ZELITREX Tablet Ref.[50340] Active ingredients: Valaciclovir

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 patient’s 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 ≥1 in 10, common ≥1 in 100 and <1 in 10, uncommon ≥1 in 1 000 and <1 in 100, rare ≥1 in 10000 and <1 in 1000, very rare <1 in 10000.

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.

Uses of higher doses of ZELITREX in Hepatic Impairment and Liver Transplantation

There are no data available on the use of high doses of ZELITREX (4 g or more per day) in patients with liver disease. Caution should therefore be exercised when administering high doses of ZELITREX to these patients. Studies of ZELITREX have not been conducted in liver transplantation; however high dose acyclovir prophylaxis has been shown to reduce CMV infection and disease.

Use in genital herpes: Suppressive therapy with ZELITREX 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 ZELITREX, it is recommended that patients use safer sex practices.

Teratogenicity: Foetal abnormalities were observed in rats. The therapeutic peak is 5,7 µg/ml after 1000 mg.