ZOVIRAX SUSPENSION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

2.  QUALITATIVE AND QUANTITATIVE COMPOSITION

3 PHARMACEUTICAL FORM

Suspension

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Zovirax 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).

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

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

Zovirax Suspension is indicated for the treatment of varicella (chickenpox) and herpes zoster (shingles) infections.

4.2 Posology and method of administration

Dosage in Adults

Treatment of herpes simplex infections: 200mg Zovirax 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 Zovirax 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 Zovirax should be taken four times daily at approximately six-hourly intervals.

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

Dosage titration down to 200mg Zovirax 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 Zovirax.

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 Zovirax 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 Zovirax 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: 800mg Zovirax 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 aciclovir is recommended.

Treatment of varicella infections:

6 years and over: 800mg Zovirax four times daily.

2 to 5 years: 400mg Zovirax four times daily.

Under 2 years: 200mg Zovirax four times daily.

Treatment should continue for five days.

Dosing may be more accurately calculated as 20mg/kg body weight (not to exceed 800mg) Zovirax 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.

Zovirax Suspension may be diluted with an equal volume of either Syrup BP or Sorbitol Solution (70%) (non-crystallising) BP. The diluted product is stable for 4 weeks at 25oC but it is recommended that all dilutions are freshly prepared.

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 200 mg 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).

4.3 Contraindications

Hypersensitivity 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.

Excipients

Zovirax Suspension contains Methyl parahydroxybenzoate and Propyl parahydroxybenzoate which may cause allergic reactions (possibly delayed).

Zovirax Suspension contains 1575 mg sorbitol per 5 mL. Hence Patients with rare hereditary problems of fructose intolerance should not take this medicine.

4.5. Interactions with other Medicaments 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 immunosuppresant 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

Pregnancy:

A post-marketing aciclovir pregnancy registry has documented pregnancy outcomes in women exposed to any formulation of Zovirax. 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 described amongst Zovirax exposed subjects have not shown any 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 however be exercised by balancing the potential benefits of treatment against any possible hazard. Findings from reproduction toxicology studies are included in Section 5.3.

Breast-feeding:

Following oral administration of 200mg Zovirax five times a day, aciclovir has been detected in breast milk at concentrations ranging from 0.6 to 4.1 times the corresponding plasma concentrations. These concentrations would potentially expose nursing infants to aciclovir dosages of up to 0.3mg/kg/day. Caution is therefore advised if Zovirax is to be administered to a nursing woman.

Fertility:

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

In a study of 20 male patients with normal sperm count, oral aciclovir administered at doses of up to 1g per day for up to six months has been shown to have no clinically significant effect on sperm count, motility or morphology.

See clinical studies in section 5.2.

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 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 and crystalluria.

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

4.9 Overdose

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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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 (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. The average oral bioavailability varies between 10 and 20%. Under fasting conditions, mean peak concentrations (Cmax) 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 (Cssmax) 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 Cssmax 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 (AUC0–00) to aciclovir ranges between 1.9 and 2.2 microgram*h/mL after a 200 mg dose. At this dose, the mean terminal plasma halflife after oral administration has been 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.

There are no pharmacokinetic data for the oral formulation in neonates. The only available pharmacokinetic data are for the IV formulation in this age group.

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.

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.

6 PHARMACEUTICAL PARTICULARS

6.1 List of Excipients

Sorbitol Solution, 70%, non-crystallising

Glycerol

Dispersible cellulose

Methyl parahydroxybenzoate

Propyl parahydroxybenzoate

Flavour, banana 5708023 (contains propylene glycol)

Vanillin

Purified water

6.2 Incompatibilities

None Known.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Store below 25oC

6.5 Nature and contents of container

Neutral amber glass bottles closed with either metal roll on pilfer proof (ROPP) caps fitted with polyvinylidene chloride (PVDC) faced wads, or closed with plastic child resistant caps (CRC) fitted with low density polyethylene-polyvinylidene chloride-low density polyethylene (LDPE-PVDC-LDPE) faced wads.

This container and these closures are applicable to both pack sizes 25ml and 125ml.

The 25ml pack is a starter pack.

The 125ml pack contains a double-ended measuring spoon.

6.6. Special precautions for disposal

No special requirements.

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