Consumer medicine information

APO-Valaciclovir for herpes zoster, ophthalmic zoster and herpes labialis

Valaciclovir

BRAND INFORMATION

Brand name

APO-Valaciclovir

Active ingredient

Valaciclovir

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APO-Valaciclovir for herpes zoster, ophthalmic zoster and herpes labialis.

What is in this leaflet

This leaflet answers some common questions about valaciclovir. 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 using 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 your medicine. You may want to read it again.

What this medicine is used for

Valaciclovir is used to treat:

  • shingles (herpes zoster)
  • shingles affecting the eye region (ophthalmic zoster)
  • cold sores (herpes labialis)

It belongs to a group of medicines called antivirals.

How it works

Valaciclovir works by stopping the multiplication of the virus which causes shingles and cold sores. It can reduce the length and severity of an outbreak, as well as reduce the duration of pain associated with shingles and cold sores.

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

For the treatment of cold sores, the tablets should be taken at the earliest symptom of a cold sore (e.g. tingling, itching, or burning).

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

Valaciclovir is more effective in patients 50 years of age and older.

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

This medicine is not addictive.

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

Before you take this medicine

When you must not take it

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

  • valaciclovir
  • aciclovir
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue, throat 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 or pharmacist.

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 or liver disease
  • anaemia (reduced red blood cells or iron stores)

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

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

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

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 interfere with each other. These include:

  • mycophenolate mofetil, cyclosporin and tacrolimus, medicines taken for organ transplantation
  • aminoglycoside antibiotics, such as gentamicin
  • pentamidine, used to treat or prevent certain infections
  • foscarnet, used against viruses
  • methotrexate, used for conditions such as rheumatoid arthritis
  • organoplatinum compounds, used in cancer
  • iodine based contrast media for scans

These medicines may be affected by this medicine 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.

Other medicines not listed above may also interact with valaciclovir.

How to take this medicine

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

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

How much to take

Shingles (herpes zoster), including shingles affecting the eye region (ophthalmic zosters):
The usual dose is two 500 mg tablets taken three times a day, or one 1000 mg tablet taken three times a day.

Cold sores (herpes labialis):
The usual dose for the one-day regimen is four 500 mg tablets taken twice a day, or two 1000 mg tablets taken twice a day. The second dose is taken about 12 hours after the first dose.

How to take it

Swallow the tablets whole with a full glass of water. You should drink plenty of fluids whilst taking valaciclovir, especially if you are elderly.

When to take it

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.

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

How long to take it for

Continue taking your medicine for as long as your doctor tells you.

Shingles (herpes zoster), including shingles affecting the eye region (ophthalmic zosters):
The usual course of treatment is seven days.

Do not stop taking it unless your doctor tells you to, even if you feel better.

Make sure you have enough to last over weekends and holidays.

Cold sores (herpes labialis):
The course of treatment should not exceed one day (2 doses) and the doses should be taken 12 hours apart.

If you forget to take it

Shingles (herpes zoster), including ophthalmic zosters (shingles affecting the eye region):
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 your medicine as you would normally.

Cold sores (herpes labialis):
Take the second dose as soon as possible once 12 hours have passed.

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

Do not take a double dose to make up for missed doses. This may increase the chance of side effects.

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

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 your nearest hospital, if you think that you or anyone else may have taken too much of this medicine. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Signs of an overdose with valaciclovir may include:

  • acute renal failure, which may present as: decreased urine; fluid retention causing swollen legs, ankles or feet; nausea; drowsiness; fatigue; difficulties breathing.
  • confusion, hallucinations, agitation, decreased consciousness and coma.
  • nausea and vomiting

While you are taking this medicine

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.

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

If you become pregnant while you are taking valaciclovir, tell your doctor immediately.

If you are about to have any blood tests, tell your doctor that you are taking this medicine.

Keep all of your doctor's appointments so that your progress can be checked. Your doctor may occasionally do tests to make sure the medicine is working and to prevent side effects.

Things you must not do

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

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

Do not stop taking your medicine, or change the dosage, without first checking with your doctor.

Things to be careful of

Be careful when driving or operating machinery until you know how valaciclovir affects you. This medicine may cause dizziness 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.

Side effects

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

This medicine helps most people, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. 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 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 if you notice any of the following:

  • headache
  • gastrointestinal discomfort (vomiting, nausea, diarrhoea, constipation, flatulence, abdominal pain, indigestion)
  • dry mouth
  • nervousness
  • drowsiness
  • increase in blood pressure
  • swelling
  • difficulty sleeping
  • muscle aches, pain or weakness

The above list includes the more common side effects of your medicine.

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

  • decreased consciousness, dizziness, weakness
  • fever, chills, infections or flu like symptoms
  • back or joint pain
  • skin rash, which may be itchy
  • sensitivity to UV light, such as development of a rash like sunburn even after short exposure to UV light

The above list includes serious side effects that may need medical attention.

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

  • allergic reaction, which may present as: shortness of breath; wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body;
  • damage to the kidney, which may present as: decreased urine; fluid retention causing swollen legs, ankles or feet; nausea; drowsiness; fatigue; difficulties breathing
  • damage to the liver, which may present as: nausea and vomiting; loss of appetite; feeling generally unwell; fever; itching; yellowing of the skin and eyes; dark coloured urine
  • unusual bruising or bleeding, which may indicate that the number of platelets (a type of blood cell responsible for blood clotting) in your blood are reduced
  • coma
  • agitation, tremor
  • uncoordinated eye and muscle movements, difficulty speaking
  • confusion, difficulty thinking, imagining sights or sounds (hallucinations), psychotic episodes
  • convulsions or seizures.

These are very serious side effects and you may need urgent medical attention or hospitalisation.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may occur in some patients.

Storage and disposal

Storage

Keep your tablets in the pack until it is time to take them. If you take the tablets out of the pack they may not keep well.

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

Do not store your medicine 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 APO-Valaciclovir looks like

500 mg tablets
Dark blue, capsule-shaped, biconvex film-coated tablets, engraved "APO" on one side, "VAL 500" on the other side.

Blisters of 2, 4, 6, 8, 10, 20, 30, 42, 60, 80, 90, 100 tablets and bottles of 100 tablets.

1000 mg tablets
White, oval shaped, biconvex film-coated tablet, partially scored and engraved "APO" on one side, "VAL 1000" on the other side.

Blisters of 3, 4, 21 tablets and bottles of 100 tablets.

Not all strengths, pack types and/or pack sizes may be available.

Ingredients

Each tablet contains valaciclovir as the active ingredient.

It also contains the following:

  • Stearic Acid
  • Colloidal Anhydrous Silica
  • Hypromellose
  • Macrogol 8000
  • Titanium Dioxide
  • Indigo Carmine Aluminium Lake

This medicine is free from gluten, lactose, sucrose, tartrazine and other azo dyes.

Australian Registration Numbers

APO-Valaciclovir 500 mg tablets (blister pack): AUST R 158911

APO-Valaciclovir 500 mg tablets (bottle): AUST R 158910

APO-Valaciclovir 1000 mg tablets (bottle): AUST R 158907

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park, NSW 2113

APO and APOTEX are registered trade marks of Apotex Inc.

This leaflet prepared in July 2018.

Published by MIMS October 2018

BRAND INFORMATION

Brand name

APO-Valaciclovir

Active ingredient

Valaciclovir

Schedule

S4

 

1 Name of Medicine

Valaciclovir hydrochloride monohydrate.

6.7 Physicochemical Properties

Chemical name: (1) L-Valine, 2-[(2-amino-1,6-dihydro- 6-oxo-9H-purin-9-yl) methoxy] ethylester, monohydrochloride (2) L-Valine, ester with 9-[(2-hydroxyethoxy) methyl] guanine, monohydrochloride.
Chemical Formula: C13H20N6O4, HCl.H2O.
Molecular Weight: 378.8.

Chemical structure.


CAS number.

124832-27-5.

2 Qualitative and Quantitative Composition

Valaciclovir is the L-valine ester of aciclovir. Aciclovir is a purine nucleoside analogue. The maximum solubility of valaciclovir hydrochloride monohydrate in water is 174 mg/mL at 25°C.
Each tablet contains 500 mg or 1000 mg of valaciclovir, as the active ingredient. In addition, each tablet contains the following inactive ingredients: Stearic acid, colloidal anhydrous silica, Hypromellose, Macrogol 8000, titanium dioxide, indigo carmine aluminium lake (500 mg tablet only).

3 Pharmaceutical Form

500 mg tablets.

Dark blue, capsule-shaped, biconvex film-coated tablets, engraved "APO" on one side, "VAL 500" on the other side.

1000 mg tablets.

White, oval shaped, biconvex film coated-tablet, partially scored and engraved "APO" on one side, "VAL 1000" on the other side.

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.

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

Clinical trials.

Herpes zoster infections.

Two doses of valaciclovir were compared to aciclovir in a double blind randomised trial in immunocompetent patients aged 50 years and over with herpes zoster (n = 1141). All patients were treated within 72 hours of the appearance of the rash. Valaciclovir 1 g three times daily for seven days achieved statistically significant reductions in the duration of zoster associated pain (which is the sum of acute pain and post-herpetic neuralgia) and in the duration of post-herpetic neuralgia when compared with aciclovir. There was no statistically significant difference between the three treatments for the resolution of rash (see Table 9).
There was no significant difference to the duration of zoster associated pain when treatment was started within 48 hours or 72 hours. Patients treated within 48 hours of rash onset were found to have faster healing rates as measured by the duration of new lesion formation and time to crusting or healing of 50% or more of lesions. Thus, greater benefit is gained if the drug is started within 48 hours (see Figure 1).
In a second, placebo controlled trial in patients under 50 years of age (n = 399), demonstration of efficacy was restricted to a small decrease in mean time to cessation of new lesion formation. No significant effects were demonstrated for other outcomes of herpes zoster in this age group. Nevertheless, the occasional younger patients with severe herpes zoster may benefit from therapy with valaciclovir. Herpes zoster is usually a milder condition in younger patients.
In ophthalmic zoster oral aciclovir has been shown to reduce the incidence of stromal keratitis and both the incidence and severity of anterior uveitis but not other ocular complications or acute pain. The recommended dose of valaciclovir produces higher plasma concentrations of aciclovir than those associated with these beneficial effects.

Cold sores (herpes labialis).

Two double blind, placebo controlled clinical trials were conducted in 1856 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 into 3 groups: valaciclovir 2 grams twice daily for one day or valaciclovir 2 grams twice daily for one day, followed by 1 gram twice daily on day 2, or placebo on both days.
An integrated analysis of both trials showed a statistically significant prevention/ blockage of onset of lesions in 44% of patients on one day therapy compared to 37% receiving placebo. The mean duration of cold sores in the integrated analysis showed a significant reduction in duration of approximately 1 day when compared to placebo. The ITT population showed the mean duration of episodes was 6.2 days in the placebo group, and 5.2 days in the 1 day group giving a treatment difference of -1.0 day (CI -1.4, -0.6).
The single study results showed the mean duration of cold sore episodes was approximately 1 day shorter in treated subjects when compared to placebo. For the ITT population, when tested as the primary endpoint, the mean duration of episodes was 6.1 days in the placebo group and 5.0 days in the 1 day group, giving a treatment difference of -1.1 days (CI -1.6, -0.6). When tested as the secondary endpoint, For the ITT population, the mean duration of episodes was 6.3 days in the placebo group and 5.3 days in the 1 day group, giving a treatment difference of -1.0 days (CI -1.5, -0.5).
The onset of lesions was prevented in the 43-44% of patients on one day valaciclovir therapy compared with 35-38% placebo treated patients. No significant difference was observed between subjects receiving valaciclovir or placebo in the prevention of progression of cold sore lesions beyond the papular stage when tested as the primary or secondary endpoint.
There are no data on the effectiveness of treatment initiated after the development of clinical signs of a cold sore i.e. papule, vesicle or ulcer. The 2 day regimen did not offer additional benefit over the 1 day regimen.
The data are based on treatment of a single episode of herpes labialis.

Acute treatment of initial and recurrent herpes simplex virus (HSV) infections.

Four large multicentre, randomised double blind trials were conducted in adults with herpes simplex infections. These studies included a total of 3569 treated patients of whom 1941 received valaciclovir.

Initial genital herpes simplex infections.

One study compared valaciclovir (1000 mg twice daily) with aciclovir (200 mg five times daily) administered for 10 days in immunocompetent patients with initial (primary or first episode) genital herpes. Patients reported to the clinic for treatment within 72 hours of the first signs or symptoms of genital herpes.
Patients were randomized to receive valaciclovir (n = 323) or Zovirax (n = 320) for 10 days. The median time to lesion healing was 9 days in each treatment group. The median time to the cessation of viral shedding was 3 days in each treatment group. Median time to cessation of pain was 5 days in each treatment group.

Recurrent genital herpes simplex infections.

The other three studies enrolled immunocompetent patients with a history of recurrent genital herpes infections. These studies compared valaciclovir (1000 mg and/or 500 mg twice daily) with aciclovir (200 mg five times daily) and/or placebo, administered for 5 days. Patients self initiated therapy within 24 hours of the first sign or symptom of a recurrent genital herpes episode.
The primary efficacy 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 acyclovir 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 Table 10.
Results show that 250 mg twice daily offered the best clinical efficacy for suppression of genital herpes recurrences in this group of patients. However, the same total daily dose given as single daily dose (i.e. 500 mg once daily) was also very effective, as confirmed with Study BQRT/95/0026.
Although 1000 mg daily was more effective than 500 mg once daily in the first study, the marginal difference between the two did not justify long term exposure to double the daily dose. The hazard ratio comparing valaciclovir 1000 mg once daily and 500mg once daily indicated an increase in efficacy of only approximately 12% (hazard ratio 0.879, 95% CI 0.637, 1.211).

Immunocompromised patients.

A study examined a total of 1062 immunocompromised patients (HIV infected, CD4+ counts of ≥ 100/mm3 at enrolment) of whom 713 received valaciclovir (1000 mg once daily, 500 mg twice daily, 48 weeks) compared with 349 patients who received aciclovir (400 mg twice daily, 48 weeks). The primary endpoint was the time to first HSV recurrence (onset of macules/ papules). The study demonstrated that valaciclovir 500 mg twice daily is as effective as aciclovir in preventing or delaying HSV infections in immunocompromised patients. Valaciclovir 500 mg twice daily was significantly more efficacious than valaciclovir 1000 mg once daily.

Reduction of genital herpes simplex virus transmission.

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, nonherpes virus) was also lower in the valaciclovir group throughout the entire study period (valaciclovir 36%, aciclovir 62%). There were no significant differences in graft rejection and survival rates between the valaciclovir and aciclovir patients at the end of the study (3 months following treatment period) (see Table 11).

Bone marrow transplant studies.

Two additional clinical studies have been conducted to assess the safety and efficacy of valaciclovir in the prophylaxis of CMV infection in bone marrow transplant recipients. The adverse event data from these trials is consistent with the current safety profile of valaciclovir.

5.2 Pharmacokinetic Properties

Absorption.

After oral administration valaciclovir is well absorbed and rapidly and almost completely converted to aciclovir and valine. This conversion is probably mediated by valaciclovir hydrolase, an enzyme isolated from human liver. Mean peak aciclovir concentrations are 10-37 microM (2.2-8.3 microgram/mL) following single doses of 250-2000 mg valaciclovir to healthy subjects with normal renal function and occur at a median time of 1.00-2.00 hours post dose. The time to peak (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 Section 5.2 Pharmacokinetic Properties, 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.

Excretion.

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

Characteristics in patients.

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

Special populations.

Renal impairment.

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

Hepatic impairment.

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

HIV infection.

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

Elderly.

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

Endstage renal disease (ESRD).

Following administration of valaciclovir to volunteers with ESRD, the average acyclovir half-life is approximately 14 hours. During haemodialysis, the acyclovir half-life is approximately 4 hours. Approximately one third of acyclovir in the body is removed by dialysis during a 4 hour haemodialysis session. Apparent plasma clearance of acyclovir 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.

5.3 Preclinical Safety Data

Genotoxicity.

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

Carcinogenicity.

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

4 Clinical Particulars

4.1 Therapeutic Indications

For the treatment of herpes zoster (shingles) in adult patients who commence therapy within 72 hours of the onset of rash.
For the treatment of ophthalmic zoster.
For the treatment of recurrent herpes labialis (cold sores).
For the treatment of clinical episodes of genital herpes simplex infections.
For the prevention of recurrent genital herpes in immunocompromised patients.
Prophylaxis of cytomegalovirus (CMV) infection and disease following solid organ transplantation in patients at risk of CMV disease.

4.3 Contraindications

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

4.4 Special Warnings and Precautions for Use

Identified 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.

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

Use in genital herpes.

Patients should be advised to avoid intercourse when symptoms are present even if treatment with an antiviral has been initiated. Continuous therapy with 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.

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 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.

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 5.1 Pharmacodynamic 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)).

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

Effect on fertility.

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

4.8 Adverse Effects (Undesirable Effects)

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

Herpes zoster infections.

Table 4 lists all adverse events reported during a six month observation period in immunocompetent patients receiving short-term treatment (7 or 14 days) with valaciclovir and reference products in controlled clinical trials.

HSV infections.

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

The adverse events reported by greater than 2% of a given treatment group in the initial and recurrent genital herpes clinical trials with valaciclovir and reference products used in the trials are listed in Table 5.

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

The adverse events reported at an incidence of 5% or greater in a given treatment group, in clinical trials for the preventative treatment of genital herpes with valaciclovir and reference products, are listed in Table 6.

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

Valaciclovir was well tolerated in the clinical studies of renal and heart transplant patients. The nature and frequency of adverse events were similar between placebo, aciclovir and valaciclovir treated patients, with the exception of adverse events relating to the CNS (hallucinations, confusion and thinking abnormality). These were reported more frequently in valaciclovir than placebo in renal transplant patients. The most common adverse events reported in the renal transplant patients were anaemia, hypertension and headache. Headache and myalgia were the most common adverse events reported in the heart transplant patients. All the clinical adverse events occurring at an incidence of > 5% or > 20% in a given treatment group, in clinical trials for CMV prophylaxis following renal and heart transplants respectively are listed in the following. See Tables 7 and 8.

Cold sores (herpes labialis).

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

Post marketing experience.

The following adverse events have been observed during post-approval use of valaciclovir.

Blood and lymphatic system disorders.

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

Immune system disorders.

Anaphylaxis.

Psychiatric and nervous system disorders.

Decreased consciousness*, dizziness*, confusion* and hallucinations*, 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 (see Section 4.4 Special Warnings and Precautions for Use). In organ transplant 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 diarrhea.

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

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.2 Dose and Method of 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 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 the prevention of genital herpes in immunocompromised patients, 500 mg twice daily.

For the prophylaxis of cytomegalovirus (CMV) infection and disease.

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

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

Dosage in renal impairment.

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

Treatment of herpes zoster and genital herpes simplex.

The dose of valaciclovir should be modified as follows in patients with significantly impaired renal function. See Table 1.

Treatment of herpes labialis.

The dose of valaciclovir should be modified as follows in patients with significantly impaired renal function. See Table 2.
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 3.
The creatinine clearance should be monitored frequently, especially during periods when renal function is changing rapidly e.g. immediately after transplantation or engraftment. The valaciclovir dosage should be adjusted accordingly.

Dosage in hepatic impairment.

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

Dosage in children.

No data are available.

Dosage in the elderly.

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

4.7 Effects on Ability to Drive and Use Machines

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

4.9 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.

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 Poison Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

In Australia, the 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

500 mg tablets.

Available in blisters of 2, 4, 6, 8, 10, 20, 30, 42, 60, 80, 90, 100, 240, 480 tablets.
AUST R 158911.
In bottles of 100, 240, 480, 50 tablets.
AUST R 158910.

1000 mg tablets.

In bottles of 100, 250 tablets.
AUST R 158907.
*Not all strengths, pack types and/or pack sizes may be available.

6.6 Special Precautions for Disposal

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

Summary Table of Changes