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ACICLOVIR DISPERSIBLE TABLETS 400MG

Active substance(s): ACICLOVIR

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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.
Dosage in Children:
Treatment of herpes simplex infections, and prophylaxis of herpes simplex
infections in the immuno-compromised: 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:
2 to 5 years:
Under 2 years:

800 mg Aciclovir four times daily.
400 mg Aciclovir four times daily.
200 mg Aciclovir four times daily

Treatment should continue for five days.
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:
In the elderly, total aciclovir body clearance declines along with creatinine
clearance.
Adequate hydration of elderly patients taking high oral doses of Aciclovir
should be maintained. Special attention should be given to dosage reduction
in elderly patients with impaired renal function.
Dosage in Renal Impairment:
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 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 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.

Contra-indications
Aciclovir Tablets are contra-indicated in patients known to be hypersensitive
to aciclovir.

4.4.

Special Warnings and Precautions for Use
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.

Interactions with other Medicaments and other forms of Interaction
Probenecid increases the aciclovir mean half-life and area under the plasma
concentration-time 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.

Pregnancy and Lactation
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. 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.
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.
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
None known.

4.8.

Undesirable Effects
Skin rashes have been reported in a few patients receiving Aciclovir Tablets;
the rashes have resolved on withdrawal of the drug.
Gastrointestinal effects including nausea, vomiting, diarrhoea and abdominal
pains have been reported in some patients receiving Aciclovir Tablets. In
double-blind, placebocontrolled trials the incidence of gastrointestinal events
has not been found to differ between placebo and aciclovir recipients.
Reversible neurological reactions, notably dizziness, confusional states,
hallucinations and somnolence, have occasionally been reported, usually in
patients with renal impairment or other predisposing factors.
Occasional reports of accelerated diffuse hair loss have been received. As this
type of hair loss has been associated with a wide variety of disease processes
and medicines, the relationship of the event to aciclovir therapy is uncertain.
Other events reported rarely in patients receiving oral formulations of
aciclovir include mild, transient rises in bilirubin and liver related enzymes,
small increases in blood urea and creatinine, small decreases in haematological
indices, headaches.

4.9.

Overdose
Aciclovir is only partly absorbed in the gastrointestinal tract. It is unlikely that
serious toxic effects would occur if a dose of up to 5 g were taken on a single
occasion. 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.

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
ss
(20.7 micrograms/ml), respectively. The corresponding trough levels (C Min)
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
14/11/2014

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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