Valzost 500 mg, 1 g TABLETS

VALZOST is indicated for the treatment of herpes zoster (shingles). VALZOST reduces the duration of zoster-associated pain, which includes acute and postherpetic neuralgia, thus accelerating resolution of pain. VALZOST also reduces the proportion of patients with zoster-associated pain.

VALZOST is indicated for the episodic treatment of recurrent genital herpes in immunocompetent adult patients.

VALZOST is indicated for the prevention (suppression) of recurrent herpes simplex infection of the skin and mucous membrane of the ano-genital area.

VALZOST is indicated for the prophylaxis of cytomegalovirus (CMV) infection, CMV disease and other herpes virus infections following organ transplantation, where special risk exists.

Dosage in adults

For the treatment of Herpes Zoster: 1000 mg of VALZOST to be taken three times per day for seven days.

Recurrent genital herpes: The recommended dosage for the treatment of recurrent genital herpes is 500 mg twice daily for 5 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. There are no data on the effectiveness of VALZOST when initiated more than 24 hours after the onset of signs and symptoms.

For the prevention (suppression) of recurrences of herpes simplex infection

Immunocompetent patients: 500 mg to be taken once daily. Some patients with very frequent recurrences (e.g. 10 or more per year) may gain additional benefit from the daily dose of 500 mg being taken as a divided dose (250 mg twice daily).

Immunocompromised patients: 500 mg twice daily.

Prophylaxis of cytomegalovirus infection (CMV) and disease: Adults and adolescents (from 12 years of age): 2000 mg to be taken four times a day. Dosing should be initiated as early as possible post-transplant. This dose should be reduced according to creatinine clearance (See u201cDosage in renal impairmentu201d). The duration of treatment will usually be 90 days, but may need to be extended in high risk patients.

Dosage in children: No data are available.

Dosage in the elderly: Dosage modification is not required unless renal function is impaired (see u201cDosage in renal impairmentu201d). Adequate hydration should be maintained.

Dosage in renal impairment: The dose of VALZOST should be modified as follows in patients with significantly impaired renal function:

HERPES ZOSTER

• Creatinine Clearance 15 - 30 mL/min: 1000 mg twice a day
• Creatinine Clearance < 15 mL/min: 1000 mg once a day

RECURRENT GENITAL HERPES

• Creatinine Clearance > 15 mL/min: 500 mg twice daily
• Creatinine Clearance 0 - 15 mL/min: 500 mg once daily

PREVENTION OF RECURRENCE

• Creatinine Clearance 15 - 30 mL/min: No dosage adjustment required
• Creatinine Clearance < 15 mL/min: 250 mg once a day

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

CMV PROPHYLAXIS: The dosage of VALZOST should be adjusted in patients with impaired renal function as shown in the table below:

Creatinine Clearance VALZOST Dose

• u2265 75 mL/min: 2000 mg four times daily
• 50 to < 75 mL/min: 1500 mg four times daily
• 25 to < 50 mL/min: 1500 mg three times daily
• 10 to < 25 mL/min: 1500 mg twice daily
• < 10 mL/min or dialysis: 1500 mg once daily

** In patients on haemodialysis, the VALZOST dosage 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 transplantation or engraftment. The VALZOST dosage should be adjusted accordingly.

Dosage in hepatic impairment: 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 shutting) do not indicate the need for dosage adjustment; however, clinical experience is limited. For higher doses recommended for CMV prophylaxis (see u201cWARNINGS AND SPECIAL PRECAUTIONSu201d).

VALZOST is contraindicated in patients known to be hypersensitive to valaciclovir, aciclovir or any component of their formulations. Safety in pregnancy and lactation has not been established. (See u201cPREGNANCY AND LACTATIONu201d).

Thrombotic, thrombocytopenic purpura/haemolytic uraemic syndrome (TTP / HUS): TTP / HUS in some cases resulted in death, has been reported in patients with advanced HIV disease and also in bone marrow transplant and renal transplant recipients.

Cases of acute renal failure have been reported in:

• Elderly patients with or without reduced renal function. Caution should be exercised when administering VALZOST to elderly patients, and dosage reduction is recommended for those with impaired renal function.
• Patients with underlying renal disease who received higher than recommended doses of VALZOST for their level of renal function. Dosage reduction is recommended when administering VALZOST to patients with renal impairment.
• Patients receiving other nephrotoxic medicines. Caution should be exercised when administering VALZOST to patients receiving potentially nephrotoxic medicines.
• Patients without adequate hydration. Precipitation of aciclovir in renal tubules may occur when solubility (2,5 mg/mL) is exceeded in the intratubular fluid. Adequate hydration should be maintained for all patients.

In the event of acute renal failure and anuria, the patient may benefit from haemodialysis until renal function is restored.

Central Nervous System (CNS) CNS adverse reactions, including agitation, hallucinations, confusion, delirium, seizures, and encephalopathy, have been reported in both adult and paediatric patients with or without reduced renal function and in patients with underlying renal disease who received higher than recommended doses of VALZOST for their level of renal function. Elderly patients are more likely to have CNS adverse reactions. VALZOST should be discontinued if CNS adverse reactions occur.

No clinically significant interactions have been identified. Cimetidine and probenecid increase the area under the plasma concentration time curve of aciclovir by reducing its renal clearance: however no dosage adjustment is necessary because of the wide therapeutic index of aciclovir. Other medicines which affect renal physiology could affect plasma levels of aciclovir.

In patients receiving high-dose VALZOST (8 g/day) for CMV prophylaxis, caution is required during concurrent administration with medicines which compete with aciclovir for elimination, because of the potential for increased plasma levels of one or both medicines 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 medicines are co-administered. Care is also required (with monitoring for changes in renal function) if administering high-dose VALZOST with medicines which affect other aspects of renal physiology (e.g. cyclosporin, tacrolimus).

Safety in pregnancy and lactation has not been established (see u201cCONTRAINDICATIONSu201d).

Teratogenicity: Foetal abnormalities were observed in rats.

When driving vehicles or using machines it should be taken into account that dizziness, weariness or visual disturbances may occur.

Blood and the lymphatic system disorders

Less Frequent: Aplastic anaemia, thrombocytopenia, haemolytic anaemia, micro-angiopathic, neutropenia, leukocytoclastic vasculitis.

Immune system disorders

Less Frequent: Acute hypersensitivity reactions and anaphylaxis and angioedema.

Nervous system disorders

Frequent: Headache. Less frequent: Decreased consciousness in patients with renal insufficiency, dizziness, somnolence, convulsions, fatigue, aggressive behaviour, agitation, ataxia, coma, confusion, dysarthria, encephalopathy, seizures and tremors.

Psychiatric disorders

Less Frequent: Mania and psychosis, including auditory and visual hallucinations.

Eye disorders

Less Frequent: Visual abnormalities.

Cardiac disorders

Less Frequent: Tachycardia.

Vascular disorder

Less Frequent: Hypertension.

Gastrointestinal disorders

Frequent: Nausea. Less frequent: Gastrointestinal disturbances such as constipation, diarrhoea, loss of appetite, stomach pain, vomiting.

Hepato - biliary disorders

Less frequent: Hepatitis with liver function test abnormalities, jaundice.

Skin and subcutaneous tissue disorders

Less Frequent: Facial oedema skin reactions such as erythema multiforme, photosensitivity, or rash (redness of the skin), alopecia, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria, pruritus.

Musculoskeletal, connective tissue and bone disorders

Less Frequent: Arthralgia.

Renal and urinary disorders

Less Frequent: Renal insufficiency manifested by increased serum creatinine, acute renal failure.

Reproductive system and breast disorders

Less Frequent: Dysmenorrhoea.

Symptoms and signs: There are at present no data available on overdose with VALZOST. In animal studies, large doses caused obstructive uropathy and crystalluria.

Management: In the event of asymptomatic VALZOST overdose occurring, aciclovir is removable by haemodialysis.