Valtrex (Oral)

Valtrex® 250 mg film-coated tablets

Film-coated tablet

250 mg tablet

White, biconvex, elongated tablet with a white to off-white core, engraved “GX CE7” on one side.

Varicella zoster virus (VZV) infections - herpes zoster

Valtrex is indicated for the treatment of herpes zoster (shingles) and ophthalmic zoster in immunocompetent adults.

Valtrex is indicated for the treatment of herpes zoster in adult patients with mild or moderate immunosuppression.

Herpes simplex virus (HSV) infections

Valtrex is indicated

- for the treatment and suppression of HSV infections of the skin and mucous membranes including:

- Treatment and suppression of recurrent ocular HSV infections in immunocompetent adults and adolescents and in immunocompromised adults

Clinical studies have not been conducted in HSV-infected patients immunocompromised for other causes than HIV-infection.

Cytomegalovirus (CMV) infections:

Valtrex is indicated for the prophylaxis of CMV infection and disease following solid organ transplantation in adults and adolescents

Varicella zoster virus (VZV) infections - herpes zoster and ophthalmic zoster

Patients should be advised to start treatment as soon as possible after a diagnosis of herpes zoster. There are no data on treatment started more than 72 hours after onset of the zoster rash.

Immunocompetent Adults

The dose in immunocompetent patients is 1000 mg three times daily for seven days (3000 mg total daily dose). This dose should be reduced according to creatinine clearance (see Renal impairment below).

Immunocompromised Adults

The dose in immunocompromised patients is 1000 mg three times daily for at least seven days (3000 mg total daily dose) and for 2 days following crusting of lesions. This dose should be reduced according to creatinine clearance (see Renal impairment below).

In immunocompromised patients, antiviral treatment is suggested for patients presenting within one week of vesicle formation or at any time before full crusting of lesions.

Treatment of herpes simplex virus (HSV) infections in adults and adolescents (>12 years)

Immunocompetent Adults and Adolescents (>12 years)

The dose is 500 mg of Valtrex to be taken twice daily (1000 mg total daily dose). This dose should be reduced according to creatinine clearance (see Renal impairment below).

For recurrent episodes, treatment should be for three to five days. For initial episodes, which can be more severe, treatment may have to be extended to ten days. Dosing should begin as early as possible. For recurrent episodes of herpes simplex, this should ideally be during the prodromal period or immediately upon appearance of the first signs or symptoms. Valtrex can prevent lesion development when taken at the first signs and symptoms of an HSV recurrence.

Herpes labialis

For herpes labialis (cold sores), valaciclovir 2000 mg twice daily for one day is effective treatment in adults and adolescents. The second dose should be taken about 12 h (no sooner than 6 h) after the first dose. This dose should be reduced according to creatinine clearance (see Renal impairment below). When using this dosing regimen, treatment should not exceed one day, since this has been shown not to provide additional clinical benefit. Therapy should be initiated at the earliest symptom of a cold sore (e.g. tingling, itching or burning).

Immunocompromised Adults

For the treatment of HSV in immunocompromised adults, the dosage is 1000 mg twice daily for at least 5 days, following assessment of the severity of the clinical condition and immunological status of the patient. For initial episodes, which can be more severe, treatment may have to be extended to ten days. Dosing should begin as early as possible. This dose should be reduced according to creatinine clearance (see Renal impairment below). For maximum clinical benefit, the treatment should be started within 48 hours. A strict monitoring of the evolution of lesions is advised.

Suppression of recurrences of herpes simplex virus (HSV) infections in adults and adolescents (>12 years)

Immunocompetent Adults and Adolescents (>12 years)

Immunocompromised Adults

The dose is 500 mg of Valtrex twice daily. This dose should be reduced according to creatinine clearance (see Renal impairment below). Treatment should be re-evaluated after 6 to 12 months of therapy.

Prophylaxis of cytomegalovirus (CMV) infection and disease in adults and adolescents (>12 years)

The dosage of Valtrex is 2000 mg four times a day, to be initiated as early as possible post-transplant. This dose should be reduced according to creatinine clearance (see Renal impairment below).

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

Special populations

Children

The efficacy of Valtrex in children below the age of 12 years has not been evaluated.

Elderly

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

Renal impairment

Caution is advised when administering Valtrex to patients with impaired renal function. Adequate hydration should be maintained. The dose of Valtrex should be reduced in patients with impaired renal function as shown in Table 1 below.

In patients on intermittent haemodialysis, the Valtrex dose should be administered after the haemodialysis has been performed. The creatinine clearance should be monitored frequently, especially during periods when renal function is changing rapidly e.g. immediately after renal transplantation or engraftment. The Valtrex dosage should be adjusted accordingly.

Hepatic impairment

Studies with a 1000 mg dose of valaciclovir in adult patients show that dose modification is not required in patients with mild or moderate cirrhosis (hepatic synthetic function maintained).

Table 1: DOSAGE ADJUSTMENT FOR RENAL IMPAIRMENT

^a For patients on intermittent haemodialysis, the dose should be given after dialysis on dialysis days.

^bFor HSV suppression in immunocompetent subjects with a history of >10 recurrences/year, better results may be obtained with 250 mg twice daily.

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 in elderly patients

Aciclovir is eliminated by renal clearance, therefore the dose of valaciclovir must be reduced in patients with renal impairment. 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.

Use of higher doses of valaciclovir in hepatic impairment and liver transplantation

Use for zoster treatment

Clinical response should be closely monitored, particularly in immunocompromised patients. Consideration should be given to intravenous antiviral therapy when response to oral therapy is considered insufficient.

Patients with complicated herpes zoster, i.e. those with visceral involvement, disseminated zoster, motor neuropathies, encephalitis and cerebrovascular complications should be treated with intravenous antiviral therapy.

Moreover, immunocompromised patients with ophthalmic zoster or those with a high risk for disease dissemination and visceral organ involvement should be treated with intravenous antiviral therapy.

Transmission of genital herpes

Patients should be advised to avoid intercourse when symptoms are present even if treatment with an antiviral has been initiated. During suppressive treatment with antiviral agents, the frequency of viral shedding is significantly reduced. However, the risk of transmission is still possible. Therefore, in addition to therapy with valaciclovir, it is recommended that patients use safer sex practices.

Use in ocular HSV infections

Clinical response should be closely monitored in these patients. Consideration should be given to intravenous antiviral therapy when response to oral therapy is unlikely to be sufficient.

Use in CMV infections

Data on the efficacy of valaciclovir from transplant patients (~200) at high risk of CMV disease (e.g. donor CMV-positive/recipient CMV negative or use of anti-thymocyte globulin induction therapy) indicate that valaciclovir should only be used in these patients when safety concerns preclude the use of valganciclovir or ganciclovir.

High dose valaciclovir as required for CMV prophylaxis may result in more frequent adverse events, including CNS abnormalities, than observed with lower doses administered for other indications. Patients should be closely monitored for changes in renal function, and doses adjusted accordingly.

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. Following 1000 mg valaciclovir, cimetidine and probenecid reduce aciclovir renal clearance and increase the AUC of aciclovir by about 25% and 45%, respectively, by inhibition of the active renal secretion of aciclovir. Cimetidine and probenecid taken together with valaciclovir increased aciclovir AUC by about 65%. Other medicinal products (including e.g. tenofovir) administered concurrently that compete with or inhibit active tubular secretion may increase aciclovir concentrations by this mechanism. Similarly, valaciclovir administration may increase plasma concentrations of the concurrently administered substance.

In patients receiving higher aciclovir exposures from valaciclovir (e.g., at doses for zoster treatment or CMV prophylaxis), caution is required during concurrent administration with drugs which inhibit active renal tubular secretion.

Increases in plasma AUCs of aciclovir and of the inactive metabolite of mycophenolate motefil, an immunosuppressant agent used in transplant patients, have been shown when the drugs are co-administered. No changes in peak concentrations or AUCs are observed with co-administration of valaciclovir and mycophenolate mofetil in healthy volunteers. There is limited clinical experience with the use of this combination.

Pregnancy

Breastfeeding

Fertility

No studies on the effects on the ability to drive and use machines have been performed. The clinical status of the patient and the adverse reaction profile of Valtrex should be borne in mind when considering the patient`s ability to drive or operate machinery. Further, a detrimental effect on such activities cannot be predicted from the pharmacology of the active substance.

The most common adverse reactions (ARs) reported in at least one indication by patients treated with Valtrex in clinical trials were headache and nausea. More serious ARs such as thrombotic thrombocytopenic purpura/haemolytic uraemic syndrome, acute renal failure and neurological disorders are discussed in greater detail in other sections of the label.

Undesirable effects are listed below by body system organ class and by frequency.

Clinical trial data have been used to assign frequency categories to ARs if, in the trials, there was evidence of an association with valaciclovir.

For ARs identified from postmarketing experience, but not observed in clinical trials, the most conservative value of point estimate (“rule of three”) has been used to assign the AR frequency category. For ARs identified as associated with valaciclovir from post-marketing experience, and observed in clinical trials, study incidence has been used to assign the AR frequency category. The clinical trial safety database is based on 5855 subjects exposed to valaciclovir in clinical trials covering multiple indications (treatment of herpes zoster, treatment/suppression of genital herpes & treatment of cold sores).

Clinical Trial Data

Post Marketing Data

Symptoms and Signs

Acute renal failure and neurological symptoms, including confusion, hallucinations, agitation, decreased consciousness and coma, have been reported in patients receiving overdoses of valaciclovir. Nausea and vomiting may also occur. Caution is required to prevent inadvertent overdosing. Many of the reported cases involved renally impaired and elderly patients receiving repeated overdoses, due to lack of appropriate dosage reduction.

Treatment

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.

Antivirals for systemic use.

Pharmacotherapeutic group: Nucleosides and nucleotides excluding reverse transcriptase inhibitors, ATC code: J05AB11.

Mechanism of action

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

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.

Pharmacodynamic effects

Resistance to aciclovir is normally due to a thymidine kinase deficient phenotype which results in a virus which is disadvantaged in the natural host. 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.

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 host and is 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).

Clinical studies

Varicella Zoster Virus Infection

Valtrex accelerates the resolution of pain: it reduces the duration of and the proportion of patients with zoster-associated pain, which includes acute and, in patients older than 50 years, also post-herpetic neuralgia. Valtrex reduces the risk of ocular complications of ophthalmic zoster.

Intravenous therapy generally is considered standard for zoster treatment in immunocompromised patients; however, limited data indicate a clinical benefit of valaciclovir in the treatment of VZV infection (herpes zoster) in certain immunocompromised patients, including those with solid organ cancer, HIV, autoimmune diseases, lymphoma, leukaemia and stem cell transplants.

Herpes Simplex Virus Infection

Valaciclovir for ocular HSV infections should be given according to applicable treatment guidelines.

Studies of valaciclovir treatment and suppression for genital herpes were performed in HIV/HSV coinfected patients with a median CD4 count of > 100cells/mm3.).

Cytomegalovirus Infection

CMV prophylaxis with valaciclovir in subjects receiving solid organ transplantation (kidney, heart) reduces the occurrence of acute graft rejection, opportunistic infections and other herpes virus infections (HSV, VZV). There is no direct comparative study versus valganciclovir to define the optimal therapeutic management of solid organ transplant patients.

Absorption

Valaciclovir is a prodrug of aciclovir. The bioavailability of aciclovir from valaciclovir is about 3.3 to 5.5-fold greater than that historically observed for oral aciclovir. 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. Valaciclovir pharmacokinetics is not dose-proportional. The rate and extent of absorption decreases with increasing dose, resulting in a less than proportional increase in Cmax over the therapeutic dose range and a reduced bioavailability at doses above 500 mg. Aciclovir pharmacokinetic (PK) parameter estimates following single doses of 250 to 2000 mg valaciclovir to healthy subjects with normal renal function are shown below.

C_max = peak concentration; T_max = time to peak concentration; AUC = area under the concentration-time curve. Values for C_max and AUC denote mean ± standard deviation. Values for T_max denote median and range.

Peak plasma concentrations of unchanged valaciclovir are only about 4% of peak aciclovir levels, occur at a median time of 30 to 100 min post-dose, and are at or below the limit of quantification 3 h after dosing. The valaciclovir and aciclovir pharmacokinetic profiles are similar after single and repeat dosing. Herpes zoster, herpes simplex and HIV infection do not significantly alter the pharmacokinetics of valaciclovir and aciclovir after oral administration of valaciclovir compared with healthy adults. 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.

Distribution

Binding of valaciclovir to plasma proteins is very low (15%). CSF penetration, determined by CSF/plasma AUC ratio, is independent of renal function and was about 25% for aciclovir and the metabolite 8-OH-ACV, and about 2.5% for the metabolite CMMG.

Biotransformation

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 metabolized by cytochrome P450 enzymes.

Elimination

Valaciclovir is eliminated in the urine principally as aciclovir (greater than 80% of the recovered dose) and the aciclovir metabolite CMMG (about 14% of the recovered dose). The metabolite 8-OH-ACV is detected only in small amounts in urine (< 2% of the recovered dose). Less than 1% of the administered dose of valaciclovir is recovered in the urine as unchanged drug. In patients with normal renal function the plasma elimination half-life of aciclovir after both single and multiple dosing with valaciclovir is approximately 3 h.

Special Populations

Renal impairment

The elimination of aciclovir is correlated to renal function, and exposure to aciclovir will increase with increased renal impairment. In patients with end-stage renal disease, the average elimination half-life of aciclovir after valaciclovir administration is approximately 14 hours, compared with about 3 hours for normal renal function.

Exposure to aciclovir and its metabolites CMMG and 8-OH-ACV in plasma and cerebrospinal fluid (CSF) was evaluated at steady-state after multiple-dose valaciclovir administration in 6 subjects with normal renal function (mean creatinine clearance 111 mL/min, range 91-144 mL/min) receiving 2000 mg every 6 hours and 3 subjects with severe renal impairment (mean CLcr 26 mL/min, range 17-31 mL/min) receiving 1500 mg every 12 hours. In plasma as well as CSF, concentrations of aciclovir, CMMG and 8-OH-ACV were on average 2, 4 and 5-6 times higher, respectively, at severe renal impairment compared with normal renal function.

Hepatic impairment

Pharmacokinetic data indicate that hepatic impairment decreases the rate of conversion of valaciclovir to aciclovir but not the extent of conversion. Aciclovir half-life is not affected.

Pregnant women

A study of the pharmacokinetics of valaciclovir and aciclovir during late pregnancy indicates that pregnancy does not affect the pharmacokinetics of valaciclovir.

Transfer into 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 times the corresponding maternal aciclovir serum concentrations. The median aciclovir concentration in breast milk was 2.24 micrograms/ml (9.95 micromoles/L). 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.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential.

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

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 and maternal toxicity were observed at subcutaneous doses that produced plasma aciclovir levels of 100 micrograms/mL (>10-fold higher than 2000 mg single dose valaciclovir in humans with normal renal function).

Tablet core

Microcrystalline cellulose

Crospovidone

Povidone

Magnesium stearate

Silica colloidal anhydrous

Film coat

Hypromellose

Titanium dioxide

Macrogol 400

Carnauba wax

Not applicable.

250 mg tablets

Two years

Store below 30°C.

Polyvinyl chloride / aluminium foil blister packs.

250 mg tablets

Packs of 60 tablets

No special requirements for disposal

The Wellcome Foundation Ltd

980 Great West Road

Brentford

Middlesex

TW8 9GS

United Kingdom

Trading as GlaxoSmithKline UK, Stockley Park West, Uxbridge, Middlesex UB11 1BT

PL 00003/0371

15 December 2011

7^th April 2014