ACICLOVIR DISPERSIBLE TABLETS 400MG

SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Aciclovir Dispersible Tablets 400 mg

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains Aciclovir BP 400 mg

3

PHARMACEUTICAL FORM
Dispersible film-coated tablet

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Aciclovir Dispersible Tablets are indicated for the treatment of herpes simplex
virus infections of the skin and mucous membranes including initial and
recurrent genital herpes; for the suppression (prevention of recurrences) of
recurrent infections in immunocompetent patients; for the prophylaxis of
herpes simplex infections in immunocompromised patients and 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: 200 mg Aciclovir 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 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 infections 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.
Paediatric population:
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.

Treatment of varicella infections:
6 years and over:
800 mg Aciclovir four times daily.
2 to 5 years:
400 mg Aciclovir four times daily.
Under 2 years:
200 mg Aciclovir 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 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.
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).

Total aciclovir body clearance declines along with creatinine
clearance.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 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.
In the treatment of varicella and herpes zoster infections it is recommended to
adjust the dosage to 800 mg aciclovir twice daily at approximately twelvehourly 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 to 25 ml/minute).
Route of Administration
Oral.
Aciclovir dispersible tablets may be dispersed in a minimum of 50 ml of water
or swallowed whole with a little water.

4.3

Contraindications
Aciclovir Tablets are contra-indicated in patients known to be hypersensitive
to aciclovir and valaciclovir or to any of the excipients..

4.4

Special warnings and precautions for use
Adequate hydration should be maintained in high oral doses of aciclovir.
The risk of renal impairment is increased by use with other nephrotoxic drugs.
Use in patients with renal impairment and in elderly patients:
Aciclovir is eliminated by renal clearance, therefore the dose must be reduced
in patients with renal impairment (see section 4.2). Elderly patients are likely
to have reduced renal function and therefore the need for dose reduction 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).
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.
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. Aciclovir was not found
to be carcinogenic in long term studies in the rat and the mouse. 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. Aciclovir Tablets have been
shown to have no definite effect upon sperm count, morphology or motility in
man.

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.
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.
Probenecid increases the aciclovir mean half-life and area under the plasma
concentrationtime curve. Other drugs affecting renal physiology could
potentially influence the pharmacokinetics of aciclovir. However clinical
experience has not identified other drug interactions with aciclovir.

4.6

Fertility, pregnancy and lactation
Fertility

There is no experience of the effects of Aciclovir Tablets on human female
fertility.
Two-generation studies in mice did not reveal any effect of aciclovir on
fertility.
Pregnancy

Experience in humans is limited so the use of Aciclovir Tablets 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 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.
Lactation

Following oral administration of 200 mg 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.

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. Furthermore, 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, confusional states
Very rare:
Agitation, confusion, tremor, ataxia, dysarthria, hallucinations,
psychoticsymptoms, 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).
Respiratory, thoracic and mediastinal disorders
Rare:
Dyspnoea
Gastrointestinal disorders
Common:
Nausea, vomiting, diarrhoea, abdominal pains

In double-blind, placebocontrolled trials the incidence of gastrointestinal
events has not been found to differ between placebo and aciclovir recipients.
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.
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).
Neurological effects including confusion, hallucinations, agitation, seizures
and coma have been described in association with overdosage.
No data are available on the consequences of the ingestion of higher doses;
such an occurrence warrants close observation of the patient.
Single intravenous doses of up to 80 mg/kg have been inadvertently
administered without adverse effects. Aciclovir is dialysable by
haemodialysis.
Treatment
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
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 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 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
a) general characteristics of the active substances
Aciclovir is only partially absorbed from the gut. Mean steady state peak
plasma concentrations (CssMax) following doses of 200 mg aciclovir
administered four hourly were 3.1 microMol (0.7 micrograms/ml) and the
equivalent trough plasma levels (CssMin) were 1.8 microMol (0.4
micrograms/ml). Corresponding steady state plasma concentrations following
doses of 400 mg and 800 mg aciclovir administered four-hourly were 5.3
microMol (1.2 micrograms/ml) and 8 microMol (1.8 micrograms/ml)
respectively, and equivalent trough plasma levels were 2.7 microMol (0.6
micrograms/ml) and 4 microMol (0.9 micrograms/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 to 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.
In adults, mean steady state peak plasma concentrations (CssMax) following a
one hour infusion of 2.5 mg/kg, 5 mg/kg and 10 mg/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
ss
(C Min) 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 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 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.
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.
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
No additional information is presented.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Cores:
Microcrystalline Cellulose EP
Aluminium Magnesium Silicate BP
Sodium Starch Glycollate BP
Povidone K30 EP
Magnesium Stearate EP
Iron Oxide Red E172 HSE
Industrial Methylated Spirit BP or Ethanol (96%) BP
Purified Water EP
Film Coat:
Coating concentrate OY-7240 clear containing:
Hypromellose EP
Polyethylene Glycol 400 USNF
Purified Water EP
Polish:
Polyethylene Glycol 8000 USNF
Purified Water EP

6.2.

Incompatibilities
None known.

6.3.

Shelf Life
36 months shelf life in the product as packaged

6.4.

Special Precautions for Storage
Store below 30°C, keep dry, protect from light.

6.5.

Nature and Contents of Container
uPVC/Aluminium foil blister packs (250 µm uPVC/20 µm Al) of 56 tablets.

6.6.

Instruction for Use/Handling
Not applicable.

7

MARKETING AUTHORISATION HOLDER
Norton Healthcare Limited
Ridings Point,
Whistler Drive,
Castleford,
West Yorkshire,
WF10 5HX

8

MARKETING AUTHORISATION NUMBER(S)
PL 0530/0494

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
30 March 1995

10

DATE OF REVISION OF THE TEXT
25/08/2016