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 Dosage and Administration).

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.
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.
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 is 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 aciclovir (n = 320) for 10 days. The median time to lesion healing was 9 days in each treatment group. The median time to the cessation of viral shedding was 3 days in each treatment group. Median time to cessation of pain was 5 days in each treatment group.

Recurrent genital herpes simplex infections.

The other three studies enrolled immunocompetent patients with a history of recurrent genital herpes infections. These studies compared valaciclovir (1000 mg and/or 500 mg twice daily) with aciclovir (200 mg five times daily) and/or placebo, administered for 5 days. Patients self initiated therapy within 24 hours of the first sign or symptom of a recurrent genital herpes episode.
The primary efficacy endpoints in each study were: lesions healing time and pain/ discomfort; proportions of patients in whom lesions were prevented (aborted lesions); viral shedding.
In one study, patients were randomized to receive five days of treatment with either valaciclovir 500 mg bid (n = 360) or placebo (n = 259).

Duration of lesions.

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

Cessation of viral shedding.

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

Cessation of pain.

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

Prevention of lesion development (aborted episodes).

Pooled analysis of the three studies also showed that the use of valaciclovir in patients who self initiated treatment in the prodrome, increased the chances of preventing lesion development (aborting episodes) by 31% to 44% compared with placebo.

Prevention of recurrent genital herpes simplex virus (HSV) infections.

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 2.
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. Treatment was administered to 1484 couples 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.
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).

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.

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 valaciclovir, it is recommended that patients use safer sex practices. (see Precautions).
Prophylaxis of cytomegalovirus (CMV) infection and disease following solid organ transplantation in patients at risk of CMV disease.

Contraindications

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

Precautions

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.

Use in patients with renal impairment.

The dose of valaciclovir must be reduced in patients with renal impairment (see Dosage and Administration). Valaciclovir is converted to aciclovir which is eliminated by renal clearance (see Pharmacology). 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 Adverse Effects).

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

There is 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.

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.

Use in pregnancy.

(Category B3)
Valaciclovir was not teratogenic in rats or rabbits given oral doses of 400 mg/kg (which results in exposures of 1.1 and 2.0 times (HZV) and 0.4 and 0.7 times (CMV) human exposure, respectively, based on body surface area) during the period of major organogenesis. Aciclovir was not teratogenic in the mouse (450 mg/kg PO), rabbit (50 mg/kg SC and IV) or rat (50 mg/kg SC) when dosed throughout the period of organogenesis. Plasma concentrations of aciclovir in the rat were 3.5 (HZV) and 0.8 (CMV) times human concentrations. In additional studies in which rats were given three SC doses of 100 mg/kg aciclovir on gestation day 10, foetal abnormalities, such as head and tail anomalies, were reported. Plasma concentrations of aciclovir in the rat were 19 (HZV) and 4.3 (CMV) times human concentrations.
There are no adequate and well controlled studies of valaciclovir or aciclovir in pregnant women. A prospective epidemiologic registry of aciclovir use during pregnancy has been ongoing since June 1984. Pregnancy registries have documented the pregnancy outcomes in women exposed to valaciclovir or to any formulation of aciclovir (the active metabolite of valaciclovir); 111 and 1246 outcomes (29 and 756 exposed during the first trimester of pregnancy), respectively, were obtained from women prospectively registered. Registry findings do not indicate an increased risk of major birth defects after aciclovir exposure in comparison with the general population. The accumulated case histories represent an insufficient sample for reaching reliable and definitive conclusions regarding the risk associated with aciclovir exposure during pregnancy. The daily aciclovir AUCs (area under plasma concentration time curve) following valaciclovir 1000 mg and 8000 mg daily would be approximately 2 and 9 times greater than that expected with oral aciclovir 1000 mg daily, respectively.
There is limited data on the use of valaciclovir in pregnancy. Valaciclovir should only be used in pregnancy if the potential benefit outweighs the potential risk.
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.

Use in lactation.

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 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 breastfeeding mother. Valaciclovir should only be administered to breastfeeding mothers if the benefits to the mother outweigh the potential risks to the baby.

Use in children.

Safety and effectiveness in children have not been established.

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 Adverse Effects).

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 & 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.

Hydration status.

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

Information for patients.

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

Use in 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 is 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 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.

Driving.

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.

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.

Interactions

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

Adverse 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.

The following table 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 Precautions).
*Leukopenia is mainly reported in immunocompromised patients.

Immune system disorders.

Anaphylaxis.

Psychiatric and nervous system disorders.

Decreased consciousness*, dizziness*, confusion* and hallucinations*, coma*, agitation*, tremor*, ataxia*, dysarthia*, psychotic symptoms*, convulsions*, encephalopathy*.
*The above events are generally reversible and usually in patients with renal impairment or with other predisposing factors (see Precautions). In organ transplant adult patients receiving high doses (8 grams daily) of valaciclovir for CMV prophylaxis, neurological reactions occurred more frequently compared with lower doses.

Respiratory, thoracic and mediastinal disorders.

Dyspnoea.

Gastrointestinal tract.

Abdominal discomfort, vomiting and diarrhoea.

Hepato-biliary disorders.

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

Skin and subcutaneous tissue disorders.

Rashes including photosensitivity, pruritus, urticaria, angioedema.

Renal and urinary disorders.

Renal impairment, acute renal failure, renal pain (renal pain may be associated with renal failure).

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.

Dosage and Administration

Dosage in adults.

For treatment of herpes zoster, 1000 mg of valaciclovir three times a day for seven days.
The recommended dosage of 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).
For treatment of first clinical presentation of genital herpes, 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.

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 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.

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

The dosage of 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 Dosage in renal impairment).

Dosage in renal impairment.

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

Treatment of herpes zoster and genital herpes simplex.

The dose of valaciclovir should be modified as follows in patients with significantly impaired renal function.

Treatment of herpes labialis.

The dose of valaciclovir should be modified as follows in patients with significantly impaired renal function.
In patients on haemodialysis the valaciclovir dose recommended for patients with a creatinine clearance of less than 15 mL/min should be used, but the dose should be administered after the haemodialysis has been performed.

CMV prophylaxis.

The dosage of valaciclovir should be adjusted in patients with impaired renal function as shown in Table 11.
The creatinine clearance should be monitored frequently, especially during periods when renal function is changing rapidly e.g. immediately after transplantation or engraftment. The valaciclovir dosage should be adjusted accordingly.

Dosage in hepatic impairment.

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

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 Dosage in renal impairment). Adequate hydration should be maintained.

Overdosage

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.
For information on the management of overdose, contact the Poisons Information Centre on 131 126.

Presentation

Tablets (blue, capsule shaped, film coated, with a partial scorebar containing F on one side), 500 mg (with a partial scorebar containing 9 and 3 on reverse): 10's*, 30's, 90's* (blister pack, AUST R 173283); 30's, 100's, 500's (bottle*, AUST R 173290); 1000 mg* (with a partial scorebar containing 8 and 3 on reverse): 10's, 30's (blister pack, AUST R 173288); 30's, 100's, 500's (bottle, AUST R 173286).
*Not currently marketed in Australia.

Storage

Store below 25°C. Store in a dry place.

Poison Schedule

S4.