Zelivire 500 mg Tablet

ZELIVIRE 500 is indicated for the treatment of herpes zoster (shingles). ZELIVIRE 500 reduces the duration of zoster associated pain, which includes acute and post-herpetic neuralgia, thus accelerating resolution of pain. ZELIVIRE 500 also reduces the proportion of patients with zoster associated pain. ZELIVIRE 500 is indicated for the episodic treatment of recurrent genital herpes in immunocompetent adult patients.

ZELIVIRE 500 is indicated for prevention (suppression) of recurrent herpes simplex infection of the skin and mucous membrane of the ano-genital area. ZELIVIRE 500 is indicated for the prophylaxis of cytomegalovirus (CMV) infection, CMV disease and other herpes virus infections following organ transplantation, where a special risk exists. Treatment should be initiated as soon as possible following the onset of signs and symptoms. In the treatment of recurrent genital herpes there are no data on effectiveness of ZELIVIRE 500 when initiated more than 24 hours after the onset of signs and symptoms.

Posology

For the treatment of herpes zoster: 1 000 mg of ZELIVIRE 500 to be taken 3 times per day for 7 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 on first signs or symptoms appearance. There are no data on effectiveness of ZELIVIRE 500 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 daily dose of 500 mg being taken as 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 4 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). Duration of treatment will usually be 90 days but may need to be extended in high risk patients.

Special populations

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.

Dosing in high-risk individuals

Dosage in renal impairment: Caution is advised when administering ZELIVIRE 500 to patients with impaired renal function. Adequate hydration should be maintained. The dose of ZELIVIRE 500 should be modified as follows in patients with significantly impaired renal function:

HERPES ZOSTER

• Creatinine Clearance 15 u2013 30 mL/min: ZELIVIRE 500 dose 1 000 mg twice daily
• Creatinine Clearance <15 mL/min: ZELIVIRE 500 dose 1 000 mg once daily

RECURRENT GENITAL HERPES

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

PREVENTION OF RECURRENCES

• Creatinine Clearance 15 u2013 30 mL/min: Immunocompetent: No dosage adjustment required; Immunocompromised: No dosage adjustment required
• Creatinine Clearance <15 mL/min: Immunocompetent: 250 mg once daily; Immunocompromised: 500 mg once daily

In patients on haemodialysis, the ZELIVIRE 500 dose recommended for patients with a creatinine clearance of <15 mL/min should be used, but the dose should be administered after the haemodialysis has been performed.

CMV Prophylaxis: Dosage of ZELIVIRE 500 should be adjusted in patients with impaired renal function as shown in the table below:

Creatinine Clearance

• > 75 mL/min: ZELIVIRE 500 dose 2 000 mg four times daily
• 50 to < 75 mL/min: ZELIVIRE 500 dose 1 500 mg four times daily
• 25 to < 50 mL/min: ZELIVIRE 500 dose 1 500 mg three times daily
• 10 to < 25 mL/min: ZELIVIRE 500 dose 1 500 mg twice daily
• < 10 mL/min or dialysis: ZELIVIRE 500 dose 1 500 mg once daily

** In patients with haemodialysis, the ZELIVIRE 500 dosage should be administered after haemodialysis has been performed. Creatinine clearance should be monitored frequently, especially during periods when renal function is changing rapidly e.g. immediately after transplantation or engraftment. The ZELIVIRE 500 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 recommended for CMV prophylaxis (4 g or more) see section 4.8.

ZELIVIRE 500 is contraindicated in patients known to be hypersensitive to valaciclovir, aciclovir or to any of the excipients listed in section 6.1. Safety in pregnancy and lactation has not been established (see section 4.6).

Drug reaction with eosinophilia and systemic symptoms (DRESS) DRESS, which can be life-threatening or fatal, has been reported in associate 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.

Thrombotic, thrombocytopenic uraemic syndrome, in some cases resulting in death, have been reported in patients with advanced HIV disease and also in bone marrow transplant and renal transplant recipients participating in clinical trials of valaciclovir. This syndrome has not been observed in immunocompetent patients treated with valaciclovir 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. 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. These reactions were generally reversible on discontinuation of treatment (see section 4.8).

Uses of higher doses of ZELIVIRE 500 in Hepatic impairment and liver transplantation: There are no data available on the use of high doses of ZELIVIRE 500 (4 g/day) in patients with liver disease. Caution should therefore be exercised when administering high doses of ZELIVIRE 500 to these patients. Studies of ZELIVIRE 500 have not been conducted in liver transplantation; however high dose acyclovir prophylaxis has been shown to reduce CMV infection and disease. In organ transplant patients receiving high doses ZELIVIRE 500 for CMV prophylaxis, neurological reactions occurred more frequently compared with lower doses.

Use in genital herpes: Suppressive therapy with ZELIVIRE 500 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 ZELIVIRE 500, it is recommended that patients use safer sex practices. Patients should avoid sexual intercourse and contact with lesions and damaged skin. Genital herpes may be transmitted in the absence of symptoms and patients should be counselled to use safer sex practices.

Teratogenicity: Foetal abnormalities were observed in rats. The therapeutic peak is 5,7 mcg/mL after 1 000 mg.

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.

Concomitant use which requires some care: In patients receiving high dose valaciclovir (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 inactive metabolites of mycophenolate mofetil, an immunosuppressant agent used in transplant patients, have been shown when these medicines are co-administered. Care is also required (with monitoring for changes in renal function) if administering high dose valaciclovir with medicines which affect other aspects of renal physiology (e.g. cyclosporin, tacrolimus).

Pregnancy: Safety in pregnancy has not been established (see section 4.3).

Breastfeeding: Safety in lactation has not been established (see section 4.3). Following oral administration of a 500 mg dose of ZELIVIRE 500, peak acyclovir concentrations (Cmax) in breast milk ranged from 0,5 to 2,3 (median 1,4) times the corresponding maternal acyclovir serum concentrations. Mothers on treatment with ZELIVIRE 500 should not breastfeed their infants.

Fertility: There is no fertility data available.

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 ZELIVIRE 500 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.

Valaciclovir was well tolerated when used for the treatment of herpes zoster or herpes simplex in clinical trials.

Tabulated list of adverse reactions

MedDRA System organ class

Frequency

Adverse reactions

Blood and lymphatic system disorders

Less frequent: Thrombocytopenia, anaemia.

Frequency Unknown: Leucopenia, neutropenia

Immune system disorders

Frequency Unknown: Hypersensitivity reactions including rash, photosensitivity, urticaria, pruritus, dyspnoea, angioedema, anaphylaxis.

Psychiatric and Nervous system disorders

Frequent: Headaches

Less frequent: Fatigue, reversible neurological reactions such as dizziness.

Frequency Unknown: Reversible neurological reactions such as agitation, aggressive behaviour, confusional states, delirium, decreased consciousness, hallucinations, tremors, ataxia, dysarthria, psychosis, somnolence, convulsions, encephalopathy, coma (especially in patients with renal impairment in whom the dosage was in excess of that recommended).

Gastrointestinal disorders

Frequent: Nausea.

Less frequent: Vomiting, diarrhoea, abdominal pains.

Hepato-biliary disorders

Less frequent: Hepatitis

Frequency Unknown: Reversible increases in bilirubin and liver enzymes, jaundice.

Renal and urinary disorders

Frequency Unknown: Increases in blood urea and creatinine, acute renal failure.

MedDRA System organ class

Frequency

Adverse reactions

Skin and subcutaneous tissue disorders

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

Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website.

Suspected adverse reactions can also be reported directly to the Holder of certificate of registration via email: [email protected] or Tel: +27(0) 12 643 2000.

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 ZELIVIRE 500. 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 ZELIVIRE 500 overdose occurring, aciclovir is removable by haemodialysis.