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ZOVIRAX TABLETS 200MG

Active substance(s): ACICLOVIR

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Zovirax Tablets 200 mg

2.

Qualitative and Quantitative Composition
Aciclovir BP 200 mg
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Dispersible film-coated tablet.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Zovirax tablets are 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 tablets are indicated for the suppression (prevention of recurrences) of
recurrent herpes simplex infections in immunocompetent patients.
Zovirax tablets are indicated for the prophylaxis of herpes simplex infections
in immunocompromised patients.
Zovirax tablets are indicated for the treatment of varicella (chickenpox) and
herpes zoster (shingles) infections.
Route of administration: Oral.

4.2

Posology and method of administration
Zovirax 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 aciclovir are
adequately hydrated.

Dosage in adults
Treatment of herpes simplex infections: 200 mg 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 400 mg 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: 200 mg
Zovirax should be taken four times daily at approximately six-hourly intervals.
Many patients may be conveniently managed on a regimen of 400 mg Zovirax twice
daily at approximately twelve-hourly intervals.
Dosage titration down to 200 mg Zovirax taken thrice daily at approximately eighthourly 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
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: 200 mg
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 400 mg 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: 800 mg 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 on neonatal herpes virus infections, intravenous aciclovir is
recommended.
Treatment of varicella infection
6 years and over:
800 mg Zovirax four times daily.
2 - 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 20 mg/kg bodyweight (not to exceed
800 mg) 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.
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).

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

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:
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 Zovirax. The registry findings have not
shown an increase in the number of birth defects amongst Zovirax 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 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 200 mg 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 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.
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
There have been no studies to investigate the effect of aciclovir on driving
performance or the ability to operate machinery. A detrimental effect on such
activities cannot be predicted from the pharmacology of the active substance,
but the adverse event profile should be borne in mind.

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 usually reported in patients with
renal impairment or with other predisposing factors (see 4.4 Special Warnings
and 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 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 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 (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.

5.2.

Pharmacokinetic Properties
Aciclovir is only partially absorbed from the gut. Mean steady state peak
plasma concentration (CssMax) following doses of 200 mg administered fourhourly were 3.1 microMol (0.7 micrograms/ml) and equivalent trough plasma
levels (CssMin) were 1.8 microMol (0.4 micrograms/ml). Corresponding
CssMax levels following doses of 400 mg and 800 mg administered fourhourly were 5.3 microMol (1.2 micrograms/ml) and 8 microMol (1.8

micrograms/ml) respectively and equivalent CssMin levels were 2.7 microMol
(0.6 micrograms/ml) and 4 microMol (0.9 micrograms/ml).
In adults the terminal plasma half life of aciclovir 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. 9carboxymethoxymethyl-guanine is the only significant metabolite of aciclovir
and accounts for approximately 10-15% of the administered dose recovered
from 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.
In adults, mean steady state peak plasma concentrations (Cssmax) following a
one hour infusion of 2.5mg/kg, 5mg/kg and 10mg/kg were 22.7 microMol (5.1
micrograms/ml), 43.6 microMol (9.8 micrograms/ml) and 92 microMol (20.7
micrograms/ml), respectively. The corresponding trough levels (Cssmin) 7
hours later were 2.2 microMol (0.5 micrograms/ml), 3.1 microMol (0.7
micrograms/ml), and 10.2 microMol (2.3 micrograms/ml), respectively.
In children over 1 year of age similar mean peak (Cssmax) and trough
(Cssmin) levels 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 5 mg/kg and a dose of
500 mg/m2 was substituted for 10 mg/kg.
In neonates and young infants (0-3 months of age) treated with doses of
10mg/kg administered by infusion over a one-hour period every 8 hours the
Cssmax was found to be 61.2 microMol (13.8 micrograms/ml) and Cssmin to
be 10.1 microMol (2.3 micrograms/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 changes 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.
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.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Core:
Microcrystalline cellulose
Aluminium magnesium silicate
Sodium starch glycollate
Povidone K30
Magnesium stearate
Purified water
Industrial methylated spirit
Or
Ethanol
Or
Absolute alcohol
Film coat*:
Coating concentrate Y-1-7000
Purified water
∗Coating concentrate contains:
Hypromellose
Polyethylene glycol 400
Titanium Dioxide
Polish:
Polyethylene glycol 8000
Purified water

6.2.

Incompatibilities
None known.

6.3.

Shelf Life
36 months.

6.4

Special precautions for storage
Do not store above 30°C.
Store in the original package.

6.5.

Nature and Contents of Container
Amber glass bottles with polyethylene snap fitting caps.
PVC/PVDC/Aluminium foil blister packs.
Pack size: 25 tablets.

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.

7

MARKETING AUTHORISATION HOLDER
The Wellcome Foundation Ltd
980 Great West Road
Brentford
Middlesex
TW8 9GS
United Kingdom
Trading as
GlaxoSmithKline UK
Stockley Park West
Uxbridge

Middlesex UB11 1BT

8.

MARKETING AUTHORIZATION NUMBER(S)
PL 00003/0344

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
07/01/2011

10

DATE OF REVISION OF THE TEXT
19/03/2015

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Source: Medicines and Healthcare Products Regulatory Agency

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