Document: spc-doc_PL 29831-0003 change

• spc-doc_PL 12762-0107
• spc-doc_PL 29831-0003
• spc-doc_PL 29831-0519

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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Aciclovir Tablets BP 800mg

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Aciclovir PhEur 800mg

3    PHARMACEUTICAL FORM

Oral - tablets

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Treatment of herpes simplex virus (HSV) infections of the skin and mucous membranes including initial and recurrent genital herpes (excluding neonatal HSV and severe HSV infections in immunocompromised children).

Suppression of recurrent herpes simplex virus infections.

Prevention of herpes simplex virus infections in immunocompromised patients.

Treatment of herpes zoster infections.

4.2    Posology and method of administration

Treatment of herpes simplex infections of the skin and mucous membranes including initial and recurrent genital herpes

Adults: 200mg five times daily (usually every four hours while awake), for five days. In severe infections, duration of treatment may be extended. Aciclovir is effective only if started at the onset of symptoms.

Renal impairment: For patients with a creatinine clearance of less than 10ml per minute, reduce dosage to 200mg every 12 hours.

Elderly: dosage reduction may be required.

Children aged two to fourteen years: adult dose.

Children under two years: half the adult dose.

Suppression of recurrent herpes simplex infections

Adults: 200mg four times daily or 400mg twice daily which can be reduced to 200mg two or three times daily. Therapy should be interrupted every six to twelve months for reassessment of the condition.

Renal impairment: For patients with a creatinine clearance of less than 10ml per minute, reduce dosage to 200mg every 12 hours.

Elderly: dosage reduction may be required.

Children aged two to fourteen years: adult dose.

Children under two years: half the adult dose.

Prevention of herpes simplex infections in immunocompromised patients

Adults: 200mg four times daily for the duration of the period of risk. In severely immunocompromised patients or patients with impaired absorption from the gut, the dose may be increased to 400mg four times daily.

Renal impairment: For patients with a creatinine clearance of less than 10ml per minute, reduce dosage to 200mg every 12 hours.

Elderly: dosage reduction may be required.

Children aged two to fourteen years: adult dose.

Children under two years: half the adult dose.

Adults: 800mg five times daily (usually every four hours while awake) for seven days. Treatment should begin as early as possible and not later than three days after the first sign of outbreak.

Renal impairment: For patients with a creatinine clearance of 10 to 25ml per minute, reduce dosage to 800mg three to four times daily. For patients with a creatinine clearance of less than 10ml per minute, reduce dosage to 800mg twice daily.

Elderly: dosage reduction may be required

4.3 Contraindications

Aciclovir tablets are contraindicated in patients known to be hypersensitive to aciclovir, valaciclovir or to any of the excipients.

4.4 Special warnings and precautions for use

Hydration status:

Care should be taken to maintain adequate hydration in patients receiving high oral doses of aciclovir.

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.

Aciclovir should also be used with caution in patients with underlying neurological abnormalities, severe hepatic or electrolyte abnormalities or significant hypoxia.

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

No clinically significant interactions have been identified.

Aciclovir is eliminated primarily unchanged in the urine via active renal tubular secretion. Any drugs administered concurrently that 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.

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

Antivirals: fatigue has been associated with the combined use of aciclovir and zidovudine.

Aciclovir may increase serum theophylline levels.

4.6 Pregnancy and lactation

Pregnancy

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 cause.

Lactation

Following oral administration of 200mg 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’ ability to drive or operate machinery.

There have been no studies to investigate the effects 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 >1/1,000 and <1/100, rare >1/10,000 and <1/1,000, very rare <1/10,000, not known (cannot be estimated from the available data).

Blood and lymphatic system disorders

Very rare: Anaemia, leukopenia, thrombocytopenia

Not known: Haematological changes, including megaloblastic anaemia

Immune system disorders

Rare: Anaphylaxis

Not known: Lymphadenopathy

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)

Not known: Paraesthesia

Eye disorders

Not known: Visual abnormalities

Cardiovascular disorders Not known: Peripheral oedema

Respiratory, thoracic and mediastinal disorders Rare: Dyspnoea

Gastrointestinal disorders

Common: Nausea, vomiting, diarrhoea, abdominal pains Hepatobiliary 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

Not known: Erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis

Musculoskeletal and connective tissue disorders Not known: Myalgia

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 Not known: Renal impairment

Renal impairment is usually reversible but may progress to acute renal failure

General disorders and administration site conditions Common: Fever, fatigue

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 20g 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).

Overdosage of intravenous aciclovir has resulted in elevations of serum creatinine, blood urea nitrogen and subsequent renal failure. 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 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

The antiviral activity of aciclovir is due to intracellular conversion to an active form that inhibits viral DNA synthesis and replication by inhibiting the herpes virus DNA polymerase enzyme as well as being incorporated into viral DNA. Herpes simplex virus type 1 appears to be the most susceptible, then type 2, followed by varicella-zoster virus.

The Epstein-Barr virus and cytomegalovirus are also susceptible to aciclovir to a lesser extent.

Aciclovir has no activity against latent viruses, but there is some evidence that it inhibits latent herpes simplex virus at an early stage of reactivation.

5.2 Pharmacokinetic properties

Aciclovir is slowly and poorly absorbed from the gastrointestinal tract and the time taken to reach peak concentrations is 1.5 to 2 hours. With multidose administration, steady-state plasma concentrations are achieved by the next day. Bioavailability is 13 to 21% and appears to decrease with increasing dosage. In adult patients with normal renal function the plasma half-life is 3.3 hours.

Aciclovir is widely distributed in tissues and body fluids including brain, kidney, lung, liver, muscle, spleen, uterus, vaginal mucosa, vaginal secretions, cerebrospinal fluid and herpetic vesicular fluid. Concentrations in kidney and lung were 10 to 13 times those of plasma concentrations after multiple dose therapy and 25 to 70% of the plasma level was found in the brain, spinal cord and cerebrospinal fluid. Limited human data show that aciclovir passes into breast milk and levels can be three to four times higher than in serum.

Aciclovir persists in the plasma of patients with renal insufficiency and the mean terminal plasma half-life recorded in patients with end stage renal disease is 19.5 hours. Aciclovir is readily removed by haemodialysis.

In infants of less than three months of age, the plasma half-life is slightly prolonged to about 3.8 hours and clearance is about one third of that found in older children and adults. In neonates (0 to 3 months of age) treated with doses of 10 mg/kg administered by infusion over a one-hour period every 8 hours the C^ssmax was found to be 61.2 micromolar (13.8 microgram/ml) and the C^ssmin to be 10.1 micromolar (2.3 microgram/ml). A separate group of neonates treated with 15 mg/kg every 8 hours showed approximate dose proportional increases, with a Cmax of 83.5 micromolar (18.8 microgram/ml) and Cmin of 14.1 micromolar (3.2 microgram/ml).

The pharmacokinetics of aciclovir in children over one year old seem to be similar to those of adults.

5.3 Preclinical safety data

There are no pre-clinical data of relevance to the prescriber that are additional to those included in other sections.

PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Gelatin PhEur Lactose PhEur Maize Starch PhEur Microcrystalline Cellulose PhEur Sodium Starch Glycollate PhEur Magnesium Stearate PhEur

6.2    Incompatibilities

None

6.3    Shelf life

36 months.

6.4    Special precautions for storage

Do not store above 25°C

6.5    Nature and contents of container

Aciclovir Tablets BP 800 mg are available in blister packs of 35 tablets.

6.6    Special precautions for disposal

No special requirements

7    MARKETING AUTHORISATION HOLDER

Wockhardt UK Limited Ash Road North Wrexham LL13 9UF