Consumer medicine information

VALNIR Treatment of herpes simplex

Valaciclovir

BRAND INFORMATION

Brand name

Valnir

Active ingredient

Valaciclovir

Schedule

What is in this leaflet

This leaflet answers some common questions about VALNIR.

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 benefits and risks. Your doctor has weighed the risks of you taking VALNIR against the benefits they expect it will have for you.

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

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

What VALNIR is used for

VALNIR is used to treat shingles (herpes zoster) and ophthalmic zoster (shingles affecting the eye region).

VALNIR contains valaciclovir (as valaciclovir hydrochloride) and belongs to a group of medicines called antivirals.

It works by stopping the multiplication of the virus which causes the shingles. VALNIR reduces the length and severity of an outbreak and the duration of pain associated with the shingles.

It is important to start treatment within three days of the shingles attack.

VALNIR tablets are more effective in patients 50 years and over.

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

VALNIR is not recommended for use in children as there have been no studies of its effects in children.

VALNIR is available only with a doctor’s prescription.

There is no evidence that it is addictive.

Before you take it

When you must not take it

Do not take VALNIR if you are allergic to medicines containing valaciclovir, aciclovir or any of the ingredients listed at the end of this leaflet. Some of the symptoms of an allergic reaction may include skin rash, itching or hives, swelling of the face, lips or tongue which may cause difficulty in swallowing or breathing, wheezing or shortness of breath or fainting.

Do not take VALNIR if the expiry date (Exp.) printed on the pack has passed.

Do not take VALNIR if the packaging is torn or shows signs of tampering.

Before you start to take it

Tell your doctor if you are allergic to any other medicines, foods, dyes or preservatives

Tell your doctor if you are pregnant or plan to become pregnant. Your doctor will discuss the risks and benefits of taking VALNIR during pregnancy.

Tell your doctor if you are breastfeeding or wish to breastfeed. Your doctor will discuss the risks and benefits of taking VALNIR when breastfeeding.

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

anaemia
kidney or liver condition.

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

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you buy without a prescription from a pharmacy, supermarket or health food shop. Some medicines may be affected by VALNIR, or may affect how well it works.

Your doctor or pharmacist will be able to tell you what to do when taking VALNIR tablets with other medicines. Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking VALNIR.

How to take it

How much to take

Follow all directions given to you by your doctor. The usual dose is two 500 mg tablets three times a day.

How to take it

Swallow the tablets with a glass of water. If you forget to take it

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 the missed dose as soon as you remember, and then go back to taking your tablets as you would normally.

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

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

How long to take it

The usual course of treatment is seven days.

Do not stop taking VALNIR, even if you feel better after a few days, unless advised by your doctor. You must take the complete course. The shingles may not be completely over.

If you take too much (overdose)

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

While you are taking it

Things you must do

Before starting any new medicine, tell your doctor or pharmacist that you are taking VALNIR.

Tell all the doctors, dentists and pharmacists who are treating you that you are taking VALNIR.

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

Visit your doctor regularly so they can check on your progress.

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.

Drink plenty of fluids while you are taking VALNIR.

Things you must not do

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

Do not use VALNIR to treat any other conditions unless your doctor tells you to.

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

Things to be careful of

Be careful driving or operating machinery until you know how VALNIR affects you. VALNIR does not normally affect alertness; however make sure you know how it affects you before driving, operating machinery or anything else that could be dangerous whilst taking this medicine.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking VALNIR. Like all other medicines, VALNIR may have unwanted side effects in some people. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

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

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

headache
vomiting, nausea, diarrhoea, constipation, abdominal pain and indigestion
dry mouth
fever
difficulty sleeping
chills
back pain
nervousness
skin rash which may be itchy
muscle weakness.

If you think you are having an allergic reaction to VALNIR tablets stop taking the tablets and tell your doctor immediately or go to Accident and Emergency at the nearest hospital.

Symptoms of an allergic reaction may be mild or severe. They usually include some or all of the following:

swelling of the lips/mouth
difficulty in breathing
hay fever
lumpy rash (hives)
fainting.

Some rare side effects of VALNIR are as follows:

sensitivity to UV light, such as development of a rash like sunburn even after short exposure to UV light. Talk to your doctor or pharmacist if you experience this.
unusual bruising or bleeding.
Tell your doctor immediately if you notice any bruising or bleeding, as this may indicate that your blood is not clotting properly.
kidney problems, which get better when VALNIR treatment is stopped
liver problems, which get better when VALNIR treatment is stopped.

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

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

After taking it

Storage

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

Keep VALNIR 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.

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

Do not store VALNIR or any other medicine in the bathroom or near a sink. Do not leave VALNIR in the car or on window sills. Heat and dampness can destroy some medicines.

Disposal

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

Product description

What it looks like

VALNIR is a capsule shaped white tablet marked with ‘VA 500’ on one side and plain on the other side.

Each pack contains 10, 30 or 42 tablets.

Ingredients

Active ingredient:
Each VALNIR tablet contains 500 mg of valaciclovir (as valaciclovir hydrochloride).

Inactive ingredients:

microcrystalline cellulose
crospovidone
povidone
purified talc
magnesium stearate
Opadry II 85F18738 White
(ARTG 12135).

VALNIR tablets do not contain gluten, lactose, sucrose, tartrazine or any other azo dyes.

Sponsor

Aspen Pharma Pty Ltd
34-36 Chandos Street
St. Leonards NSW 2065
Australia

Australian registration number:
AUST R 147607

This leaflet was revised in November 2011.

Published by MIMS April 2014

BRAND INFORMATION

Brand name

Valnir

Active ingredient

Valaciclovir

Schedule

Name of the medicine

Valaciclovir hydrochloride.

Excipients.

Microcrystalline cellulose, crospovidone, povidone, purified talc, magnesium stearate and Opadry II 85F18378 White (ARTG 12135). The tablets are gluten free.

Description

Chemical name: 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl) methyoxy]ethyl-valinate hydrochloride. Molecular formula: C₁₃H₂₀N₆O₄.HCl. MW: 360.8. CAS: 124832-27-5. Valaciclovir hydrochloride is a white, crystalline powder which is odourless. It is freely soluble in water.

Pharmacology

Microbiology.

Valaciclovir is rapidly and almost completely converted in humans 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 I and type II (IC₅₀ 0.1 to 3.0 micromolar), varicella zoster virus (VZV) (IC₅₀ 1.6 to 5.1 micromolar) and human cytomegalovirus (HCMV) (IC₅₀ 10 to > 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 monophosphate 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.

Resistance Development.

Resistance of HSV and VZV to aciclovir can result from qualitative and quantitative changes in the viral (thymidine kinase) TK and/or DNA polymerase. Clinical isolates of VZV with reduced susceptibility to aciclovir have been recovered from patients with AIDS. In these cases, TK deficient mutants of VZV have been recovered.
Resistance of HSV and VZV to aciclovir occurs by the same mechanisms. While most of the aciclovir resistant mutants isolated thus far from immunocompromised patients have been found to be TK deficient mutants, other mutants involving the viral TK gene (TK partial and TK altered) and DNA polymerase have also been isolated. TK negative mutants may cause severe disease in immunocompromised patients. The possibility of viral resistance to valaciclovir (and therefore, to aciclovir) should be considered in patients who show poor clinical response during therapy.

Pharmacokinetics.

General characteristics.

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 to 37 micromolar (2.2 to 8.3 microgram/mL) following single doses of valaciclovir 250 to 2000 mg to healthy subjects with normal renal function and occur at a median time of 1.00 to 2.00 hours postdose. The time to peak concentration (T_max) is 1.6 hours for two 500 mg tablets and 1.9 hours for one 1,000 mg tablet. Aciclovir maximum concentration (C_max) and area under the aciclovir concentration time curve (AUC_(0-)) after single dose administration of 500 mg of Valnir (valaciclovir) to healthy volunteers resulted in the mean C_max (± SD) of 2874 (± 655) nanogram/mL, and a mean AUC_(0-) (± SD) of 9442.0 (± 2261) hr.nanogram/mL. The bioavailability of aciclovir following a dose of valaciclovir 1000 mg is 54% and is unaffected by food. Peak plasma concentrations of valaciclovir are only 4% of aciclovir levels, occur 30 to 100 minutes post dose, and are at or below the limit of quantification three hours after dosing. The valaciclovir and aciclovir pharmacokinetic profiles are similar after single and repeat dosing. Binding of aciclovir to plasma proteins is very low (9 to 33%).
In patients with normal renal function the plasma elimination half-life of aciclovir after both single and multiple dosing with valaciclovir is approximately three hours. In patients with endstage renal disease, the average elimination half-life of aciclovir after valaciclovir administration is approximately 14 hours. Less than 1% of the administered dose of valaciclovir is recovered in the urine as unchanged drug. Valaciclovir is eliminated principally as aciclovir (greater than 80% of the recovered dose) and the known aciclovir metabolite, 9-(carboxymethoxy)methylguanine (CMMG), in the urine.

Characteristics in patients.

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

End-Stage Renal Disease (ESRD)

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

Clinical Trials

Herpes zoster infections.

Two doses of valaciclovir were compared to aciclovir in a double blind randomised trial in immunocompetent patients aged 50 years and over with herpes zoster (n = 1141). All patients were treated within 72 hours of the appearance of the rash. Valaciclovir 1 g three times daily for seven days achieved statistically significant reductions in the duration of zoster associated pain (which is the sum of acute pain and postherpetic neuralgia) and in the duration of postherpetic neuralgia when compared with aciclovir (see Table 1). There was no statistically significant difference between the three treatments for the resolution of rash.

There was no significant difference in the duration of zoster associated pain when treatment was started within 48 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, an occasional younger patient with severe herpes zoster may benefit from therapy with valaciclovir. Herpes zoster is usually a milder condition in younger patients.
In ophthalmic zoster, oral aciclovir has been shown to reduce the incidence of stromal keratitis and both the incidence and severity of anterior uveitis, but not other ocular complications or acute pain. The recommended dose of valaciclovir produces higher plasma concentrations of aciclovir than those associated with these beneficial effects.

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

Four large, multicentre, randomised, double blind trials were conducted in adults with herpes simplex infections. These studies included a total of 3,569 treated patients of whom 1,941 received valaciclovir.

Initial genital herpes simplex infections.

One study compared valaciclovir 1000 mg twice daily with aciclovir 200 mg five times daily, administered for ten 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 randomised to receive valaciclovir (n = 323) or aciclovir (n = 320) for ten days. The median time to lesion healing was nine days in each treatment group. The median time to the cessation of viral shedding was three days in each treatment group. Median time to cessation of pain was five 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 five 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: lesion healing time and pain/ discomfort; proportion of patients in whom lesions were prevented (aborted lesions); viral shedding.
In one study, patients were randomised to receive five days of treatment with either valaciclovir 500 mg twice daily (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 (human immunodeficiency virus (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, once daily treatment with valaciclovir 500 mg was compared with placebo in patients with a history of at least eight 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 analysis was conducted according to recurrence history. The results from the proportional hazards analyses (hazard ratios and 95% confidence interval (CI)) for the active treatment comparisons with placebo obtained within each subgroup are presented in Table 2.

Results show that valaciclovir 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. valaciclovir 500 mg once daily) was also very effective, as confirmed with study BQRT/95/0026.
Although valaciclovir 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 greater than or equal to 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 ten recurrences per year. Susceptible partners could not be seropostive 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 versus 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 valaciclovir 2 g 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 three 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 versus 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 (three 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 (three months following treatment period). The results for the primary and secondary endpoints in the pivotal trials are presented in Table 3.

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 are consistent with the current safety profile of valaciclovir.

Indications

Treatment of herpes zoster (shingles) in adult patients who commence therapy within 72 hours of the onset of rash; treatment of ophthalmic zoster; treatment of clinical episodes of genital herpes simplex infections; prevention of recurrent genital herpes; reduction of transmission of genital herpes in patients suffering from recurrent genital herpes. In addition to therapy with Valnir, 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

Known hypersensitivity to valaciclovir, aciclovir or any component of the formulation.

Precautions

Thrombotic thrombocytopenic purpura or haemolytic uraemic syndrome, in some cases resulting in death, has occured in patients with advanced human immunodeficiency virus (HIV) disease who were treated with valaciclovir for prolonged periods and also in allogeneic bone marrow transplant and renal transplant recipients who were treated with valaciclovir while participating in clinical trials at doses of 8 g per day.
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 occurences 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.

Use in genital herpes.

Continuous therapy with Valnir 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 Valnir, it is recommended that patients use safer sex practices.

Impaired renal function.

The dose of valaciclovir must be reduced in patients with renal impairment (see Dosage and Administration). Aciclovir delivered by valaciclovir 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).
Precipitation of aciclovir in renal tubules may occur when the solubility (2.5 mg/mL) is exceeded in the intratubular fluid. Adequate hydration should be maintained. In the event of acute renal failure and anuria, the patient may benefit from hemodialysis until renal function is restored (see Dosage and Administration).

Impaired hepatic function.

There are no data available on the use of high doses of valaciclovir (8 g/day) in patients with liver disease. Caution should therefore be exercised when administering high doses of valaciclovir to these patients. Specific studies of valaciclovir have not been conducted in liver transplantation, however high dose aciclovir has been studied in this population.

Effects on fertility.

Teratogenesis.

Valaciclovir was not teratogenic in rats or rabbits given oral doses of 400 mg/kg (which results in exposures of 1.1 and 2.0 times (HZV) and 0.4 and 0.7 times (CMV) human exposure, respectively, based on body surface area) during the period of major organogenesis. Aciclovir was not teratogenic in the mouse (oral dose of 450 mg/kg/day), rabbit (subcutaneous and intravenous dose of 50 mg/kg/day) or rat (subcutaneous dose of 50 mg/kg/day) when dosed throughout the period of organogenesis. Plasma concentrations of aciclovir in the rat were 3.5 (VZV) and 0.8 (CMV) times human concentrations. In additional studies in which rats were given three subcutaneous doses of aciclovir 100 mg/kg on gestation day 10, fetal 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.
Valaciclovir did not impair fertility or reproduction in rats at 200 mg/kg/day, corresponding to plasma levels 2.8 (VZV) and 0.3 (CMV) times human plasma concentrations (AUC).

Use in pregnancy.

(Category B3)
There are no adequate and well controlled studies of valaciclovir or aciclovir in pregnant women. A prospective epidemiological registry of aciclovir use during pregnancy has been ongoing since June 1984. As of July 1998, outcomes of live births have been documented in 574 women exposed to systemic aciclovir during the first trimester of pregnancy (most at oral doses up to 1000 mg/day). 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.

Use in lactation.

Lactating rats given an oral dose of ¹⁴C-valaciclovir 25 mg/kg showed peak milk radioactivity levels of 26 microgram/eq/g two hours postdose. The milk radioactivity levels declined more slowly than in plasma and were undetectable at 12 hours. Suckling pups had radioactivity in the stomach and intestinal contents up to seven hours postdose, but not in tissues.
Limited data show that aciclovir does pass into human breast milk. Aciclovir has been detected in breast milk at concentrations ranging from 0.6 to 4.1 times the corresponding aciclovir plasma concentrations. Caution is therefore advised if valaciclovir is to be administered to a breastfeeding mother. Valnir should only be administered to breastfeeding mothers if the benefits to the mother outweigh the potential risks to the baby.

Paediatric use.

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).
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.

Carcinogenicity.

The data presented below include references to the steady state aciclovir AUC observed in humans treated with valaciclovir 1 g given orally three times a day to treat herpes zoster (HZV) or with valaciclovir 2 g 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 (CMV) times human levels in the mouse bioassay and 1.3 (HZV) and 0.1 (CMV) times human concentrations in the rat bioassay.

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 greater than or equal to 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 four microbial assays. Positive results were obtained in two of seven genetic toxicity assays using mammalian cells in vitro (positive in human lymphocytes in vitro and one locus in mouse lymphoma cells, negative at two other loci in mouse lymphoma cells and three 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 humans at therapeutic dose levels.

Effect on ability to drive or operate machinery.

No special precautions are 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.

Instructions to patients.

Patients should be informed that Valnir (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.

Interactions

No clinically significant interactions have been identified.
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. These effects are not considered to be of clinical significance in subjects with normal renal function. Therefore, no dosage adjustment is recommended when Valnir is coadministered with cimetidine, or probenecid in subjects with normal renal function.
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. cyclosporin, 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.