Valtrex^TM Tablets 500mg

500mg of valaciclovir

Film coated tablets

Valtrex is indicated for the treatment of herpes zoster (shingles).

Valtrex is indicated for the treatment of herpes simplex infections of the skin and mucous membranes, including initial and recurrent genital herpes.

Valtrex is indicated for the suppression (prevention) of recurrent herpes simplex infections of the skin and mucous membranes, including genital herpes.

Valtrex can reduce transmission of genital herpes when taken as suppressive therapy and combined with safer sex practices (particularly the use of condoms).

Valtrex is indicated for the prophylaxis of cytomegalovirus (CMV) infection and disease, following renal transplantation.

Route of administration: oral

DOSAGE IN ADULTS:

•Treatment of herpes zoster:

1000 mg of Valtrex to be taken 3 times daily for 7 days.

•Treatment of herpes simplex:

Valtrex can prevent lesion development when taken at the first signs and symptoms of an HSV recurrence.

500 mg of Valtrex to be taken twice daily. For recurrent episodes, treatment should be 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 immediately the first signs or symptoms appear.

•Suppression (prevention) of herpes simplex infection:

In immunocompetent patients, 500mg of Valtrex is to be taken once daily. .

Some patients with very frequent recurrences (e.g. more than 10 per year) may benefit from taking 500mg as a divided dose (250mg twice daily).

For immunocompromised patients the dose is 500mg twice daily.

•Reduction of transmission of genital herpes:

In immunocompetent heterosexual adult patients with 9 or fewer recurrences per year, 500 mg of Valtrex 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) and disease

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

The dosage of Valtrex is 2g four times a day, to be initiated within 72 hours post-transplant, or as soon as oral medication can be tolerated. This dose should be reduced according to creatinine clearance (see Dosage in renal impairment below).

The duration of treatment will usually be 90 days.

DOSAGE IN CHILDREN:

There are no data available on the use of Valtrex in children.

DOSAGE IN THE ELDERLY:

The possibility of renal impairment in the elderly must be considered and the dosage should be adjusted accordingly (see Renal impairment below).

Adequate hydration should be maintained.

DOSAGE IN RENAL IMPAIRMENT:

•Herpes zoster treatment and herpes simplex treatment, suppression and reduction of transmission:

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

The dosage of Valtrex should be reduced in patients with significantly impaired renal function as shown in Table 1 below:

Table 1

In patients on haemodialysis, the Valtrex dosage recommended for patients with a creatinine clearance of less than 15 ml/min should be used, but this should be administered after the haemodialysis has been performed.

•CMV prophylaxis:

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

The dosage of Valtrex should be reduced in patients with impaired renal function as shown in Table 2 below:

Table 2

In patients on haemodialysis, the Valtrex dosage should be administered after the haemodialysis has been performed.

The creatinine clearance should be monitored frequently, and the Valtrex dosage adjusted accordingly. It is recommended that creatinine clearance is monitored daily for optimum dose adjustments, especially during the first 10 days post-transplant, and at least twice weekly during hospitalisation, and as considered necessary thereafter.

DOSAGE IN HEPATIC IMPAIRMENT:

Studies with a 1g unit dose of Valtrex 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.

There are no data available on the use of higher doses of Valtrex (for CMV prophylaxis) in patients with liver disease. However, following a 1g unit dose of Valtrex, aciclovir AUCs were elevated in patients with moderate or severe cirrhosis. Therefore, caution should be exercised when administering higher doses of Valtrex to patients with hepatic impairment.

Valtrex is contra-indicated in patients known to be hypersensitive to valaciclovir, aciclovir or any components of formulations of Valtrex.

Hydration status:

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

Use in patients with renal impairment and elderly patients:

Aciclovir is eliminated by renal clearance, therefore the dose of Valtrex must be reduced in patients with renal impairment (see 4.2 Dosage and Administration). Elderly patients are likely to have reduced renal function and therefore the need for dose reduction must be considered in this group of patients. Both elderly patients and 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 4.8 Adverse Reactions).

Use of high dose Valtrex in hepatic impairment:

There are no data available on the use of higher doses of Valtrex (for CMV prophylaxis) in patients with liver disease. However, following a 1g unit dose of Valtrex, aciclovir AUCs were elevated in patients with moderate or severe cirrhosis. Therefore, caution should be exercised when administering higher doses of Valtrex to patients with hepatic impairment.

Use in genital herpes: Suppressive therapy with Valtrex 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 Valtrex, it is recommended that patients use safer sex practices (particularly the use of condoms).

No clinically significant interactions have been identified.

Aciclovir is eliminated primarily unchanged in the urine via active tubular secretion. Any drugs administered concurrently that compete with this mechanism for elimination may increase aciclovir plasma concentrations following Valtrex administration.

In patients receiving high dose Valtrex (4g/day) for CMV prophylaxis, caution is required during concurrent administration with drugs which compete with aciclovir elimination, because of the potential for increased plasma levels of one or both drugs or their metabolites. Following 1g Valtrex, 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 of 1g because of the wide therapeutic index of aciclovir. Alternative agents, which do not interact with other agents excreted primarily via the kidney, may be considered for the management of excess gastric acid production and urate-lowering therapy when administering high dose valaciclovir.

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; there is limited clinical experience with the use of this combination.

Care is also required, with monitoring for changes in renal function (see 4.2, Posology and Method of Administration), if administering high-doses of Valtrex (4g or more/day) with drugs which affect other aspects of renal physiology (e.g.ciclosporin, tacrolimus).

Teratogenicity:

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

Fertility:

Valaciclovir did not affect fertility in male or female rats dosed by the oral route.

Pregnancy:

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

A post-marketing acyclovir pregnancy registry has documented pregnancy outcomes in women exposed to Valtrex or any formulation of Zovirax (aciclovir, the inactive metabolite of valaciclovir). The birth defects described amongst aciclovir exposed subjects have not shown any 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 5.2 Pharmacokinetic Properties).

The daily aciclovir AUC (area under plasma concentration-time curve) following Valtrex 1000 mg and 8000 mg daily would be approximately 2 and 9 times greater than that expected with oral aciclovir 1000 mg daily, respectively.

Lactation:

Aciclovir, the principle metabolite of valaciclovir, is excreted in breast milk. 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 breast milk to maternal serum AUC ratios ranged from 1.4 to 2.6 (median 2.2). The median aciclovir concentration in breast milk was 2.24 μg/ml (9.95 μM). With a maternal valaciclovir dosage of 500 mg twice daily, this level would expose a nursing infant to a daily oral aciclovir dosage of about 0.61 mg/kg/day. The elimination half-life of aciclovir from breast milk was similar to that for serum.

Unchanged valaciclovir was not detected in maternal serum, breast milk, or infant urine.

Caution is advised if Valtrex is to be administered to a nursing woman. However, aciclovir is used to treat neonatal herpes simplex at intravenous doses of 30 mg/kg /day.

No special precautions necessary.

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

The frequency categories used are:

Very common 1 in 10,

Common 1 in 100 and < 1 in 10,

Uncommon 1 in 1,000 and < 1 in 100,

Rare 1 in 10,000 and < 1 in 1,000,

Very rare < 1 in 10,000.

Blood and lymphatic system disorders

Very rare: Leukopenia / Neutropenia, thrombocytopenia.

Leukopenia / Neutropenia is mainly reported in immunocompromised patients.

Immune system disorders

Very rare: Anaphylaxis.

Psychiatric and nervous system disorders

Common: *Headache

Rare: Dizziness, confusion, hallucinations, decreased consciousness.

Very rare: Agitation, tremor, ataxia, dysarthria, psychotic symptoms convulsions, encephalopathy, coma.

The above events are generally reversible and usually seen in patients with renal impairment or with other predisposing factors (see 4.4 Special Warnings & Precautions for Use). In renal transplant patients receiving high doses (8 g daily) of Valtrex for CMV prophylaxis, psychiatric reactions (confusion, hallucinations and thinking disorders) occurred more frequently compared with lower doses for other indications. They were mainly mild to moderate in nature, reversible upon dose adjustment, and occurred mainly in the immediate post-transplant period. Therefore, it is important to monitor creatinine clearance frequently in these patients, and to adjust the dose accordingly (see 4.2 Posology and Method of Administration). The cause of these events appears to be multi-factorial, including over-exposure to aciclovir, renal impairment, dialysis, administration of psychotropic agents, and other underlying medical conditions.

Respiratory, thoracic and mediastinal disorders

Uncommon: Dyspnoea.

Gastrointestinal disorders

Common: *Nausea

Rare: Abdominal discomfort, vomiting, diarrhoea.

Hepato-biliary disorders

Very rare: Reversible increases in liver function tests.

These 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, renal pain.

Renal pain may be associated with renal failure.

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

* Clinical trial data have been used to assign frequency categories to these adverse reactions. For all other adverse events, spontaneous post-marketing data has been used as a basis for allocating frequency.

Symptoms and signs:

Acute renal failure and neurological symptoms, including confusion, hallucinations, agitation, decreased consciousness and coma, have been reported in patients receiving overdoses of Valtrex. 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.

Pharmacotherapeutic group:

Valaciclovir, an antiviral, is the L-valine ester of aciclovir. Aciclovir is a purine (guanine) nucleoside analogue.

Mode of action:

Valaciclovir is rapidly and almost completely converted in man 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 (TK), 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.

CMV prophylaxis with Valtrex significantly reduces HSV disease in renal transplant patients.

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. solid 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 that 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 μM (2.2-8.3μg/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.

Peak plasma concentrations of valaciclovir are only 4% of aciclovir levels, occur at a median 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 elimination plasma half-life of aciclovir after both single and multiple dosing with valaciclovir is approximately 3 hours. In patients with end-stage renal disease, the average elimination half-life of aciclovir after valaciclovir administration is approximately 14 hours. Less than 1% of the administered dose of valaciclovir is recovered in the urine as unchanged drug. Valaciclovir is eliminated principally as aciclovir (greater than 80% of the recovered dose) and the known aciclovir metabolite, 9-carboxymethoxymethylguanine (CMMG), in the urine.

Characteristics in patients:

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

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

In renal transplant recipients receiving valaciclovir 2g 4 times daily, aciclovir peak concentrations are similar to or greater than those in healthy volunteers with comparable doses and renal function. However, 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 bio-assays performed in mice and rats.

Tablet core:

Microcrystalline cellulose

Crospovidone

Povidone K90

Magnesium stearate

Colloidal silicon dioxide

Purified water

Film coat:

White Colour Concentrate YS-1-18043 containing;

Hydroxypropylmethylcellulose

Titanium dioxide

Polyethylene glycol 400

Polysorbate 80

Purified water

Printing ink:

Brilliant Blue Printing Ink FT203 containing Brilliant Blue, E133

Polish:

Carnauba wax

No data.

Three years

Store below 30°C

Tablets are packed into blister packs prepared from unplasticised polyvinyl chloride and aluminium foil.

Tablets are packed into polypropylene containers with polyethylene snap-fitting caps Pack size: 500 x 500mg

No special instructions for use.

The Wellcome Foundation Ltd

Glaxo Wellcome House

Berkeley Avenue

Greenford

Middlesex

UB6 0NN

PL 00003/0352

20 January 1995

11 August 2008

POM