Aciclovir 400mg Tablets

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.

Aciclovir tablets may be dispersed in a minimum of 50 ml of water or swallowed whole with a little water. Ensure that patients on high doses of acyclovir are adequately hydrated.

Dosage in adults

Treatment of herpes simplex infections: 200 mg Aciclovir should be taken five times daily at approximately four hourly intervals omitting the night timed dose. Treatment should continue for 5 days, but in severe initial infections this may have to be extended.

In severely immunocompromised patients (e.g. after marrow transplant) or in patients with impaired absorption from the gut the dose can be doubled to 400 mg Aciclovir or alternatively intravenous dosing could be considered.

Dosing should begin as early as possible after the start of an infection; for recurrent episodes this should preferably be during the prodromal period or when lesions first appear.

Suppression of herpes simplex infections in immunocompetent patients: 200 mg Aciclovir should be taken four times daily at approximately six-hourly intervals.

Many patients may be conveniently managed on a regimen of 400 mg Aciclovir twice daily at approximately twelve-hourly intervals.

Dosage titration down to 200 mg Aciclovir taken thrice daily at approximately eight-hourly intervals or even twice daily at approximately twelve-hourly intervals may prove effective.

Some patients may experience break-through infection on total daily doses of 800 mg Aciclovir.

Therapy should be interrupted periodically 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 patients: 200 mg Aciclovir should be taken four times daily at approximately six-hourly intervals.

In severely immunocompromised patients (e.g. after marrow transplant) or in patients with impaired absorption from the gut, the dose can be doubled to 400 mg Aciclovir, or alternatively, intravenous dosing could be considered.

The duration of prophylactic administration is determined by the duration of the period at risk.

Treatment of varicella and herpes zoster infections: 800 mg Aciclovir should be taken five times daily at approximately four-hourly intervals, omitting the night time dose. Treatment should continue for seven days.

In severely immunocompromised patients (e.g. after marrow transplant) or in patients with impaired absorption from the gut, consideration should be given to intravenous dosing.

Dosing should begin as early as possible after the start of an infection: Treatment of herpes zoster yields better results if initiated as soon as possible after the onset of the rash. Treatment of chickenpox in immunocompetent patients should begin within 24 hours after onset of the rash.

Dosage in children

Treatment of herpes simplex infections, and prophylaxis of herpes simplex infections in the immunocompromised: Children aged two years and over should be given adult dosages and children below the age of two years should be given half the adult dose.

For treatment on neonatal herpes virus infections, intravenous aciclovir is recommended.

Treatment of varicella infection

Treatment should continue for five days.

Dosing may be more accurately calculated as 20 mg/kg bodyweight (not to exceed 800 mg) Aciclovir four times daily.

No specific data are available on the suppression of herpes simplex infections or the treatment of herpes zoster infections in immunocompetent children.

Dosage in the elderly:

The possibility of renal impairment in the elderly must be considered and the dosage should be adjusted accordingly (see Dosage in renal impairment below).

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

Dosage in 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 impaired renal function, the recommended oral doses will not lead to accumulation of aciclovir above levels that have been established safe by intravenous infusion. However for 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).

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

Hydration status:

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

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

The data currently available from clinical studies is not sufficient to conclude that treatment with acyclovir reduces the incidence of chickenpox-associated complications in immunocompetent patients.

This medicine contains less than 1 mmol sodium (23mg) per dosage unit, that is to say, essentially 'sodium-free'.

Cases of severe cutaneous adverse reactions (SCARs), including toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS) and erythema multiforme (EM) have been reported in patients treated with aciclovir. As SCARs can be life-threatening or fatal, if signs and symptoms suggestive of SCARs appear, treatment with aciclovir must be discontinued immediately, and alternative treatment should be given. Patients who have developed SCARs with the use of aciclovir or valaciclovir must not receive aciclovir (see Contraindications and Adverse Reactions)

Use in patients with renal impairment and in elderly patients:

Aciclovir is eliminated by renal clearance, therefore the dose must be adjusted in patients with renal impairment (see section 4.2 Posology and Method of Administration). Elderly patients are likely to have reduced renal function and therefore the need for dose adjustment 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 Undesirable Effects).

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).

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.

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 co-administered. 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.

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.

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

Caution should therefore be exercised by balancing the potential benefits of treatment against any possible hazard. Findings from reproduction toxicology studies are included in Section 5.3.

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.

Fertility

There is no information on the effect of aciclovir on human female fertility.

See clinical studies in section 5.2

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.

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 Special Warnings and Precautions for Use)

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

Very rare: Toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme (EM) (See Special warnings and precautions for use).

Not known: Erythema multiforme, 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 and crystalluria

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 or search for MHRA Yellow Card in the Google Play or Apple App store

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.

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.

Pharmacotherapeutic group: Direct acting antivirals, Nucleosides and nucleotides excl. reverse transcriptase inhibitors

ATC code: J05AB01.

Aciclovir is a synthetic purine nucleoside analogue with in vitro and in vivo inhibitory activity against human herpes viruses, including herpes simplex virus (HSV) types I and II and varicella zoster virus (VZV). The inhibitory activity of aciclovir for HSV I, HSV II and VZV is highly selective. The enzyme thymidine kinase (TK) of normal, uninfected cells does not use aciclovir effectively as a substrate, hence toxicity of mammalian host cells is low; however, TK encoded by HSV and VZV converts aciclovir to aciclovir monophosphate, a nucleoside analogue which is further converted to the diphosphate and finally to the triphosphate by cellular enzymes. Aciclovir triphosphate interferes with the viral DNA polymerase and inhibits viral DNA replication with resultant chain termination following its incorporation into the viral DNA.

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. Most of the clinical isolates with reduced sensitivity have been relatively deficient in viral TK, however, strains with altered viral TK or viral DNA polymerase have also been reported. In vitro exposure of HSV isolates to aciclovir can also lead to the emergence of less sensitive strains. The relationship between the in vitro determined sensitivity of HSV isolates and clinical response to aciclovir therapy is not clear.

Absorption

Aciclovir is only partially absorbed from the gut. The average oral bioavailability varies between 10 and 20%. Under fasting conditions, mean peak concentrations (C_max) of 0.4 microgram/ml are achieved at approximately 1.6 hours after a 200 mg dose administered as oral suspension or capsule. Mean peak plasma concentrations (C_ssmax) increase to 0.7 microgram/ml (3.1 micromoles) at steady state following doses of 200 mg administered every four hours. A less than proportional increase is observed for C_ssmax concentrations following doses of 400 mg and 800 mg administered four-hourly, with values reaching 1.2 and 1.8 microgram/ml (5.3 and 8 micromoles), respectively.

Distribution

The mean volume of distribution of 26 L indicates that aciclovir is distributed within total body water. Apparent values after oral administration (Vd/F) ranged from 2.3 to 17.8 L/kg. As plasma protein binding is relatively low (9 to 33%), drug interactions involving binding site displacement are not anticipated. Cerebrospinal fluid concentrations are approximately 50% of corresponding plasma concentrations at steady-state.

Metabolism

Aciclovir is predominantly excreted unchanged by the kidney. The only significant urinary metabolite is 9-[(carboxymethoxy) methyl]guanine, and accounts for 10-15% of the dose excreted in the urine.

Elimination

In adults mean systemic exposure (AUC_0-∞) to aciclovir ranges between 1.9 and 2.2 microgram*h/mL after a 200 mg dose. At this dose, the mean terminal plasma half-life after oral administration has been shown to vary between 2.8 and 4.1 hours.

In adults, the terminal plasma half-life of aciclovir after administration of aciclovir for injection is about 2.9 hours. Renal clearance of aciclovir (CLr=14.3 L/h) is substantially greater than creatinine clearance, indicating that tubular secretion, in addition to glomerular filtration, contributes to the renal elimination of the drug. The half-life and total clearance of aciclovir are dependent on renal function. Therefore, dosage adjustment is recommended for renally impaired patients.

In adults, mean steady state peak plasma concentrations (C_ssmax) following a one-hour infusion of 2.5 mg/kg, 5 mg/kg and 10 mg/kg were 22.7 micromolar (5.1 microgram/ml), 43.6 micromolar (9.8 microgram/ml) and 92 micromolar (20.7 microgram/ml) respectively. The corresponding trough concentrations (C_ssmin) 7 hours later were 2.2 micromolar (0.5 microgram/ml), 3.1 micromolar (0.7 microgram/ml) and 10.2 micromolar (2.3 microgram/ml) respectively. In children over 1 year of age similar mean peak (C_ssmax) and trough (C_ssmin) concentrations were observed when a dose of 250 mg/m² was substituted for 5 mg/kg and a dose of 500 mg/m² was substituted for 10 mg/kg.

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 C_max of 83.5 micromolar (18.8 microgram/ml) and C_min of 14.1 micromolar (3.2 microgram/ml). The terminal plasma half-life in these patients was 3.8 hours.

Special Patient Populations

Elderly

In the elderly patients with normal renal function total clearance falls with increasing age due to decreases in creatinine clearance. However, the possibility of renal impairment in the elderly must be considered and the dosage should be adjusted accordingly.

Renal impairment

In patients with chronic renal failure the mean terminal half-life was found to be 19.5 hours. The mean aciclovir half-life during haemodialysis was 5.7 hours. Plasma aciclovir concentrations dropped approximately 60% during dialysis.

Weight

In a clinical study in which morbidly obese female patients (n=7) were dosed with intravenous aciclovir based on their actual body weight, plasma concentrations were found to be approximately twice that of normal weight patients (n=5), consistent with the difference in body weight between the two groups.

Mutagenicity:

The results of a wide range of mutagenicity test in vitro and in vivo indicate that aciclovir is unlikely to pose a genetic risk to man.

Carcinogenicity:

Aciclovir was not found to be carcinogenic in long-term studies in the rat and the mouse.

Teratogenicity:

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

Fertility:

Largely reversible adverse effects on spermatogenesis in association with overall toxicity in rats and dogs have been reported only at doses of aciclovir greatly in excess of those employed therapeutically. Two-generation studies in mice did not reveal any effect of (orally administered) aciclovir on fertility.

Gelatin PhEur

Lactose PhEur

Maize Starch PhEur

Microcrystalline Cellulose PhEur

Sodium Starch Glycollate PhEur

Magnesium Stearate PhEur

None

36 months

Do not store above 25°C

Aciclovir Tablets BP 400 mg are available in blister packs of 25, 30, 56, 60, 70 and 100 tablets.

No special requirements.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.