Lovire 200 mg and 400 mg Tablets

LOVIRE u00ae Tablets are indicated for:

• Treatment of initial and recurrent Herpes simplex infections of the skin and mucous membranes including initial and recurrent genital Herpes simplex virus infections in both immunocompetent and immunocompromised patients.
• Suppression of recurrent genital Herpes simplex infections in immunocompetent patients.
• Prophylaxis of Herpes simplex infections in immunocompromised patients.
• Treatment of Herpes zoster (shingles) infections if the lesions are not older than 72 hours.
• Treatment of Varicella zoster (chicken pox) infection within 24 hours after appearance of the typical chicken pox lesions.
• Reduction of mortality and risk of developing herpes virus infections in certain severely immunocompromised patients, namely those with advanced HIV disease (CD4+ counts <200/mm3 including patients with AIDS or ARC) or following bone marrow transplantation. In patients with advanced HIV disease, LOVIRE u00ae Tablets has been used in conjunction with oral zidovudine.
• In patients following bone-marrow transplantation oral LOVIRE u00ae Tablets must be preceded by one monthu2019s intravenous treatment with acyclovir*.

* The applicant does not have an intravenous dosage form registered nor marketed, another acyclovir brand can be used.

LOVIRE u00ae Tablets may be taken with or without meals. The tablets must be dispersed in 50 ml of water or swallowed whole.

Treatment of Herpes simplex infections of the skin and mucous membranes

Adults: 200 mg every four hours, five times a day (omitting the night time dose) for 5 days. In severe infections, the duration of treatment may be extended.

In severely immunocompromised patients or in patients with impaired gastro-intestinal absorption, the dose may be increased to 400 mg five times per day. Alternatively, intravenous administration may be considered.

Treatment should be initiated as early as possible after the start of an infection, or in the case of recurrent episodes, treatment should be started during the prodromal period or when lesions first appear.

Suppression of recurrent genital Herpes simplex infections in immunocompetent adults

Adults: 200 mg four times a day at approximately six-hourly intervals. Some patients may be adequately treated with 400 mg twice a day at approximately twelve-hourly intervals, while 200 mg three times per day, or even twice daily at approximately twelve-hourly intervals, may be suitable for some patients. Some patients may experience breakthrough infections on total daily doses of 800 mg acyclovir. Therapy should be periodically interrupted at intervals of six to twelve months, in order to observe possible changes in the natural history of the disease.

Prophylaxis of Herpes simplex infections in immunocompromised adults

Adults: 200 mg four times per day, at approximately six-hourly intervals. In severely immunocompromised patients (e.g. after marrow transplant) or in patients with impaired gastro-intestinal absorption, the dose may be increased to 400 mg four times per day or change to intravenous administration. The duration of prophylactic administration is determined by the duration of the period at risk.

Treatment of Herpes zoster and Varicella zoster infections

Adults: 800 mg five times per day (omitting the night time dose) for 7 days. Intravenous (IV) administration should be considered for severely immunocompromised patients (e.g. after marrow transplant) or in patients with impaired gastro-intestinal absorption. Treatment should be initiated as soon as possible after the rash appears. Intravenous administration may be considered if necessary.

For treatment of varicella-zoster infections in adolescents (12 to 18 years): A dose of 800 mg oral LOVIRE u00ae Tablets should be taken four times daily for five days.

Severely immunocompromised patients

Adults: 800 mg four times per day at six hourly intervals. Bone marrow recipients should receive intravenous (IV) aciclovir 3 times daily for one month prior to receiving oral therapy. Duration of therapy is 6 months from 1 to 7 months post-transplant) and 12 months in patients with advanced HIV disease.

Special populations

Elderly Population: Adequate hydration must be ensured in patients taking high doses of LOVIRE u00ae Tablets. Plasma concentrations of LOVIRE u00ae Tablets are higher in geriatric patients compared to younger patients, in part due to age-related changes in renal function. Dose reductions may be necessary in the elderly with impaired renal function (See section 4.4).

Renal function impairment: Caution is advised when administering LOVIRE u00ae Tablets to patients with impaired renal function. Adequate hydration should be maintained.

Treatment and prophylaxis of Herpes simplex infections

Mild to moderate impairment u2013 No dose adjustment necessary.

Severe impairment (creatinine clearance less than 10 ml/min) u2013 200 mg every 12 hours.

Treatment of Varicella and Herpes zoster infections and management of severely immunocompromised patients (usual dose is 800 mg every four hours)

Moderate impairment (creatinine clearance of 10 to 25 ml/min) u2013 800 mg every 8 hours.

Severe impairment (creatinine clearance less than 10 ml/min) u2013 800 mg every 12 hours.

Adjusted Dosage

Normal Dosage (5 times daily) Creatinine Clearance (ml/min/1,73 m2) Dose (mg) Dosing Interval (hours) 200 mg every 4 hours > 10 200 every 4 hours 5 times daily 0-10 200 every 12 hours 800 mg every 4 hours 10-25 800 every 8 hours 0-10 800 every 12 hours

Paediatric population

Treatment of Herpes simplex infections and prophylaxis of Herpes simplex infections in immunocompromised children: Two years and older: Adult dosage. Under two years: Half the adult dose (limited data).

Treatment of Herpes zoster and Varicella zoster infections in children: Two years and older: Adult dosage. Below two years: Half the adult dosage. LOVIRE u00ae Tablets in children less than 2 years of age has not been fully studied. Dosing for varicella (chickenpox) may be more accurately calculated as 20 mg LOVIRE u00ae Tablets per kilogram bodymass (not to exceed 800 mg) four times daily. Treatment should continue for five days and should start within 24 hours after appearance of typical chickenpox rash. Limited data suggest that for management of severely immunocompromised children, over two years of age, the adult dose may be given.

Method of administration: The tablets must be dispersed in 50 ml of water or swallowed whole with a little water.

Hypersensitivity to aciclovir, valaciclovir or to any components of LOVIRE u00ae Tablets

Drug reaction with eosinophilia and systemic symptoms (DRESS) DRESS, which can be life-threatening or fatal, has been reported in associate with aciclovir 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, LOVIRE u00ae Tablets should be withdrawn immediately and an alternative treatment considered (as appropriate). If the patient has developed DRESS with the use of LOVIRE u00ae Tablets, treatment with LOVIRE u00ae Tablets must not be restarted in this patient at any time.

There is limited data on the use of LOVIRE u00ae Tablets in pregnancy and lactation (see section 4.6). Care should be taken to maintain adequate hydration in patients receiving high doses of LOVIRE u00ae Tablets. LOVIRE u00ae Tablets should be administered with caution with renal impairment and doses should be adjusted according to creatinine clearance. Severe renal impairment u2013 A dose reduction is required in patients with a creatinine clearance of <10 mL/minute (See Section 4.2). In the elderly, total acyclovir body clearance declines in parallel with creatinine clearance. Adequate hydration of elderly patients taking high oral doses of should be maintained. Special attention should be given to dosage reduction in elderly patients with impaired renal function. Accidental, repeated overdoses of oral acyclovir over several days have been associated with gastrointestinal effects (such as nausea and vomiting) and neurological effects (headache and confusion).

Although no clinically significant interactions have been reported, any medicine which is excreted via renal tubular secretion may compete with and thus interact with LOVIRE u00ae Tablets. Probenecid and Cimetidine has been shown to decrease renal excretion of aciclovir and to increase the area under the curve (AUC) of aciclovir. No significant increase in toxicity was noted when zidovudine was given together with acyclovir.

There is limited data on the use of LOVIRE u00ae Tablets in pregnancy and lactation. The data is insufficient to establish safety. Safety and efficacy in pregnancy and lactation have not been established.

Pregnancy: A post-marketing acyclovir pregnancy registry has documented pregnancy outcomes in women exposed to LOVIRE u00ae Tablets. The registry findings have not shown an increase in the number of birth defects amongst aciclovir (as contained in LOVIRE u00ae Tablets) exposed subjects compared with the general population, and any birth defects showed no uniqueness or consistent pattern to suggest a common cause.

Lactation: Following oral administration of 200 mg acyclovir as contained in LOVIRE u00ae five times a day, acyclovir has been detected in breast milk at concentrations ranging from 0,6 to 4,1 times the corresponding plasma levels. These levels would potentially expose nursing infants to aciclovir dosages of up to 0,3 mg/kg/day.

Fertility: There is no information on the effect of LOVIRE u00ae on human female fertility. In a reported study of 20 male patients with normal sperm count, oral acyclovir administered at doses of up to 1 g per day for up to six months has been shown to have no clinically significant effect on sperm count, motility or morphology.

LOVIRE u00ae may influence the ability to drive and use machines. When driving vehicles or operating machines, it should be taken into account that dizziness may occur during treatment.

The frequency categories associated with the adverse events below are estimates. For most events, suitable data for estimating incidence were not available. In addition, adverse events may vary in their incidence depending on the indication.

Table 1: Tabulated List of Undesirable effects

System organ class Frequent Less frequent Frequency Not known

Blood and lymphatic system disorders - Anaemia, leucopenia, thrombocytopenia, neutropenia -

Immune system disorders - Hypersensitivity reactions including rash, photosensitivity, urticaria, pruritus, dyspnoea, angioedema, anaphylaxis. -

Psychiatric disorders Headache, dizziness Reversible neurological reactions such as, confusional states, hallucinations, tremors, psychosis, agitation, somnolence, convulsions, coma (especially in patients with renal impairment in whom the dosage was in excess of that recommended.

Nervous system disorders Headache Fatigue

Gastro-intestinal disorders Nausea, vomiting, diarrhoea, Abdominal pain

Hepato-biliary disorders - Reversible increases in bilirubin and liver enzymes, hepatitis, jaundice -

Skin and subcutaneous tissue disorders - Diffuse hair loss -

Renal and urinary disorders - Increases in blood urea and creatinine, acute renal failure -

General disorders and administration site conditions Fatigue, fever - -

Table 1: Tabulated List of Post marketing undesirable effects

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)

See Undesirable effects

Symptoms of overdose LOVIRE u00ae Tablets have a wide therapeutic window and therefore excessive doses of LOVIRE u00ae Tablets are generally well tolerated. Repeated overdoses of oral aciclovir have been associated with gastro-intestinal effects (such as nausea and vomiting) and neurological effects (such as headache) and psychiatric effects (such as confusion).

Treatment of overdose Patients should be observed closely for signs of toxicity. Treatment is symptomatic and supportive. Haemodialysis, if required, significantly enhances the removal of LOVIRE u00ae Tablets from the blood.