SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Fyris 400 mg Tablets Aciclovir 400 mg Tablets BP

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains aciclovir Ph. Eur 400 mg.

For excipients, see 6. 1.

3. PHARMACEUTICAL FORM

Tablet

Pink, flat bevel-edged, round tablets engraved 1F2.

4    CLINICAL PARTICULARS

4.1.    Therapeutic Indications

Aciclovir Tablets may be used in the treatment of infections of the skin and mucous membranes due to herpes simplex virus including initial and recurrent genital herpes; chickenpox (varicella) and shingles (herpes zoster); the suppression (prevention of recurrence) of recurrent infections due to herpes simplex in immunocompetent patients or the prophylaxis of infections due to herpes simplex in immunocompromised patients.

4.2 Posology and method of administration

For oral administration.

Aciclovir 400 mg Tablets should be swallowed whole with a little water. Adults:

Treatment of infections due to herpes simplex virus 200 mg five times a day, with approximately four hours between doses omitting the night time dose, for five days.

In severe initial infections the duration of treatment may have to be extended.

The dose can be doubled to 400 mg five times a day for patients with impaired absorption from the gut or for severely immunocompromised patients. Treatment should start as early as possible; for recurring infections, at the onset, or when lesions first appear.

Treatment of varicella and herpes zoster

800 mg five times a day, with approximately four hours between doses, omitting the night time dose, for seven days. Treatment should start as early as possible; within 24 hours of the chickenpox rash appearing; treatment of shingles gives better results if started early after the onset of the rash.

Suppression of infections due to herpes simplex in immunocompetent patients

200 mg four times a day with approximately six hours between doses or 400 mg two times a day with approximately twelve hours between doses.

The dose may prove effective when titrated down to 200 mg three times a day with approximately eight hours between doses or 200 mg two times a day with approximately twelve hours between doses.

Some patients taking as much as 800 mg aciclovir a day may experience break-through infections.

Periodic interruption of treatment at six to twelve month intervals will allow possible changes in the natural history of the disease to be observed.

Prophylaxis of infections due to herpes simplex in immunocompromised patients

200 mg four times a day with approximately six hours between doses.

The dose can be doubled to 400 mg four times a day for patients with impaired absorption from the gut or severely immunocompromised patients.

The period of patient risk will determine the duration of administration of prophylaxis.

Paediatric population

Treatment and prophylaxis of infections due to herpes simplex in the immunocompromised

Two years and above: adult doses are appropriate.

Under two years: half the adult dose.

Treatment of varicella

6 years and above: 800 mg four times a day.

2 to 5 years: 400 mg four times a day.

Under 2 years: 200 mg four times a day

or 20 mg/kg bodyweight (not to exceed 800 mg) four times a day.

Treatment should continue for five days.

Specific data are not available on the suppression of infections due to herpes simplex or the treatment of herpes zoster in immunocompetent children.

Elderly

Total aciclovir body clearance and creatinine clearance show concomitant decline. The possibility of renal impairment in the Elderlry patients must be considered and the dosage should be adjusted accordingly.(see Dosage in renal impairment below).

Adequate hydration of Elderlry patients taking high oral doses of aciclovir should be maintained.

Patients with renal impairment:

Caution is advised when administering aciclovir to patients with impaired renal function.

Adequate hydration should be maintained.

In the management of herpes simplex infections in patients with severe renal impairment (creatinine clearance less than 10 ml/minute) an adjustment of dosage to 200 mg aciclovir twice daily at approximately twelve-hourly intervals is recommended.

In the treatment of herpes zoster infections it is recommended to adjust the dosage to 800 mg aciclovir twice daily at approximately twelve - hourly intervals for patients with severe renal impairment (creatinine clearance less than 10 ml/minute), and to 800 mg aciclovir three times daily at intervals of approximately eight hours for patients with moderate renal impairment (creatinine clearance in the range 10 - 25 ml/minute).

4.3 Contraindications

Known hypersensitivity to aciclovir or valaciclovir or to any of the excipients.

4.4 Special warnings and precautions for use

Adequate hydration should be maintained in patients given high oral doses of aciclovir e.g. for the treatment of herpes zoster infection (4 g daily), in order to avoid the possibility of renal toxicity.

The risk of renal impairment is increased by use with other nephrotoxic drugs.

Use in patients with renal impairment and in Elderly Patients:

Aciclovir is eliminated by renal clearance, therefore the dose must be reduced in patients with renal impairment (see section 4.2). 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 section 4.8).

Prolonged or repeated courses of aciclovir in severely immune-compromised individuals may result in the selection of virus strains with reduced sensitivity, which may not respond to continued aciclovir treatment (see section 5.1).

Clinical study data currently available is not sufficient to enable the conclusion that aciclovir treatment reduces the incidence of chickenpox-associated complications in immunocompetent patients.

Despite reports of largely reversible effects on spermatogenesis in rats and dogs at doses greatly exceeding those used therapeutically, aciclovir tablets have been shown to have no definite effect upon sperm count, morphology or motility in man.

This medicinal product contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Aciclovir is eliminated primarily unchanged in the urine via active renal tubular secretion. Any drugs administered concurrentlythat compete with this mechanism may increase aciclovir plasma concentrations. Probenecid and cimetidine increase the AUC of aciclovir by this mechanism, and reduce aciclovir renal clearance. Similarly 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 drugs are coadministered. However, no dosage adjustment is necessary because of the wide therapeutic index of aciclovir.

An experimental study on five male subjects indicates that concomitant therapy with aciclovir increases AUC of totally administered theophylline with approximately 50%. It is recommended to measure plasma concentrations during concomitant therapy with aciclovir.

4.6 Fertility, pregnancy and lactation

Fertility

There is no experience of the effect of aciclovir tablets on human female fertility. Two-generation studies in mice did not reveal any effects of aciclovir on fertility.

Pregnancy

Experience of use in pregnancy is limited, and the use of aciclovir should be considered only when the potential benefits outweigh the possibility of unknown risks.

A post-marketing aciclovir pregnancy registry has documented pregnancy outcomes in women exposed to any formulation of aciclovir. The registry findings have not shown an increase in the number of birth defects amongst aciclovir exposed subjects compared with the general population, and any birth defects showed no uniqueness or consistent pattern to suggest a common caus.

Systemic administration of aciclovir in internationally accepted standard tests did not produce embryotoxic or teratogenic effects in rats, rabbits or mice.

In a non-standard test in rats, foetal abnormalities were observed, but only following such high subcutaneous doses that maternal toxicity was produced.

The clinical relevance of these findings is uncertain.

Lactation

Following oral administration of 200 mg aciclovir five times a day, aciclovir 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. Caution is therefore advised if aciclovir is to be administered to a nursing woman.

4.7 Effects on ability to drive and use machines

The clinical status of the patient and the adverse event profile of aciclovir should be borne in mind when considering the patients’s ability to drive or operate machinery.

There have been no studies to investigate the effect of aciclovir 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.

4.8 Undesirable effects

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.

The following convention has been used for the classification of undesirable effects in terms of frequency:- Very common >1/10, common >1/100 and <1/10, uncommon >1/1000 and <1/100, rare >1/10,000 and <1/1000, very rare <1/10,000.

Blood and lymphatic system disorders

Rare:    Anaemia, leukopenia, thrombocytopenia

Immune system disorders

Rare:    Anaphylaxis

*Psychiatric and nervous system disorders

Common:    Headache, dizziness

Very rare:    Agitation, confusion, tremor, ataxia, dysarthria, hallucinations,

psychotic symptoms,convulsions, somnolence, encephalopathy, coma

*The above events are generally reversible and usually reported in patients with renal impairment, or with other predisposing factors (see section 4.4).

Respiratory, thoracic and mediastinal disorders

Rare:    Dyspnoea

Gastrointestinal disorders

Common:    Nausea, vomiting, diarrhoea, abdominal pains

Hepato-biliary disorders

Rare:    Reversible rises in bilirubin and liver related enzymes

Very rare:    Hepatitis, jaundice

Skin and subcutaneous tissue disorders

Common:    Pruritus, rashes (including photosensitivity)

Uncommon:    Urticaria, accelerated diffuse hair loss.

Accelerated diffuse hair loss has been associated with a wide variety of disease processes and medicines, the relationship of the event to aciclovir therapy is uncertain.

Rare:    Angioedema

Renal and urinary disorders

Rare:    Increases in blood urea and creatinine

Very rare:    Acute renal failure, renal pain

Renal pain may be associated with renal failure.

General disorders and administration site conditions

Common:    Fatigue, fever

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Symptoms and signs:

Aciclovir is only partly absorbed in the gastrointestinal tract. Patients have ingested overdoses of up to 20 g of aciclovir on a single occasion, usually without toxic effects. Accidental, repeated overdoses of oral aciclovir over several days have been associated with gastrointestinal effects (such as nausea and vomiting) and neurological effects (headache and confusion).

Neurological effects including confusion, hallucinations, agitation, seizures and coma have been described in association with overdosage.

Treatment

Patients should be observed closely for signs of toxicity. Haemodialysis significantly enhances the removal of aciclovir from the blood and may, therefore, be considered a management option in the event of symptomatic overdose.

5.1. Pharmacodynamic Properties

ATC Code: DO6B B03 Antivirals

Aciclovir is a synthetic purine nucleoside analogue structurally related to guanine. It is used in the treatment of viral infections due to herpes simplex virus (types 1 and 2) and varicella and herpes zoster virus. Initial and recurrent infections can be treated successfully. Extended treatment can reduce the incidence of recurrence, this is important in immunocompromised patients. However, when treatment is withdrawn infections may recur.

5.2. Pharmacokinetic Properties

15 to 30% of an oral dose of aciclovir is considered to be absorbed from the gastrointestinal tract. 200 mg aciclovir every 4 hours is reported to produce minimum and maximum steady-state plasma concentrations of 0.29 and 0.56 pg per ml respectively; equivalent values following 400 mg doses are 0.6 and 1.2 pg per ml.

Aciclovir crosses the placenta and is excreted in breast milk in concentrations up to approximately 4 times higher than those in maternal serum.

5.3 Preclinical safety data

Preclinical information has not been included because the safety profile of aciclovir has been established after many years of clinical use. Please refer to section 4.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Lactose Monohydrate Microcrystalline Cellulose Sodium Starch Glycollate (Type A)

Povidone (E1201)

Magnesium Stearate (E572)

Dispersed red (E122).

6.2. Incompatibilities

None known.

Not applicable.

6.3. Shelf Life

36 months.

6.4. Special Precautions for Storage

Blister: Do not store above 25°C. Store in the original package.

HDPE containers: Do not store above 25°C. Keep the container tightly closed.

6.5. Nature and Content of Container

Blister strips in pack sizes of 25, 28, 35 or 56 tablets.

HDPE containers with caps or child resistant closures with 100 tablets. Not all pack sizes may be marketed.

6.6. Instructions for Use, Handling and Disposal

Not applicable.

7    MARKETING AUTHORISATION HOLDER

Teva UK Limited, Eastbourne, BN22 9AG

8.    MARKETING AUTHORISATION NUMBER(S)

PL 0289/0295

9.    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

24 June 1997

10 DATE OF REVISION OF THE TEXT

26/09/2014