Zelitrex 250mg & 500mg Tablet

ZELITREX is indicated for the treatment of herpes zoster (shingles). ZELITREX reduces the duration of zoster-associated pain, which includes acute and postherpetic neuralgia, thus accelerating resolution of pain. ZELITREX also reduces the proportion of patients with zoster-associated pain. ZELITREX is indicated for the episodic treatment of recurrent genital herpes in immunocompetent adult patients. ZELITREX is indicated for the prevention (suppression) of recurrent herpes simplex infection of the skin and mucous membrane of the ano-genital area.

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

Dosage in adults:

For treatment of herpes zoster: 1 000 mg of ZELITREX 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 ZELITREX 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): 2 000 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 Dosage in renal impairment). 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: 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: Caution is advised when administering ZELITREX to patients with impaired renal function. Adequate hydration should be maintained. The dose of ZELITREX should be modified as follows in patients with significantly impaired renal function:

Therapeutic indication

• Creatinine Clearance
• ZELITREX Dose

Herpes zoster

• 15-30 ml/min: 1 000 mg twice a day
• < 15 ml/min: 1 000 mg once a day

Recurrent genital herpes

• > 15 ml/min: 500 mg twice daily
• 0-15 ml/min: 500 mg once daily

Prevention of recurrences

• Immunocompetent
• 15-30 ml/min: No dosage adjustment
• < 15 ml/min: 250 mg once daily

• Immunocompromised
• 15-30 ml/min: No dosage adjustment
• < 15 ml/min: 500 mg once daily

In patients on haemodialysis the ZELITREX 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 ZELITREX should be adjusted in patients with impaired renal function as shown in the table below:

Creatinine Clearance

• ZELITREX Dose

u2265 75 ml/min: 2 000 mg four times daily

50 to < 75 ml/min: 1 500 mg four times daily

25 to < 50 ml/min: 1 500 mg three times daily

10 to < 25 ml/min: 1 500 mg twice daily

< 10 ml/min or dialysis: 1 500 mg once daily

** In patients on haemodialysis, the ZELITREX 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 ZELITREX 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 shunting) do not indicate the need for dosage adjustment; however, clinical experience is limited. For higher doses (4 g or more) see SIDE EFFECTS.

ZELITREX is contra-indicated in patients known to be hypersensitive to valaciclovir, acyclovir or any component of their formulations.

Thrombotic, thrombocytopenic purpura/haemolytic uremic syndrome, in some cases resulting in death, has been reported in patients with advanced HIV disease and also in bone marrow transplant and renal transplant recipients participating in clinical trials of ZELITREX. This syndrome has not been observed in immunocompetent patients treated with ZELITREX in clinical trials.

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: Acyclovir is eliminated by renal clearance, therefore the ZELITREX dose should be adjusted in patients with renal impairment (see DOSAGE AND DIRECTIONS FOR USE: Dosage in 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 (see SIDE EFFECTS).

No clinically significant interactions have been identified. Cimetidine and probenecid increase the area under the plasma concentration time curve of acyclovir by reducing its renal clearance. However no dosage adjustment is necessary because of the wide therapeutic index of acyclovir. Other medicines which affect renal physiology could affect plasma levels of acyclovir. In patients receiving high-dose ZELITREX (8 g/day) for CMV prophylaxis, caution is required during concurrent administration with medicines which compete with acyclovir for elimination, because of the potential for increased plasma levels of one or both medicines or their metabolites. Increases in plasma AUCs of acyclovir 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 ZELITREX with medicines which affect other aspects of renal physiology (e.g. cyclosporin, tacrolimus).

Pregnancy: Safety in pregnancy has not been established.

Lactation: Following oral administration of a 500 mg dose of ZELITREX, peak acyclovir concentrations (C max) in breast milk ranged from 0,5 to 2,3 (median 1,4) times the corresponding maternal acyclovir serum concentrations. Mothers on treatment with ZELITREX should not breastfeed their infants.

The clinical status of the patient and the adverse event profile of valaciclovir should be borne in mind when considering the patientu2019s ability to drive or operate machinery. There have been no studies to investigate the effect of ZELITREX on driving performance or the ability to operate machinery. Further a detrimental effect on such activities cannot be predicted from the pharmacology of the active substance.

Adverse reactions are listed below by body system organ class and by frequency. The frequency categories used are: very common u2265 1 in 10, common u2265 1 in 100 and < 1 in 10, uncommon u2265 1 in 1 000 and < 1 in 100, rare u2265 1 in 10 000 and < 1 in 1 000, very rare < 1 in 10 000. Clinical trial data have been used to assign frequency categories to adverse reactions if, in the trials, there was evidence of an association with valaciclovir (i.e. there was a statistically significant difference between the incidence in patients taking valaciclovir and placebo).

Clinical Trial Data:

Nervous system disorders: Common: Headache

Gastrointestinal disorders: Common: Nausea

Post-marketing Data:

Blood and lymphatic system disorders: Leukopenia, thrombocytopenia. Leukopenia is mainly reported in immunocompromised patients.

Immune system disorders: Anaphylaxis

Psychiatric and nervous system disorders: Dizziness, confusion, hallucinations, decreased consciousness, 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 WARNINGS AND SPECIAL PRECAUTIONS). In organ transplant patients receiving high doses ZELITREX for CMV prophylaxis, neurological reactions occurred more frequently compared with lower doses.

Respiratory, thoracic and mediastinal disorders: Dyspnoea.

Gastrointestinal disorders: Abdominal discomfort, vomiting, diarrhoea.

Hepato-biliary disorders: Reversible increases in liver function tests. These are occasionally described as hepatitis.

Skin and subcutaneous tissue disorders: Rashes including photosensitivity, pruritus, urticaria, angioedema.

Renal and urinary disorders: Renal impairment, acute renal failure, renal pain.

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, and also in bone marrow transplant and renal transplant recipients receiving high doses of ZELITREX for prolonged periods in clinical trials. These findings have also been observed in patients not treated with ZELITREX who have the same underlying or concurrent conditions.

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 ZELITREX. Nausea and vomiting may also occur. Caution is required to prevent inadvertent overdosing. Many of these reported cases involved renally impaired and elderly patients receiving repeated overdoses, due to lack of appropriate dosage reduction.

Management: In the event of a symptomatic ZELITREX overdose occurring, acyclovir is removable by haemodialysis.