Document: spc-doc_PL 39307-0035 change

• spc-doc_PL 00427-0120
• spc-doc_PL 39307-0035

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Aciclovir 400mg/5ml Oral Suspension

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

The active substance is aciclovir.

Each 5ml of oral suspension contains 400mg aciclovir.

Excipient(s) with known effect:

Each 5ml of suspension contains 2.25g sorbitol liquid (non-crystallising) (E420) and 10mg of methyl parahydroxybenzoate (E218).

For the full list of excipients, see section 6.1

3    PHARMACEUTICAL FORM

Oral Suspension

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

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

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.

4.2 Posology and method of administration

Dosage in Adults

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.

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.

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.

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 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 of neonatal herpes virus infections, intravenous acyclovir is recommended.

Treatment of varicella infections:

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

2 to 5 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 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 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 aciclovir twice daily at approximately twelve-hourly intervals for patients with severe renal impairment (creatinine clearance less than 10ml/minute), and to 800mg aciclovir 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.

4.3 Contraindications

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

4.4 Special warnings and precautions for use

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 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 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).

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

This 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 aciclovir reduces the incidence of chickenpox-associated complications in immunocompetent patients.

This medicinal product contains sorbitol liquid (non-crystallising) (E420). Patients with rare hereditary problems of fructose intolerance should not take this medicine. It also contains methyl parahydroxybenzoate (E218). This may cause an allergic reaction (possibly delayed).

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 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.

When aciclovir is administered concomitantly with theophylline close monitoring of theophylline concentrations and possible theophylline dose reduction is recommended. A study has shown that when theophylline was given as a single 320mg doses before and with the sixth dose of aciclovir 800mg five times daily for 2 days, the AUC of the theophylline was increased by 45% (189.9 to 274.9 micrograms .h/ml) and total body clearance was reduced by 30%.

4.6 Fertility, pregnancy and lactation

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.

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

Fertility:

See Section 5.3

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:

Very 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 are usually reported in patients with renal impairment, or with other predisposing factors (see 4.4 Special Warnings & Precautions for Use).

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

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 (VSV).

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 to 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 the resultant chain termination following its incorporation into the viral DNA.

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.

5.2 Pharmacokinetic properties Absorption

Aciclovir is only partially absorbed from the gut. Mean steady state peak plasma concentrations (C^SSmax) following doses of 200mg aciclovir administered four-hourly were 3.1 microMol (0.7 microgram/ml) and the equivalent trough plasma levels (C^SSmin) were 1.8 microMol (0.4 microgram/ml). Corresponding steady-state plasma concentrations following doses of 400mg and 800mg aciclovir administered four-hourly were 5.3 microMol (1.2 microgram/ml) and 8 microMol (1.8 microgram/ml) respectively, and equivalent trough plasma levels were 2.7 microMol (0.6 microgram/ml) and 4 microMol (0.9 microgram/ml).

In adults the terminal plasma half-life after administration of intravenous aciclovir is about 2.9 hours. Most of the drug is excreted unchanged by the kidney. Renal clearance of aciclovir is substantially greater than creatinine clearance, indicating that tubular secretion, in addition to glomerular filtration, contributes to the renal elimination of the drug.

9-carboxymethoxymethylguanine is the only significant metabolite of aciclovir, and accounts for 10-15% of the dose excreted in the urine. When aciclovir is given one hour after 1 gram of probenecid the terminal half-life and the area under the plasma concentration time curve is extended by 18% and 40% respectively.

Elimination

In adults, mean steady state peak plasma concentrations (C^SSmax) following a one hour infusion of 2.5mg/kg, 5mg/kg and 10mg/kg were 22.7 microMol (5.1 microgram/ml), 43.6 microMol (9.8 microgram/ml) and 92 microMol (20.7 microgram/ml), respectively. The corresponding trough levels (C^SSmin) 7 hours later were 2.2 microMol (0.5 microgram/ml), 3.1 microMol (0.7 microgram/ml) and 10.2 microMol (2.3 microgram/ml), respectively.

In children over 1 year of age similar mean peak (C^SSmax) and trough (C^SSmin) levels were observed when a dose of 250mg/m² was substituted for 5mg/kg and a dose of 500mg/m² was substituted for 10mg/kg. In neonates (0 to 3 months of age) treated with doses of 10mg/kg administered by infusion over a one-hour period every 8 hours the C^SSmax was found to be 61.2 microMol (13.8 microgram/ml) and C^SSmin to be 10.1 microMol (2.3 microgram/ml). The terminal plasma half-life in these patients was 3.8 hours. 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).

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.

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.

Distribution

Cerebrospinal fluid levels are approximately 50% of corresponding plasma levels. Plasma protein binding is relatively low (9 to 33%) and drug interactions involving binding site displacement are not anticipated.

5.3 Preclinical safety data

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.

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.

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 aciclovir on 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.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

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

6.2 Incompatibilities

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

6.3 Shelf life

18 months

Discard 30 days after first opening.

6.4 Special precautions for storage

Do not store above 25°C.

Do not refrigerate or freeze.

6.5 Nature and contents of container

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

6.6 Special precautions for disposal

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.

7 MARKETING AUTHORISATION HOLDER

Syri Limited t/a Thame Laboratories,

Unit 4, Bradfield Road,

Ruislip,

Middlesex HA4 0NU, UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 39307/0035

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

13/05/2016

10    DATE OF REVISION OF THE TEXT

13/05/2016