4.1. Therapeutic indications

Varicella zoster virus (VZV) infections – herpes zoster

Valaciclovir is indicated for the treatment of herpes zoster (shingles) and ophthalmic zoster in immunocompetent adults (see sections 4.4).

Valaciclovir is indicated for the treatment of herpes zoster in adult patients with mild or moderate immunosuppression (see section 4.4).

Herpes simplex virus (HSV) infections

Valaciclovir is indicated

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

- treatment of first-episode of genital herpes in immunocompetent adults and adolescents and in immunocompromised adults

- treatment of recurrences of genital herpes in immunocompetent adults and adolescents, and in immunocompromised adults

- suppression of recurrent genital herpes in immunocompetent adults and adolescents and in immunocompromised adults

• Treatment and suppression of recurrent ocular HSV infections in immunocompetent adults and adolescents and in immunocompromised adults (see section 4.4)

Clinical studies have not been conducted in HSV-infected patients immunocompromised for other causes than HIV-infection (see section 5.1).

Cytomegalovirus (CMV) infections:

Valaciclovir is indicated for the prophylaxis of CMV infection and disease following solid organ transplantation in adults and adolescents (see section 4.4)

4.2. Posology and method of administration

Method of administration

Oral use.

The tablet should be swallowed with a sufficient amount of fluid (e.g. one glass of water). The tablet can be taken with or without food.

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 Valaciclovir 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. Valaciclovir 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)

The dose is 500 mg of Valaciclovir to be taken once daily. Some patients with very frequent recurrences (≥ 10/year in absence of therapy) may gain additional benefit from the daily dose of 500 mg being taken as a divided dose (250 mg 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.

Immunocompromised Adults

The dose is 500 mg of Valaciclovir 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 Valaciclovir 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

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 Valaciclovir to patients with impaired renal function. Adequate hydration should be maintained. The dose of Valaciclovir should be reduced in patients with impaired renal function as shown in Table 1 below.

In patients on intermittent haemodialysis, the Valaciclovir 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 Valaciclovir 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). Pharmacokinetic data in adult patients with advanced cirrhosis (impaired hepatic synthetic function and evidence of portal-systemic shunting) do not indicate the need for dose adjustment; however, clinical experience is limited. For higher doses (4000 mg or more per day), see section 4.4.

Table 1: DOSAGE ADJUSTMENT FOR RENAL IMPAIRMENT

Therapeutic Indication

Creatinine Clearance (mL/min)

Valaciclovir Dosage a

Varicella-Zoster Virus (VZV) Infections

Treatment of herpes zoster (shingles)

in immunocompetent and immunocompromised adults

≥ 50

30 to 49

10 to 29

<10

1000 mg three times daily

1000 mg twice daily

1000 mg once daily

500 mg once daily

Herpes Simplex Virus (HSV) Infections

Treatment of HSV infections

- immunocompetent adults and adolescents

≥ 30

< 30

500 mg twice daily

500 mg once daily

- immunocompromised adults

≥ 30

< 30

1000 mg twice daily

1000 mg once daily

Treatment of herpes labialis (cold sores) in immunocompetent adults and adolescents (alternative 1-day regimen)

≥50

30 to 49

10 to 29

<10

2000mg twice in one day

1000 mg twice in one day

500 mg twice in one day

500 mg single dose

Suppression of HSV infections

- immunocompetent adults and adolescents

≥ 30

< 30

500 mg once daily b

250 mg once daily

- immunocompromised adults

≥ 30

< 30

500 mg twice daily

500 mg once daily

Cytomegalovirus (CMV) Infections

CMV prophylaxis in solid organ transplant recipients in adults and adolescents

≥75

50 to <75

25 to <50

10 to <25

<10 or on dialysis

2000 mg four times daily

1500 mg four times daily

1500 mg three times daily

1500 mg twice daily

1500 mg once daily

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

b For HSV suppression in immunocompetent subjects with a history of ≥10 = recurrences/year, better results may be obtained with 250 mg twice daily.

Paediatric populations

The safety and efficacy of Valaciclovir in children below the age of 12 years has not been established.

4.3. Contraindications

Hypersensitivity to valaciclovir or aciclovir or any of the excipients ( listed in section 6.1).

4.4. Special warnings and precautions for use

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 (see section 4.2). 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 section 4.8).

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

There are no data available on the use of higher doses of valaciclovir (4000 mg or more per day) in patients with liver disease. Specific studies of valaciclovir have not been conducted in liver transplantation, and hence caution should be exercised when administering daily doses greater than 4000 mg to these patients.

Use 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 (see section 4.8). Patients should be closely monitored for changes in renal function, and doses adjusted accordingly (see section 4.2).

Drug reaction with eosinophilia and systemic symptoms (DRESS):

DRESS, which can be life-threatening or fatal, has been reported in association with valaciclovir treatment. At the time of prescription patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of DRESS appear, valaciclovir should be withdrawn immediately and an alternative treatment considered (as appropriate). If the patient has developed DRESS with the use of valaciclovir, treatment with valaciclovir must not be restarted in this patient at any time.

4.5. Interaction with other medicinal products and other forms of interaction

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.

4.6. Fertility, pregnancy and lactation

Pregnancy

A limited amount of data on the use of valaciclovir and a moderate amount of data on the use of aciclovir in pregnancy is available from pregnancy registries (which have documented the pregnancy outcomes in women exposed to valaciclovir or to oral or intravenous aciclovir (the active metabolite of valaciclovir); 111 and 1246 outcomes (29 and 756 exposed during the first trimester of pregnancy, respectively) and postmarketing experience indicate no malformative or foeto/neonatal toxicity. Animal studies do not show reproductive toxicity for valaciclovir (see section 5.3). Valaciclovir should only be used in pregnancy if the potential benefits of treatment outweigh the potential risk.

Breastfeeding

Aciclovir, the principle metabolite of valaciclovir, is excreted in breast milk. However, at therapeutic doses of valaciclovir, no effects on the breastfed newborns/infants are anticipated since the dose ingested by the child is less than 2% of the therapeutic dose of intravenous aciclovir for treatment of neonatal herpes (see Section 5.2). Valaciclovir should be used with caution during breast feeding and only when clinically indicated.

Fertility

Valaciclovir did not affect fertility in rats dosed by the oral route. At high parenteral doses of aciclovir testicular atrophy and aspermatogenesis have been observed in rats and dogs. No human fertility studies were performed with valaciclovir, but no changes in sperm count, motility or morphology were reported in 20 patients after 6 months of daily treatment with 400 to 1000 mg aciclovir.

4.7. Effects on ability to drive and use machines

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 Valaciclovir 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.

4.8. Undesirable effects

The most common adverse reactions (ARs) reported in at least one indication by patients treated with valaciclovir in clinical trials were headache and nausea. More serious ARs such as thrombotic thrombocytopenic purpura/haemolytic uraemic syndrome, acute renal failure and neurological disorders and DRESS (see section 4.4) are discussed in greater detail in other sections of the label.

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

The following frequency categories are used for classification of adverse effects:

Very common ≥ 1/10,

Common ≥1/100 to < 1/10,

Uncommon ≥ 1/1,000 to < 1/100,

Rare ≥ 1/10,000 to < 1/1000,

Very rare < 1/10,000

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

Nervous system disorders

Very common:

Headache

Gastrointestinal disorders

Common:

Nausea

Post Marketing Data

Blood and lymphatic system disorders

Uncommon:

Leucopenia, thrombocytopenia

Leucopenia is mainly reported in immunocompromised patients.

Immune system disorders

Rare:

Anaphylaxis

Psychiatric and nervous system disorders

Common:

Dizziness

Uncommon:

Confusion, hallucinations, decreased consciousness, tremor, agitation

Rare:

Ataxia, dysarthria, convulsions, encephalopathy, coma, psychotic symptoms, delirium .

Neurological disorders, sometimes severe, may be linked to encephalopathy and include confusion, agitation, convulsions, hallucinations, coma. These events are generally reversible and usually seen in patients with renal impairment or with other predisposing factors (see section 4.4). In organ transplant patients receiving high doses (8000 mg daily) of valaciclovir for CMV prophylaxis, neurological reactions occurred more frequently compared with lower doses used for other indications.

Respiratory, thoracic and mediastinal disorders

Uncommon:

Dyspnoea

Gastrointestinal disorders

Common:

Vomiting, diarrhoea.

Uncommon:

Abdominal discomfort

Hepato-biliary disorders

Uncommon:

Reversible increases in liver function tests (e.g. bilirubin, liver enzymes).

Skin and subcutaneous tissue disorders

Common:

Rashes including photosensitivity, pruritus. .

Uncommon:

Urticaria

Rare:

Angioedema

Not known:

Drug reaction with eosinophilia and systemic symptoms (DRESS) (see section 4.4)

Renal and urinary disorders

Uncommon:

Renal pain,haematuria (often associated with other renal events)

Rare:

Renal impairment, acute renal failure (especially in elderly patients or in patients with renal impairment receiving higher than the recommended doses).

Not Known:

Tubulointerstitial nephritis

Renal pain may be associated with renal failure.

Intratubular precipitation of aciclovir crystals in the kidney has also been reported. Adequate fluid intake should be ensured during treatment (see section 4.4).

Additional information on special populations

There have been reports of renal insufficiency, microangiopathic haemolytic anaemia and thrombocytopenia (sometimes in combination) in severely immunocompromised adult patients, particularly those with advanced HIV disease, receiving high doses (8000 mg daily) of valaciclovir for prolonged periods in clinical trials. These findings have also been observed in patients not treated with valaciclovir who have the same underlying or concurrent conditions.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard.

4.9. Overdose

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.