Valaciclovir 500mg film coated tablets

Each film-coated tablet contains valaciclovir 500 mg as valaciclovir hydrochloride.

For a full list of excipients, see section 6.1.

Film coated tablet.

White, oblong, biconvex film coated tablets

Treatment of shingles (herpes zoster) infection.

Herpes simplex infections of the skin and mucous membranes, including initial and recurrent genital herpes.

Prophylaxis of recurrent herpes simplex infections of the skin and mucous membranes, including genital herpes.

Prophylaxis of cytomegalovirus (CMV) infection following renal transplantation.

Treatment of shingles (herpes zoster)

The dosage in adults is 1000 mg three times a day for 7 days. The treatment should be started as soon as possible after the symptoms appear, preferably within 72 hours.

Treatment of herpes simplex infections

The dosage in adults is 500 mg of valaciclovir twice daily.

For recurrent infections, treatment should be maintained for 5 days. For initial episodes, which can be more severe, treatment may have to be extended to 10 days. Dosing should begin as early as possible. For recurrent episodes of herpes simplex, this should ideally be during the prodromal period or as soon as the first signs appear.

Prophylaxis of recurrences of herpes simplex infections

Immunocompetent patients should take 500 mg of valaciclovir once daily.

Some patients with very frequent recurrences (e.g. more than 10 per year) may benefit from the daily dose of 500 mg being taken as a divided dose (250 mg twice daily). Valaciclovir 500mg film coated tablets is not suitable for these patients since it is not available as 250 mg tablets.

For immunocompromised adult patients the dose is 500 mg twice daily.

Reduction of transmission of genital herpes:

Valaciclovir 500mg film coated tablets can reduce transmission of genital herpes when taken as suppressive therapy and combined with safer sex practices.

Recommended dosage in immunocompetent heterosexual adult patients with 9 or fewer recurrences per year, 500 mg of Valaciclovir 500mg film coated tablets to be taken once daily by the infected partner in order to reduce transmission to a sexual partner negative for HSV-2 antibodies. Safer sex practices (particularly condom use) should be maintained, and sexual contact avoided if lesions are present.

There are no data on the reduction of transmission beyond 8 months in other patient populations.

Prophylaxis of cytomegalovirus infection (CMV)

Dosage in adults and children over 12 years of age

Two g (four tablets) four times a day. The first dose should be administered as early as possible post-transplant. This dose should be reduced according to creatinine clearance (see Dosage in patients with renal impairment below).

The duration of treatment will usually be 90 days, but may need to be extended in high risk patients.

Dosage in patients with renal impairment

Herpes zoster treatment and herpes simplex treatment or prophylaxis:

The dosage of valaciclovir should be reduced in patients with significantly impaired renal function as shown in the table below:

In patients on haemodialysis the same dosage is recommended as for patients with creatinine clearance less than 15 ml/min. The dose should be administered following each dialysis.

Prophylaxis of cytomegalovirus infection:

Doses for patients with impaired renal function should be adjusted according to the following table:

*Administration to dialysis patients should follow each dialysis.

The creatinine clearance should be monitored closely, especially during periods when renal function is changing rapidly e.g. immediately after transplantation or engraftment. The dosage should be adjusted according to creatinine clearance.

Dosage in patients with hepatic impairment:

Studies with a single 1 g dose of valaciclovir show that dose adjustment 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; but clinical experience is limited. For high doses recommended in CMV prophylaxis, see section 4.4.

Dosage in children under 12 years of age:

No information with respect to this age group is available.

Dosage in the elderly:

No dose adjustment is necessary except in case of severe renal impairment (see Dosage in patients with renal impairment above). Sufficient fluid intake must be considered.

Hypersensitivity to valaciclovir, aciclovir or any of the excipients.

Fluid balance

Care should be taken to ensure adequate fluid intake in patients who are at risk of dehydration, particularly the elderly and patients with reduced creatinine clearance.

Use in patients with renal impairment

The dosage should be adjusted in patients with renal impairment (see section 4.2). Patients with a history of renal impairment are also at increased risk of developing neurological effects (see section 4.8).

Use of higher doses of the medicinal product in patients with hepatic impairment

There is no data available on the use of higher doses of the product (8 g/day) in patients with liver disease. Caution should therefore be exercised when administering higher doses of valaciclovir to these patients.

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

No clinically significant interactions have been identified.

Aciclovir is excreted primarily unchanged in the urine via active renal tubular secretion. Any medicinal products administered concurrently that are excreted the same way may increase aciclovir blood concentrations following valaciclovir administration.

Following administration of 1 g of valaciclovir, cimetidine and probenecid increase the AUC of aciclovir by this mechanism, and reduce aciclovir urine excretion. However, no dosage adjustment is necessary at this dose because of the high therapeutic index of aciclovir.

In patients receiving higher doses of valaciclovir (8 g /day) as cytomegalovirus prophylaxis, caution is required during concurrent administration with medicinal products which compete with aciclovir for elimination, because of the potential for increased blood levels of one or both products. Increases in AUCs of aciclovir and of the inactive metabolite of mycophenolate mofetil, an immunosuppressant agent used in transplant patients, have been seen when the medicinal products are co-administered.

Caution is also required (with monitoring for changes in renal function) if administering high doses of valaciclovir with medicinal products which affect other aspects of renal function (e.g. ciclosporin, tacrolimus).

Pregnancy

There is limited data on the use of valaciclovir in pregnancy. Valaciclovir should only be used in pregnancy if the potential benefits of treatment outweigh the potential risk.

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 cases (29 and 756 exposed during the first trimester of pregnancy), respectively. The findings of the aciclovir pregnancy registry have not shown an increase in the number of birth defects amongst aciclovir-exposed subjects compared with the general population, and any birth defects showed no uniqueness or consistent pattern to suggest a common cause. Given the small number of women enrolled into the valaciclovir pregnancy registry, reliable and definitive conclusions could not be reached regarding the safety of valaciclovir in pregnancy. (See also section 5.2).

Lactation

The principle metabolite of valaciclovir is aciclovir which is excreted in breast milk. Aciclovir has been detected in breast milk at concentrations ranging from 0.6 to 4.1 times the corresponding aciclovir blood concentrations. Following oral administration of 200 mg aciclovir five times a day, the peak plasma concentration (C^ssmax) is 3.1 microM (0.7 mcg/ml). These levels would potentially expose nursing infants to aciclovir dosages of up to 0.3 mg/kg/day. The elimination half-life of aciclovir from breast milk has been measured 2.8 hours, similar to that in blood. Caution is therefore advised if valaciclovir is to be administered to nursing women. However aciclovir is used to treat neonatal herpes simplex at intravenous doses of 30 mg/kg/day.

The clinical status of the patient and the adverse event profile of valaciclovir should be borne in mind when considering the patient's ability to drive or operate machinery. There have been no studies to investigate the effect of valaciclovir on driving performance or the ability to operate machinery. A detrimental effect on such activities cannot be predicted from the pharmacology of the active substance.

Adverse reactions are listed below by MedDRA body system organ class and by frequency.

The frequency categories used are:

Results from clinical trials have been used to evaluate the frequency of adverse reactions, when the trials established association with valaciclovir (i.e. there was a statistically significant difference between the incidence in patients taking valaciclovir and placebo). The frequency of other adverse reactions has been assessed by post-marketing adverse reactions reports.

Clinical Trial Data

Nervous system disorders

Common: Headache.

Gastrointestinal disorders

Common: Nausea.

Post Marketing Data

Blood and lymphatic system disorders

Very rare: Thrombocytopenia, leukopenia

Immune system disorders

Very rare: Anaphylaxis.

Psychiatric and nervous system disorders

Rare: Dizziness, confusion, hallucinations, decreased consciousness.

Very rare: Tremor, ataxia, dysarthria, convulsions, encephalopathy, coma.

The above adverse reactions are reversible and 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 cytomegalovirus infection prophylaxis, neurological reactions occurred more frequently compared with lower doses.

Respiratory, thoracic and mediastinal disorders

Uncommon: Dyspnoea.

Gastrointestinal disorders

Rare: Abdominal discomfort, vomiting, diarrhoea.

Hepato-biliary disorders

Very rare: Reversible increases in liver function tests, which are occasionally described as hepatitis.

Skin and subcutaneous tissue disorders

Uncommon: Rashes including photosensitivity.

Rare: Pruritus.

Very rare: Urticaria, angioedema.

Renal and urinary disorders

Rare: Renal impairment.

Very rare: Acute renal failure.

Other adverse reactions

There have been reports of renal impairment, 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. These findings have also been observed in patients not treated with valaciclovir who have the same underlying or concurrent conditions.

There is limited data available on overdosage with valaciclovir. However patients have ingested single overdoses of up to 20 g of aciclovir, which is only partially absorbed in the gastrointestinal tract, usually without toxic effects. Accidental, repeated overdoses of oral aciclovir over several days have been associated with gastrointestinal effects (such as nausea and vomiting) and neurological effects (headache and confusion). Overdosage of intravenous aciclovir has resulted in elevations of serum creatinine and subsequent renal failure. Neurological effects including confusion, hallucinations, agitation, seizures and coma have been described in association with intravenous overdosage.

Haemodialysis significantly enhances the removal of aciclovir from the blood and may, therefore, be considered a management option in the event of overdose.

Pharmacotherapeutic group: Nucleosides and nucleotides excl. reverse transcriptase inhibitors,

ATC code: J 05 A B 11

Valaciclovir is the L-valine ester of aciclovir. Aciclovir is a guanine nucleoside analogue.

Following absorption valaciclovir is rapidly and almost completely converted to aciclovir and valine, probably by the enzyme referred to as 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, varicella zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr Virus (EBV), and human herpes virus 6 (HHV-6). 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. In the case of HSV, VZV and EBV this enzyme is the viral thymidine kinase, which is only present in virus infected cells. Selectivity is maintained in CMV with phosphorylation, at least in part, being mediated through the phosphotransferase gene product of UL97. This requirement for activation of aciclovir by a virus specific enzyme largely explains its 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.

Extensive monitoring of clinical HSV and VZV isolates from patients receiving aciclovir therapy or prophylaxis has revealed that virus with reduced sensitivity to aciclovir is extremely rare in the immunocompetent and is only found infrequently in severely immunocompromised individuals e.g. organ or bone marrow transplant recipients, patients receiving chemotherapy for malignant disease and people infected with the human immunodeficiency virus (HIV).

Resistance is normally due to a thymidine kinase deficient phenotype which results in a virus which is profoundly disadvantaged in the natural host. Infrequently, reduced sensitivity to aciclovir has been described as a result of subtle alterations in either the virus thymidine kinase or DNA polymerase. The virulence of these variants resembles that of the wild-type virus.

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 an enzyme isolated from human liver referred to as valaciclovir hydrolase.

The bioavailability of aciclovir from 1000 mg valaciclovir is 54%, and is not reduced by food. Mean peak aciclovir concentrations are 10-37 microM (2.2-8.3mcg/ml) following single doses of 250-2000 mg valaciclovir to healthy subjects with normal renal function, and occur at a mean time of 1.00-2.00 hours post dose.

Peak plasma concentrations of valaciclovir are only 4% of aciclovir levels, occur at a mean time of 30 to 100 minutes post dose, and are at or below the limit of quantification 3 hours after dosing. The valaciclovir and aciclovir pharmacokinetic profiles are similar after single and repeat dosing. Binding of valaciclovir to plasma proteins is very low (15%).

In patients with normal renal function the plasma elimination half-life of aciclovir after both single and multiple dosing with valaciclovir is approximately 3 hours. In patients with end-stage renal disease, the average elimination half-life of aciclovir after valaciclovir administration is approximately 14 hours. Less than 1% of the administered dose of valaciclovir is recovered in the urine as unchanged drug. Valaciclovir is excreted in the urine principally as aciclovir (greater than 80% of the recovered dose) and the known aciclovir metabolite, 9-(carboxymethoxy)methylguanine (CMMG).

Characteristics in patients:

Herpes zoster and herpes simplex do not significantly alter the pharmacokinetics of valaciclovir and aciclovir after oral administration of valaciclovir.

In a study of the pharmacokinetics of valaciclovir and aciclovir during late pregnancy, the daily aciclovir AUC (area under plasma concentration-time curve) following valaciclovir 1000 mg was approximately 2 times greater than that observed with oral aciclovir at 1200 mg daily.

In patients with HIV infection, the disposition and pharmacokinetic characteristics of aciclovir after oral administration of single or multiple doses of valaciclovir 1000 mg or 2000 mg are unaltered compared with healthy subjects.

In transplant recipients receiving valaciclovir 2000 mg 4 times daily, aciclovir peak concentrations are similar to or greater than those in healthy volunteers receiving the same dose. The estimated daily AUCs are appreciably greater.

Mutagenicity:

The results of mutagenicity tests in vitro and in vivo indicate that valaciclovir is unlikely to pose a genetic risk to humans.

Carcinogenicity:

Valaciclovir was not carcinogenic in studies performed in mice and rats.

Teratogenicity

Valaciclovir was not teratogenic in rats and rabbits. Valaciclovir is almost completely metabolised to aciclovir. Experiments with subcutaneous administration of aciclovir did not produce teratogenic effects in rats and rabbits. In additional studies in rats, foetal abnormalities were observed at subcutaneous doses that produced plasma levels of 100 mcg/ml and maternal toxicity.

Fertility

Oral valaciclovir did not affect fertility in male or female rats.

Tablet core

Calcium hydrogen phosphate (dehydrate), sodium starch glycolate, hydroxy prophyl cellulose, talcum, magnesium stearate.

Film-coat

Hypromellose, lactose (monohydrate), titanium dioxide (E171), macrogol 4000

Not applicable.

36 months

Store below 30°C.

PVC/PE/PVDC/aluminium blister packs:

Pack sizes:

10 tablets, 40 tablets or 42 tablets.

No special requirements.

Alliance Pharmaceuticals Ltd

Avonbridge House

Bath Road

Chippenham

Wiltshire

SN15 2BB

PL 16853/0131

22/01/2010

17 April 2012