Aciclovir

Aciclovir 400mg/5ml Oral Suspension

The active substance is aciclovir.

Each 5ml of oral suspension contains 400mg aciclovir.

Excipient(s) with known effect:

Each 5ml of suspension contains 1575mg sorbitol (E420), 10mg of methyl parahydroxybenzoate (E218) and 5 mg propylene glycol (E1520).

For the full list of excipients, see section 6.1.

Oral Suspension

White to off-white uniform oral suspension with orange and vanilla odour

Aciclovir Suspension is indicated for the treatment of herpes simplex virus infections of the skin and mucous membranes including initial and recurrent genital herpes (excluding neonatal HSV and severe HSV infections in immunocompromised children).

Aciclovir Suspension is indicated for the suppression (prevention of recurrences) of recurrent herpes simplex infections in immunocompetent patients.

Aciclovir Suspension is indicated for the prophylaxis of herpes simplex infections in immunocompromised patients.

Aciclovir Suspension is indicated for the treatment of varicella (chickenpox) and herpes zoster (shingles) infections. Studies have shown that early treatment of shingles with Aciclovir Suspension has a beneficial effect on pain and can reduce the incidence of post-herpetic neuralgia (zoster-associated pain).

Dosage for treatment of herpes simplex in Adults:

For treatment of herpes simplex infections, 200mg Aciclovir suspension should be taken five times daily at approximately four hourly intervals omitting the night time 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 400mg Aciclovir suspension 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.

Dosage for suppression of herpes simplex in adults:

For suppression of Herpes simplex infections in immunocompetent patients, 200mg Aciclovir suspension should be taken FOUR times daily at approximately six-hourly intervals.

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

Dosage titration down to 200mg Aciclovir suspension 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 800mg Aciclovir suspension.

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.

Dosage for prophylaxis of herpes simplex in adults:

For prophylaxis of herpes simplex infections in immunocompromised patients, 200mg Aciclovir suspension 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 400mg Aciclovir suspension or, alternatively, intravenous dosing could be considered.

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

Dosage for treatment of varicella and herpes zoster in adults:

For treatment of varicella and Herpes zoster infections, 800mg Aciclovir suspension 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 yields better results if initiated as soon as possible after the onset of the rash.

Dosage for Infants and Children

For 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. Infants and children below the age of two years should be given half the adult dose. Do not dilute the oral suspension formulation.

For treatment of varicella infections for Infants and children:

6 years and over: 800mg Aciclovir suspension four times daily.

2 to < 6 years: 400mg Aciclovir suspension four times daily.

Under 2 years: 200mg Aciclovir suspension four times daily.

Treatment should continue for five days.

Dosing may be more accurately calculated as 20mg/kg body weight (not to exceed 800mg) Aciclovir suspension 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 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 by intravenous infusion. However, for patients with severe renal impairment (creatinine clearance less than 10 ml/minute) an adjustment of dosage to 200mg aciclovir twice daily at approximately twelve-hourly intervals is recommended.

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

Method of administration

For oral use only.

Aciclovir Suspension is contraindicated in patients known to be hypersensitive to aciclovir and valaciclovir, or to any of the excipients listed in section 6.1.

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 ) 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 ). 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).

Hydration status

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

Excipients Warnings:

Sorbitol (E420): This medicinal product contains 1575mg sorbitol in each 5ml which is equivalent to 315mg/ml. Patients with hereditary fructose intolerance (HFI) should not take/be given this medicinal product.

Methyl parahydroxybenzoate (E218): May cause an allergic reaction (possibly delayed).

Propylene glycol (E1520): This medicinal product contains 5mg propylene glycol in each 5 ml which is equivalent to 1mg/ml.

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.

Pregnancy:

The use of acyclovir 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 suspension. 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.

Breast-feeding:

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 0.3mg/kg/day. Caution is therefore advised if Aciclovir suspension is to be administered to a nursing woman.

Fertility:

See clinical studies in section 5.3

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

There have been no studies to investigate the effect of Aciclovir Suspension 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 to <1/10), uncommon (˃1/1,000 to <1/100), rare (˃1/10,000 to <1/1,000), very rare (<1/10,000).

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 Website at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Symptoms & 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 intravenous overdosage.

Management

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: group Anti-infective.

ATC code: J05AB01

Mechanism of Action

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), Epstein Barr virus (EBV) and cytomegalovirus (CMV). In cell culture, aciclovir has the greatest antiviral activity against HSV-1, followed (in decreasing order of potency) by HSV-2, VZV, EBV and CMV.

The inhibitory activity of aciclovir for HSV I, HSV II, VZV, EBV and CMV is highly selective. The enzyme thymidine kinase (TK) of normal, non-infected cells does not use aciclovir effectively as a substrate, hence toxicity to mammalian host cells is low; however, TK encoded by HSV, VZV and EBV 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 the resultant chain termination following its incorporation into the viral DNA.

Pharmacodynamic Effects

Prolonged or repeated courses of aciclovir in severely immunocompromised 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 200mg 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 200mg administered every four-hours. A less than proportional increase is observed for C_ssmax levels following doses of 400mg and 800mg 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 oval administration (Vd/F) range from 2.3 to 17.8L/Kg. As plasma protein binding is relatively low (9 to 33%), and drug interactions involving binding site displacement are not anticipated. Cerebrospinal fluid levels are approximately 50% of corresponding plasma levels at steady-state.

Metabolism

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

Elimination

Mean systemic exposure (AUC _O-∞) to aciclovir ranges between 1.9 and 2.2 microgram*h/ml after a 200mg dose. In adults, the terminal plasma half-life after oral administration has shown to vary between 2.8 and 4.1 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 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 terminal plasma half-life was 3.8 hours.

Special patient population

Elderly

In the elderly total body clearance falls with increasing age associated with decreases in creatinine clearance although there is little change in the terminal plasma half-life.

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 levels dropped approximately 60% during dialysis.

Fertility:

There is no information on the effect of aciclovir oral formulations or IV for infusion on human female fertility. In a study of 20 male patients with normal sperm count, oral aciclovir 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.

Teratogenicity:

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.

NON-CLINICAL INFORMATION

Mutagenicity

The results of a wide range of mutagenicity tests 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.

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.

Xanthan gum (E415)

Sorbitol liquid (non-crystallising) (E420)

Methyl parahydroxybenzoate (E218)

Orange flavour (containing propylene glycol (E1520))

Vanilla flavour (containing propylene glycol (E1520))

Purified water

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

18 months

Discard 30 days after first opening.

Do not store above 25°C.

Do not refrigerate or freeze.

Bottle: Ph. Eur. Type III Amber glass

Closure: Tamper evident, child resistant, plastic (Polypropylene/ Polyethylene) cap with EPE liner

Dosing Device: Double ended white polypropylene plastic spoon with 2.5ml and 5ml measuring ends.

Pack size: 100ml

This product may settle during storage. Shake the bottle before use.

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

Syri Limited,

Unit 4, Bradfield Road,

Ruislip, Middlesex,

HA4 0NU, UK

Trading as:

Thame Laboratories,

Unit 4, Bradfield Road,

Ruislip, Middlesex,

HA4 0NU, UK

OR

Trading as:

SyriMed,

Unit 4, Bradfield Road,

Ruislip, Middlesex,

HA4 0NU, UK

PL 39307/0035

Date of first authorisation: 13 May 2016

Date of latest renewal: 15 April 2021

18/08/2022