ZOVIRAX SUSPENSION

Canada - English - Health Canada

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Active ingredient:
ACYCLOVIR
Available from:
GLAXOSMITHKLINE INC
ATC code:
J05AB01
INN (International Name):
ACYCLOVIR
Dosage:
200MG
Pharmaceutical form:
SUSPENSION
Composition:
ACYCLOVIR 200MG
Administration route:
ORAL
Units in package:
125ML
Prescription type:
Prescription
Therapeutic area:
NUCLEOSIDES AND NUCLEOTIDES
Product summary:
Active ingredient group (AIG) number: 0115506003; AHFS: 08:18.32
Authorization status:
APPROVED
Authorization number:
00886157
Authorization date:
2001-08-07

Documents

Page 1 of 39

PRODUCT MONOGRAPH

Pr

ZOVIRAX

®

Acyclovir Oral Suspension USP, 200 mg /5 mL

Antiviral Agent

GlaxoSmithKline Inc.

7333 Mississauga Road

Mississauga, Ontario

L5N 6L4

Date of Revision:

May 30, 2016

Submission Control No: 191703

©

2016 GlaxoSmithKline Inc. All Rights Reserved

ZOVIRAX is a registered trademark of GlaxoSmithKline Inc.

Page 2 of 39

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION .........................................................3

SUMMARY PRODUCT INFORMATION ........................................................................3

INDICATIONS AND CLINICAL USE ..............................................................................3

CONTRAINDICATIONS ...................................................................................................4

WARNINGS AND PRECAUTIONS ..................................................................................4

ADVERSE REACTIONS ....................................................................................................6

DRUG INTERACTIONS ....................................................................................................9

DOSAGE AND ADMINISTRATION ..............................................................................10

OVERDOSAGE ................................................................................................................11

ACTION AND CLINICAL PHARMACOLOGY ............................................................12

STORAGE AND STABILITY ..........................................................................................14

DOSAGE FORMS, COMPOSITION AND PACKAGING .............................................14

PART II: SCIENTIFIC INFORMATION ...............................................................................15

PHARMACEUTICAL INFORMATION ..........................................................................15

CLINICAL TRIALS ..........................................................................................................15

DETALILED PHARMACOLOGY...................................................................................16

VIROLOGY .......................................................................................................................16

TOXICOLOGY .................................................................................................................18

REFERENCES ..................................................................................................................30

PART III: CONSUMER INFORMATION..............................................................................37

Page 3 of 39

Pr

ZOVIRAX

®

Acyclovir

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

Route of

Administration

Dosage Form / Strength

Clinically Relevant Non-medicinal

Ingredients

Oral

Oral suspension

200 mg/5 mL

None

For a complete listing see Dosage Forms,

Composition and Packaging section.

INDICATIONS AND CLINICAL USE

ZOVIRAX

(acyclovir) is indicated for the following conditions:

The treatment of initial episodes of herpes genitalis.

The suppression of unusually frequent recurrences of herpes genitalis (6 or more

episodes per year).

The acute treatment of herpes zoster (shingles) and varicella (chickenpox).

The results of clinical studies suggest that some patients with recurrent genital herpes

may derive clinical benefit from the administration of oral ZOVIRAX

if taken at the

first sign of an impending episode. Those most likely to benefit are patients who

experience severe, prolonged recurrences; such intermittent therapy may be more

appropriate than suppressive therapy when these recurrences are infrequent.

Early treatment of acute herpes zoster (shingles) in immunocompetent individuals with

oral ZOVIRAX

resulted in decreased viral shedding; decreased time to healing; less

dissemination; and alleviation of acute pain.

Treatment of varicella (chickenpox) in immunocompetent patients with oral ZOVIRAX

reduced the total number of lesions, accelerated the progression of lesions to the crusted

and healed stages, and decreased the number of residual hypopigmented lesions. In

addition, ZOVIRAX

decreased fever and constitutional symptoms associated with

chickenpox.

The prophylactic use of acyclovir in chickenpox has not been established.

Page 4 of 39

Geriatrics (≥ 65 years of age): Use in the geriatric population may be associated with

differences in safety due to age-related changes in renal function and a brief discussion

can be found in the appropriate sections (see WARNINGS AND PRECAUTIONS).

Pediatrics (< 2 years old): No data are available.

CONTRAINDICATIONS

ZOVIRAX

(acyclovir) is contraindicated for patients who develop hypersensitivity or

who are hypersensitive to acyclovir, valacyclovir or any other components of

ZOVIRAX

. For a complete listing, see Dosage Forms, Composition and Packaging

section of the product monograph.

WARNINGS AND PRECAUTIONS

General

Care should be taken to maintain adequate hydration in patients receiving high oral doses

of acyclovir.

Suppressive therapy of herpes genitalis with ZOVIRAX

(acyclovir) should be

considered only for severely affected patients. Periodic evaluation of the need for

continued suppressive therapy is recommended. In some patients, there is a tendency for

the first recurrent episode to be more severe following cessation of suppressive therapy.

In severely immunocompromised patients, the physician should be aware that prolonged

or repeated courses of acyclovir may result in selection of resistant viruses associated

with infections which may not respond. Thrombotic thrombocytopenic

purpura/haemolytic uremic syndrome (TTP/HUS), which has resulted in death, has

occurred in immunocompromised patients receiving ZOVIRAX

therapy.

The recommended dosage and length of treatment should not be exceeded (see DOSAGE

AND ADMINISTRATION). The decision to prescribe a course of suppressive therapy

should be weighed in the light of our present knowledge about the long-term effects of

ZOVIRAX

and must clearly relate to the condition of the patient.

Whereas cutaneous lesions associated with herpes simplex infections are often

pathognomonic, Tzanck smears prepared from lesion exudate or scrapings may assist in

the diagnosis. Positive cultures for herpes simplex virus offer the only absolute means

for confirmation of the diagnosis. Appropriate examinations should be performed to rule

out other sexually transmitted diseases. All patients should be advised to take particular

care to avoid potential transmission of virus if active lesions are present while they are on

therapy. Genital herpes can also be transmitted in the absence of symptoms through

asymptomatic viral shedding.

Page 5 of 39

The clinical status of the patient and the adverse event profile of ZOVIRAX

should be

borne in mind when considering the patient’s ability to drive or operate machinery.

There have been no studies to investigate the effect of ZOVIRAX

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.

Although chickenpox in otherwise healthy children is usually a self-limited disease of

mild to moderate severity, adolescents and adults tend to have more severe disease.

Treatment was initiated within 24 hours of the typical chickenpox rash in the controlled

studies, and there is no information regarding the effects of treatment begun later in the

disease course. It is unknown whether the treatment of chickenpox in childhood has any

effect on long-term immunity. However, there is no evidence to indicate that treatment

of chickenpox with ZOVIRAX

would have any effect on either decreasing or increasing

the incidence or severity of subsequent recurrences of herpes zoster (shingles) later in

life.

Carcinogenesis and Mutagenesis

ZOVIRAX

has caused mutagenesis in some acute studies at high concentrations of the

drug (see Part II, TOXICOLOGY).

Renal

Renal insufficiency or acute renal failure has been observed in patients taking

ZOVIRAX

at the recommended dosage and/or with no previous renal conditions and

may be associated with renal pain (see ADVERSE REACTIONS, Post-Market Adverse

Drug Reactions).

Acyclovir is eliminated by renal clearance, therefore the dose must be reduced in patients

with renal impairment (see DOSAGE AND ADMINISTRATION, Patients with Acute or

Chronic Renal Impairment). 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 ADVERSE REACTIONS).

Caution should be exercised when administering to patients receiving potentially

nephrotoxic agents since this may increase the risk of renal dysfunction.

Sexual Function/Reproduction

In a study of 20 male patients with normal sperm count, oral acyclovir 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. There is no information on the

effect of acyclovir oral formulations on human female fertility.

Page 6 of 39

Special Populations

Pregnant Women: Teratology studies carried out to date in animals have been negative

in general. However, in a non-standard test in rats, there were fetal abnormalities such as

head and tail anomalies, and maternal toxicity; since such studies are not always

predictive of human response, ZOVIRAX

should not be used during pregnancy unless

the physician feels the potential benefit justifies the risk of possible harm to the fetus.

The potential for high concentrations of acyclovir to cause chromosome breaks in vitro

should be taken into consideration in making this decision.

A post-marketing acyclovir 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 subjects exposed to

ZOVIRAX

compared with the general population, and any birth defects showed no

uniqueness or consistent pattern to suggest a common cause.

Nursing Women: Acyclovir concentrations have been documented in breast milk in

2 women following oral administration of acyclovir and ranged from 0.6 to 4.1 times

corresponding plasma levels. These concentrations would potentially expose the nursing

infant to a dose of acyclovir up to 0.3 mg/kg per day. Caution should therefore be

exercised when ZOVIRAX

is administered to a nursing woman.

Pediatrics: Safety and effectiveness in children less than 2 years of age have not been

adequately studied.

Geriatrics: The possibility of renal impairment in the elderly must be considered and the

dosage should be adjusted accordingly (see WARNINGS AND PRECAUTIONS, Renal,

and DOSAGE AND ADMINISTRATION, Patients with Acute or Chronic Renal

Impairment). Adequate hydration of elderly patients taking high oral doses of acyclovir

should be maintained.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

The most frequent adverse reactions associated with the use of ZOVIRAX

(acyclovir)

are headache and nausea.

Neurological side effects have also been reported in rare instances. Elderly patients and

patients with a history of renal impairment are at increased risk of developing these

effects. In the reported cases, these reactions were generally reversible on

discontinuation of treatment (see WARNINGS AND PRECAUTIONS and ADVERSE

REACTIONS, Post-Market Adverse Drug Reactions).

Page 7 of 39

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse

reaction rates observed in the clinical trials may not reflect the rates observed in

practice and should not be compared to the rates in the clinical trials of another

drug. Adverse drug reaction information from clinical trials is useful for

identifying drug-related adverse events and for approximating rates.

Treatment of Herpes Simplex: Short-term administration (5-10 days): The most

frequent adverse reactions reported during clinical trials of treatment of genital herpes

with oral ZOVIRAX

in 298 patients are listed in Table 1.

Table 1

Adverse Reactions Reported in Clinical Trials of

Treatment of Genital Herpes with Acyclovir

Adverse Reactions

Total

%

Nausea and/or Vomiting

Suppression of Herpes Simplex: Long-term administration: The most frequent adverse

events reported in a clinical trial for the prevention of recurrences with continuous

administration of 400 mg (two 200 mg capsules) 2 times daily are listed in Table 2.

Table 2

Adverse Reactions Reported in a Clinical Trial for the

Prevention of Recurrences of Genital Herpes with Acyclovir

Adverse Reactions

1st Year

(n=586)

%

2nd Year

(n=390)

%

3rd Year

(n=329)

%

Nausea

Diarrhea

Headache

Rash

Paresthesia

Asthenia

Evidence so far from clinical trials suggests that the severity and frequency of adverse

events is unlikely to necessitate discontinuation of therapy.

Herpes Zoster: The most frequent adverse reactions reported during three clinical trials

of treatment of herpes zoster (shingles) with 800 mg of oral ZOVIRAX

5 times daily for

7 or 10 days or placebo are listed in Table 3.

Page 8 of 39

Table 3

Adverse Reactions Reported in Clinical Trials of

Treatment of Herpes Zoster

Adverse Reactions

ZOVIRAX

®

(n=323)

%

Placebo

(n=323)

%

Malaise

11.5

11.1

Nausea

11.5

Headache

11.1

Vomiting

Diarrhea

Chickenpox: The most frequent adverse events reported during three clinical trials of

treatment of chickenpox with oral ZOVIRAX

or placebo are listed in Table 4.

Table 4

Adverse Reactions Reported in Clinical Trials of Treatment

of Chickenpox

Adverse Reactions

ZOVIRAX

®

(n=495)

%

Placebo

(n=498)

%

Diarrhea

Less Common Clinical Trial Adverse Drug Reactions (<1%)

Other adverse reactions reported in less than 1% of patients receiving ZOVIRAX

in any

clinical trial included: abdominal pain, anorexia, constipation, dizziness, edema, fatigue,

flatulence, inguinal adenopathy, insomnia, leg pain, medication taste, skin rash, sore

throat, spasmodic hand movement and urticaria.

Abnormal Hematologic and Clinical Chemistry Findings

No clinically significant changes in laboratory values have been observed in clinical trials

for the treatment of chickenpox and zoster, and for the treatment and suppression of

genital herpes with ZOVIRAX

Post-Market Adverse Drug Reactions

The following events have been reported voluntarily during post-market use of

ZOVIRAX

in clinical practice. These events have been chosen for inclusion due to

either their seriousness, frequency of reporting, potential causal connection to

ZOVIRAX

or a combination of these factors. Post-market adverse events are reported

spontaneously from a population of unknown size, thus estimates of frequency cannot be

made.

General: Fever, headache, pain and peripheral edema.

Page 9 of 39

Nervous: Dizziness, paresthesia, agitation, confusion, tremor, ataxia, dysarthria,

hallucinations, psychotic symptoms, convulsions, somnolence, encephalopathy and coma

have been reported. These events are generally reversible and usually reported in patients

with renal impairment, or with other predisposing factors (see WARNINGS AND

PRECAUTIONS). These symptoms may be marked, particularly in older adults.

Digestive: Diarrhea, gastrointestinal distress and nausea.

Hematogical and Lymphatic: Anaemia, leukopenia, lymphadenopathy and

thrombocytopenia.

Hypersensitivity and Skin: Alopecia, erythema multiforme, Stevens-Johnson

syndrome, toxic epidermal necrolysis, rashes including photosensitivity, pruritus,

urticaria, dyspnoea, angioedema and anaphylaxis.

Hepatobiliary Tract and Pancreas: Reports of reversible hyperbilirubinemia and

elevated liver related enzymes. Hepatitis and jaundice.

Musculoskeletal: Myalgia.

Special Senses: Visual abnormalities.

Urogenital: Elevated blood creatinine and blood urea nitrogen (BUN). Acute renal

failure, renal pain and hematuria have been reported. Renal pain may be associated with

renal failure (see WARNINGS AND PRECAUTIONS).

DRUG INTERACTIONS

Drug-Drug Interactions

No clinically significant interactions have been identified.

Acyclovir is eliminated primarily unchanged in the urine via active renal tubular

secretion. Any drugs administered concurrently that compete with this mechanism may

increase acyclovir plasma concentrations. Probenecid and cimetidine increase the area

under the curve (AUC) of acyclovir by this mechanism, and reduce acyclovir renal

clearance. Similarly, increases in plasma AUCs of acyclovir 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 acyclovir.

Drug-Food Interactions

There is no known interaction with food (see ACTION AND CLINICAL

PHARMACOLOGY, Pharmacokinetics).

Page 10 of 39

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

DOSAGE AND ADMINISTRATION

Dosing Considerations

The dosage of ZOVIRAX

(acyclovir) should be reduced in patients with

impaired renal function.

Therapy should be initiated as soon as possible after a diagnosis of chickenpox or

herpes zoster, or at the first sign or symptoms of an outbreak of genital herpes.

The recommended dose and duration of use is dependent on the indication.

Recommended Dose and Dosage Adjustment

Treatment of Initial Infection of Herpes Genitalis: 200 mg ( one teaspoonful of

suspension [5 mL]) every 4 hours, 5 times daily for a total of 1 g daily for 10 days.

Therapy should be initiated as early as possible following onset of signs and symptoms.

Suppressive Therapy for Recurrent Herpes Genitalis: The initial recommended dose

is 200 mg ( one teaspoonful of suspension [5 mL]) three times daily. This can be

increased if breakthrough occurs up to a dosage of one teaspoonful [5 mL] of

suspension, five times daily. If necessary, a dose of 400 mg ( two teaspoonfuls of

suspension [10 mL]) given twice daily may be considered. Periodic re-evaluation of the

need for therapy is recommended.

Administration of ZOVIRAX

for intermittent therapy is 200 mg ( one teaspoonful [5

mL] of suspension) every 4 hours 5 times daily for 5 days. Therapy should be initiated at

the earliest sign or symptom (prodrome) of recurrence.

Treatment of Herpes Zoster: 800 mg of oral ZOVIRAX

, every 4 hours, 5 times daily

for 7 to 10 days. Treatment should be initiated within 72 hours of the onset of lesions. In

clinical trials, the greatest benefit occurred when treatment was begun within 48 hours of

the onset of lesions.

Treatment of Chickenpox: 20 mg/kg (not to exceed 800 mg) orally, 4 times daily for

5 days. Therapy should be initiated within 24 hours of the appearance of rash.

Patients With Acute or Chronic Renal Impairment: Caution is advised when

administering acyclovir to patients with impaired renal function. Adequate hydration

should be maintained.

Comprehensive pharmacokinetic studies have been completed following intravenous

acyclovir infusions in patients with renal impairment.

Page 11 of 39

Based on these studies, dosage adjustments are recommended in Table 5 for genital

herpes and herpes zoster indications.

Table 5

Dosage Modification for Renal Impairment

Normal Dosage Regimen

Creatinine Clearance

(mL/min/1.73m

2

)

Adjusted Dosage Regimen

Dose (mg)

Dosing Interval (hours)

200 mg every 4 hours

>10

every 4 hours, 5 x daily

0-10

every 12 hours

400 mg every 12 hours

>10

every 12 hours

0-10

every 12 hours

800 mg every 4 hours

>25

Every 4 hours, 5 x daily

10-25

every 8 hours

0-10

every 12 hours

Hemodialysis: For patients who require hemodialysis, the mean plasma half-life of

acyclovir during hemodialysis is approximately 5 hours. This results in a 60% decrease

in plasma concentrations following a six-hour dialysis period. Therefore, the patient's

dosing schedule should be adjusted so that an additional dose is administered after each

dialysis.

Peritoneal Dialysis: No supplement dose appears to be necessary after adjustment of the

dosing interval.

Missed Dose

If a dose of ZOVIRAX

is missed, the patient should be advised to take it as soon as

he/she remembers, and then continue with the next dose at the proper time interval.

OVERDOSAGE

For management of a suspected drug overdose, contact your regional Poison

Control Centre.

Activated charcoal may be administered to aid in the removal of unabsorbed drug.

General supportive measures are recommended.

Acyclovir is only partly absorbed in the gastrointestinal tract. Patients have ingested up

to 20 g acyclovir on a single occasion, with no unexpected adverse effects. In clinical

studies, the highest plasma concentration observed in a single patient at these doses was

10.0 μg/mL. Accidental, repeated overdoses of oral acyclovir over several days have

been associated with gastrointestinal effects (such as nausea and vomiting) and

neurological effects (headache and confusion).

Page 12 of 39

Intravenous doses administered to humans have been as high as 1,200 mg/m

(28 mg/kg)

3 times daily for up to 2 weeks. Peak plasma concentrations have reached 80 μg/mL.

Overdosage of intravenous acyclovir 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.

Patients should be observed closely for signs of toxicity. Hemodialysis significantly

enhances the removal of acyclovir from the blood and may, therefore be considered a

management option in the event of symptomatic overdose. Precipitation of acyclovir in

renal tubules may occur if the solubility (2.5 mg/mL) in the intratubular fluid is exceeded.

In the event of renal failure and anuria, the patient may benefit from hemodialysis until

renal function is restored (see DOSAGE AND ADMINISTRATION).

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

ZOVIRAX

(acyclovir), a synthetic acyclic purine nucleoside analog, is a substrate with

a high degree of specificity for herpes simplex and varicella-zoster specified thymidine

kinase. Acyclovir is a poor substrate for host cell-specified thymidine kinase. Herpes

simplex and varicella-zoster specified thymidine kinase transform acyclovir to its

monophosphate which is then transformed by a number of cellular enzymes to acyclovir

diphosphate and acyclovir triphosphate. Acyclovir triphosphate is both an inhibitor of,

and a substrate for, herpesvirus-specified DNA polymerase. Although the cellular α-

DNA polymerase in infected cells may also be inhibited by acyclovir triphosphate, this

occurs only at concentrations of acyclovir triphosphate which are higher than those which

inhibit the herpesvirus-specified DNA polymerase. Acyclovir is selectively converted to

its active form in herpesvirus-infected cells and is thus preferentially taken up by these

cells. Acyclovir has demonstrated a very much lower toxic potential in vitro for normal

uninfected cells because: 1) less is taken up; 2) less is converted to the active form; and

3) cellular α-DNA polymerase has a lower sensitivity to the action of the active form of

the drug. A combination of the thymidine kinase specificity, inhibition of DNA

polymerase and premature termination of DNA synthesis results in inhibition of herpes

virus replication. No effect on latent non-replicating virus has been demonstrated.

Inhibition of the virus reduces the period of viral shedding, limits the degree of spread

and level of pathology, and thereby facilitates healing. During suppression there is no

evidence that acyclovir prevents neural migration of the virus. It aborts episodes of

recurrent herpes due to inhibition of viral replication following reactivation.

Pharmacokinetics

The pharmacokinetics of acyclovir after oral administration have been evaluated in

6 clinical studies involving 110 adult patients.

Page 13 of 39

Absorption: In one study of 35 immunocompromised patients with herpes simplex or

varicella-zoster infection given ZOVIRAX

Capsules in doses of 200 to 1,000 mg every

4 hours, 6 times daily for 5 days, the bioavailability was estimated to be 15 to 20%. In

this study, steady-state plasma levels were reached by the second day of dosing. Mean

steady-state peak and trough concentrations following the last 200 mg dose were

0.49 μg/mL (0.47 to 0.54 μg/mL) and 0.31 μg/mL (0.18 to 0.41 μg/mL), respectively and

following the last 800 mg dose were 2.8 μg/mL (2.3 to 3.1 μg/mL) and 1.8 μg/mL (1.3 to

2.5 μg/mL). In another study, 20 immunocompetent patients with recurrent genital

herpes simplex infections given ZOVIRAX

Capsules in dose of 800 mg every 6 hours,

4 times daily for 5 days, the mean steady-state peak and trough concentrations were

1.4 μg/mL (0.66 to 1.8 μg/mL) and 0.55 μg/mL (0.14 to 1.1 μg/mL).

In a multiple-dose crossover study where 23 volunteers received ZOVIRAX

as one

200 mg capsule, one 400 mg tablet and one 800 mg tablet 6 times daily, absorption

decreased with increasing dose and the estimated bioavailabilities of acyclovir were 20,

15 and 10%, respectively. The decrease in bioavailability is believed to be a function of

the dose and not the dosage form. It was demonstrated that acyclovir is not dose

proportional over the dosing range 200 to 800 mg. In this study, steady-state peak and

trough concentrations of acyclovir were 0.83 and 0.46 μg/mL, 1.21 and 0.63 μg/mL, and

1.61 and 0.83 μg/mL for the 200, 400 and 800 mg dosage regimens, respectively.

In another study in 6 volunteers, the influence of food on the absorption of acyclovir was

not apparent.

A single oral dose bioavailability study in 23 normal volunteers showed that ZOVIRAX

Capsules 200 mg are bioequivalent to 200 mg acyclovir in aqueous solution. In a

separate study in 20 volunteers, it was shown that ZOVIRAX

Suspension is

bioequivalent to ZOVIRAX

Capsules.

Distribution: Plasma protein binding is relatively low (9 to 33%) and drug interactions

involving binding site displacement are not anticipated.

Elimination: Following oral administration, the mean plasma half-life of acyclovir in

volunteers and patients with normal renal function ranged from 2.5 to 3.3 hours. The

mean renal excretion of unchanged drug accounts for 14.4% (8.6 to 19.8%) of the orally

administered dose. The only urinary metabolite (identified by high performance liquid

chromatography) is 9-[(carboxymethoxy) methyl] guanine.

Special Populations and Conditions

Pediatrics: In general, the pharmacokinetics of acyclovir in children is similar to adults.

Mean half-life after oral doses of 300 and 600 mg/m

, in children aged 7 months to 7

years, was 2.6 hours (range 1.59 to 3.74 hours).

Orally administered acyclovir in children less than 2 years of age has not yet been fully

studied.

Page 14 of 39

Geriatrics: 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. Dosage reduction may be required in geriatric patients with reduced renal

function (see DOSAGE AND ADMINISTRATION).

Renal Insufficiency: The half-life and total body clearance of acyclovir are dependent

on renal function.

A dosage adjustment is recommended for patients with reduced renal function (see

DOSAGE AND ADMINISTRATION).

STORAGE AND STABILITY

ZOVIRAX

Suspension should be stored at controlled room temperature (15 to 25°C).

DOSAGE FORMS, COMPOSITION AND PACKAGING

Each teaspoonful (5 mL) of ZOVIRAX

Suspension contains 200 mg acyclovir and the

non-medicinal ingredients banana flavour, cellulose, glycerin, methylparaben,

propylparaben, sorbitol, vanillin, and water.

ZOVIRAX

Suspension is available in bottles of 475 mL. .

Page 15 of 39

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name:

acyclovir

Chemical name:

9-[(2-hydroxyethoxy)methyl]guanine

Other name:

acycloguanosine

Molecular formula:

Molecular mass:

225.2

Structural formula:

Physicochemical properties: Acyclovir is a white, crystalline powder with a

maximum solubility in water of 1.3 mg/mL at 25°C.

CLINICAL TRIALS

Initial Genital Herpes

Double blind, placebo controlled studies have demonstrated that orally administered

ZOVIRAX

significantly reduced the duration of acute infection and duration of lesion

healing. The duration of pain and new lesion formation was decreased in some patient

groups.

Recurrent Genital Herpes

In a study of patients who received ZOVIRAX

400 mg twice daily for 3 years, 45, 52,

and 63% of patients remained free of recurrences in the first, second, and third years,

respectively. Serial analyses of the 3 month recurrence rates for the patients showed that

71 to 87% were recurrence free in each quarter.

Page 16 of 39

Herpes Zoster Infections

In a double blind, placebo controlled study of immunocompetent patients with localized

cutaneous zoster infection, ZOVIRAX

(800 mg 5 times daily for 10 days) shortened the

times to lesion scabbing, healing, and complete cessation of pain, and reduced the

duration of viral shedding and the duration of new lesion formation.

In a similar double blind, placebo controlled study, ZOVIRAX

(800 mg 5 times daily

for 7 days) shortened the times to complete lesion scabbing, healing, and cessation of

pain, and reduced the duration of new lesion formation.

Treatment was begun within 72 hours of rash onset and was most effective if started

within the first 48 hours. Adults greater than 50 years of age showed greater benefit.

Chickenpox

Three randomized, double-blind, placebo-controlled trials were conducted in 993

pediatric patients aged 2 to 18 years with chickenpox. All patients were treated within

24 hours after the onset of rash. In two trials, ZOVIRAX

was administered at 20 mg/kg

four times daily (up to 3,200 mg per day) for 5 days. In the third trial, doses of 10, 15, or

20 mg/kg were administered four times daily for 5 to 7 days. Treatment with ZOVIRAX

shortened the time to 50% healing, reduced the maximum number of lesions, reduced the

median number of vesicles, decreased the median number of residual lesions on day 28,

and decreased the proportion of patients with fever, anorexia, and lethargy by day 2.

Treatment with ZOVIRAX

did not affect varicella zoster virus specific humoral or

cellular immune responses at 1 month or 1 year following treatment.

DETAILED PHARMACOLOGY

See Part I, ACTION AND CLINICAL PHARMACOLOGY.

VIROLOGY

The quantitative relationship between the in vitro susceptibility of herpes simplex virus

(HSV) and varicella-zoster viruses (VZV) to acyclovir and the clinical response to

therapy has not been established in man, and virus sensitivity testing has not been

standardized. Sensitivity testing results, expressed as the concentration of drug required

to inhibit by 50% the growth of virus in cell culture (ID

), vary greatly depending upon

the particular assay used, the cell type employed, and the laboratory performing the test.

The ID

of acyclovir against HSV-1 isolates may range from 0.02 μg/mL (plaque

reduction in Vero cells) to 5.9-13.5 μg/mL (plaque reduction in green monkey kidney

[GMK] cells). The ID

against HSV-2 ranges from 0.01 to 9.9 μg/mL (plaque reduction

in Vero and GMK cells, respectively).

Page 17 of 39

Using a dye-uptake method in Vero cells, which gives ID

values approximately 5 to 10-

fold higher than plaque reduction assays, 1,417 HSV isolates (553 HSV-1 and 864 HSV-

2) from approximately 500 patients were examined over a 5-year period. These assays

found that 90% of HSV-1 isolates were sensitive to ≤0.9 μg/mL acyclovir and 50% of all

isolates were sensitive to ≤0.2 μg/mL acyclovir. For HSV-2 isolates, 90% were sensitive

to ≤2.2 μg/mL and 50% of all isolates were sensitive to ≤0.7 μg/mL of acyclovir. Isolates

with significantly diminished sensitivity were found in 44 patients. It must be

emphasized that neither the patients nor the isolates were randomly selected and,

therefore, do not represent the general population. Most of the less sensitive HSV

clinical isolates have been relatively deficient in the viral thymidine kinase (TK). Strains

with alterations in viral TK or viral DNA polymerase have also been reported.

The ID

against VZV ranges from 0.17-1.53 μg/mL (yield reduction, human foreskin

fibroblasts) to 1.85-3.98 μg/mL (foci reduction, human embryo fibroblasts [HEF]).

Reproduction of EBV genome is suppressed by 50% in superinfected Raji cells or P3HR-

1 lymphoblastoid cells by 1.5 μg/mL acyclovir. Cytomegalovirus (CMV) is relatively

resistant to acyclovir with ID

values ranging from 2.3-17.6 μg/mL (plaque reduction,

HEF cells) to 1.82-56.8 μg/mL (DNA hybridization, HEF cells). The latent state of the

genome of any of the human herpesviruses is not known to be sensitive to acyclovir.

Resistance

Prolonged exposure of HSV to subinhibitory concentrations (0.1 μg/mL) of acyclovir in

cell culture has resulted in the emergence of a variety of acyclovir-resistant strains. The

emergence of resistant strains is believed to occur by "selection" of naturally occurring

viruses with relatively low susceptibility to acyclovir. Such strains have been reported in

pre-therapy isolates from several clinical studies.

Two resistance mechanisms involving viral thymidine kinase (required for acyclovir

activation) have been described. These are: (a) selection of thymidine-kinase-deficient

mutants that induce little or no enzyme activity after infection, and (b) selection of

mutants possessing a thymidine kinase of altered substrate specificity that is able to

phosphorylate the natural nucleoside thymidine but not acyclovir. The majority of less

susceptible viruses arising in vitro are of the thymidine-kinase-deficient type which have

reduced infectivity and pathogenicity and less likelihood of inducing latency in animals.

However, an acyclovir-resistant HSV infection in an immunosuppressed bone marrow

transplant recipient on extended acyclovir therapy was found to be due to a clinical

isolate which had a normal thymidine kinase but an altered DNA polymerase. This third

mechanism of resistance involving herpes simplex virus DNA polymerase is due to the

selection of mutants encoding an altered enzyme, which is resistant to inactivation by

acyclovir triphosphate.

VZV appears to manifest resistance to acyclovir via mechanisms similar to those seen in

HSV.

Page 18 of 39

However, limited clinical investigation has revealed no evidence of a significant change

in in vitro susceptibility of VZV with acyclovir therapy, although resistant mutants of this

virus can be isolated in vitro in a manner analogous to HSV. Analysis of a small number

of clinical isolates from patients who received oral acyclovir or placebo for acute herpes

zoster suggests that in vivo emergence of resistant VZV may occur infrequently.

Prolonged acyclovir treatment of highly immunocompromised patients with acquired

immunodeficiency syndrome and severe VZV may lead to the appearance of resistant

virus.

Cross-resistance to other antivirals occurs in vitro in acyclovir-resistant mutants. HSV

mutants which are resistant to acyclovir due to an absence of viral thymidine kinase are

cross-resistant to other agents which are phosphorylated by herpesvirus thymidine kinase,

such as bromovinyldeoxyuridine, ganciclovir and the 2'-fluoropyrimidine nucleosides,

such as, 2'-fluoro-5-iodoarabinosyl-cytosine (FIAC).

The clinical response to acyclovir treatment has usually been good for patients with

normal immunity from whom HSV having reduced susceptibility to acyclovir has been

recovered, either before, during or after therapy. However, certain patient groups, such

as the severely immunocompromised (especially bone marrow transplant recipients) and

those undergoing chronic suppressive regimens have been identified as being most

frequently associated with the emergence of resistant herpes simplex strains, which may

or may not accompany a poor response to the drug. The possibility of the appearance of

less sensitive viruses must be recognized when treating such patients, and susceptibility

monitoring of clinical isolates from these patients should be encouraged.

In summary, the quantitative relationship between the in vitro susceptibility of HSV and

VZV to acyclovir and the clinical response to therapy has not been clearly established in

man. Standardized methods of virus sensitivity testing are required to allow more precise

correlations between in vitro virus sensitivity and clinical response to acyclovir therapy.

TOXICOLOGY

Acute Toxicity Studies

Adult Mice and Rats: The acute toxicity of oral acyclovir was determined as shown in

Table 6.

Table 6

Acute Toxicity Studies

Species

Sex

Route

LD

50

(mg/kg)

95% Conf. Level

Signs

Mouse

Oral

Oral

>10 000

>20 000

None

None

Page 19 of 39

Neonatal, Immature, and Adult Rats: Groups of 10 male and 10 female Charles River

CD (Sprague-Dawley) rats were given single large doses (5 different dose levels) of a

solution (pH 11.0) of acyclovir by subcutaneous injection when they were 3, 10, 28 and

71 days of age. They were observed for 14 days after treatment and LD

values were

calculated by the Litchfield and Wilcoxon method (see Table 7 below). This study was

done to determine if age at exposure affects the acute toxicity of acyclovir; there was no

evidence that young rats were more sensitive than older rats to the acute toxic effects of

acyclovir.

Table 7

LD50 in Rats

Age When Treated

LD

50

(mg/kg body weight)

Males

Females

3 Days

1070

1281

10 Days

28 Days

71 Days

1 477

There was no apparent relationship between length of survival after treatment and age at

which treatment was given. Clinical signs for the rats treated at 3 and 10 days of age

included red and purple cutaneous blisters, blue areas, scabs, scars, necrotic and sloughed

skin, open wounds, body tremors and alopecia. Decreased activity, lacrimation, closed

eyelids, red-brown or brown material around the eyes, nose and mouth, ataxia,

prostration, body tremors, urine stains around the abdomen or genital area, scabbed or

necrotic areas and alopecia were observed in rats treated at 28 and 71 days of age.

Subchronic Oral Toxicity Study

Mice: Four groups each consisting of 28 male and 28 female Charles River CD-1 (ICR)

mice were orally dosed by stomach tube for 33 days with suspensions of acyclovir. Daily

dose levels were 0, 50, 150 and 450 mg/kg. Hematology and clinical chemistry

measurements were made on an additional 8 male and 8 female mice per group (dosed in

the same manner) after the first and fourth weeks of dosing and during the 3rd postdose

week.

Plasma drug concentrations were measured in pooled samples from an additional 4 male

and 4 female mice per group on dose days 1, 15 and 30.

Based on preliminary experiments with rats and mice, the high dose of 450 mg/kg was

selected to produce the highest drug plasma levels attainable, in a practical manner, by

oral dosing in a rodent species. Averaged drug plasma concentrations ranged from

approximately 3.4 (at the low dose) to 11.0 (at the high dose) μg/mL of plasma one hour

after oral dosing.

Page 20 of 39

No changes in health, growth rate, hematology and clinical chemistry measurements

occurred that could be definitely attributed to dosing with acyclovir. Gross and

histopathologic examinations of 16 male and 16 female rats from the high-dose and

control groups at the end of the dose period revealed nothing remarkable.

Chronic Toxicity Studies

Lifetime Oral Toxicity Study in Rats Given Acyclovir by Gastric Intubation:

Charles River CD (Sprague-Dawley) rats were given suspensions of acyclovir by gavage.

There were 50 male and 50 female rats at each of the following dose levels: 0, 50, 150

and 450 mg/kg. After 30 and 52 weeks of treatment, 10 male and 10 female rats from

each group were necropsied. The remaining rats were dosed each day until natural

mortality decreased a group size to approximately 20% of the number of animals of that

sex present in the test groups when the study was started. All remaining rats were killed

and necropsied when the 20% cut-off point was reached. This was during week 110 for

the male rats and week 122 for the female rats. Tissues from control rats and those in the

high-dose group were evaluated by light microscopy. Tissues from rats in the low and

mid-dose groups having masses, nodules or unusual lesions were also examined by light

microscopy. Fixed tissues from rats that were found dead during the first 52 weeks of the

study were also evaluated by light microscopy.

No signs of toxicosis were observed. Plasma samples were collected 1.5 hours after

dosing on days 7, 90, 209, 369, 771 (males only) and 852 (females only). Mean plasma

levels found in high-dose males (450 mg/kg/day) at the times indicated above were as

follows: 1.54, 1.63, 1.39, 1.60 and 1.70 μg/mL (6.84, 7.26, 6.17, 7.10 and 7.56 μM).

Corresponding mean plasma levels for the high-dose females for the corresponding time

periods were 1.76, 2.38, 2.12, 1.71 and 1.81 μg/mL (7.82, 10.58, 9.44, 7.62 and

8.03 μM). Plasma levels in both males and females at all dose levels after one year of

treatment were generally comparable to plasma levels obtained at earlier samplings.

Values for laboratory tests including hematology, clinical chemistry and ophthalmoscopy

were all within the normal range. There were no drug-induced gross or microscopic

lesions and there was no evidence that acyclovir affected survival.

Lifetime Oral Carcinogenicity Study in Rats: There were no signs of toxicosis in

Charles River CD (Sprague-Dawley) rats (100 rats/sex/dose group) given acyclovir by

oral gavage at 50, 150 and 450 mg/kg in a lifetime oral carcinogenicity study. Mean

plasma levels obtained in high-dose males 1.5 hours after dosing at various sampling

times during the study were as follows: 1.54, 1.63, 1.39, 1.60 and 1.70 μg/mL (6.84,

7.26, 6.17, 7.10 and 7.56 μM) at days 7, 90, 209, 369 and 771, respectively.

Corresponding mean values for the high-dose females were 1.76, 2.38, 2.12, 1.71 and

1.81 μg/mL (7.82, 10.58, 9.44, 7.62 and 8.03 μM) at days 7, 90, 209, 369 and 852,

respectively.

Page 21 of 39

Values for clinical laboratory tests including hematology, clinical chemistry, urinalysis,

body weight, food consumption and ophthalmoscopy were all within normal ranges.

There were no drug-induced gross or microscopic lesions and there was no evidence that

acyclovir affected survival, temporal patterns of tumor incidence or tumor counts for

benign or malignant neoplasms.

Most of the relatively few rats found dead or moribund during the first 52 weeks of this

study suffered dosing accidents as evidenced by postmortem findings of esophageal

perforation causing pleural effusion, pneumonia, or mediastinitis.

Lifetime Oral Carcinogenicity Study in Mice: There were no signs of toxicosis in

Charles River CD-1 (ICR) mice (115 mice/sex/dose group) given acyclovir by oral

gavage at 50, 150 and 450 mg/kg/day in a lifetime oral carcinogenicity study. Mean

plasma levels obtained in high-dose males 1.5 hours after dosing at various sampling

times during the study were as follows: 2.83, 3.17 and 1.82 μg/mL (12.59, 14.10 and

8.10 μM) at days 90, 365 and 541, respectively. Corresponding mean values for the

high-dose females were 9.81, 5.85 and 4.0 μg/mL (43.60, 26.0 and 17.79 μM).

Values for clinical laboratory tests including hematology, body weight and food

consumption were all within normal ranges. There were no drug-induced gross or

microscopic lesions. Female mice given 150 and 450 mg/kg acyclovir survived

significantly longer than control female mice; survival of treated males was comparable

to survival of control males. Patterns of tumor incidence and tumor counts for benign or

malignant neoplasms were not affected by treatment with acyclovir.

Chronic 12-Month Oral Toxicity Study in Dogs: Purebred Beagle dogs were given 0,

15, 45 or 150 mg/kg/day of acyclovir each day for the first two weeks of a one-year

study. There were 9 male and 9 female dogs in each test group. The dogs were given

gelatin capsules that contained the appropriate dose. They were treated t.i.d., hence the

dosages administered at each of three equally spaced dose periods were 0, 5, 15 and 50

mg/kg. The 45 and 150 mg/kg dose levels induced diarrhea, emesis, decreased food

consumption and weight loss in both male and female dogs during the first two weeks of

the study. For this reason, during the third week of the study the decision was made to

decrease the mid- and high-dosage levels to 30 and 60 mg/kg/day (10 and 20 mg/kg

t.i.d.). The low dose of 15 mg/kg/day (5 mg/kg t.i.d.) was unchanged. Dogs given 60

mg/kg/day occasionally vomited and occasionally had diarrhea but did well for the

duration of the test, and values for body weight gain and food consumption were

comparable to control values.

Page 22 of 39

During the toxicosis induced by the larger doses of acyclovir, plasma levels of the drug

were likely very high (as indicated by initial mean values of 24.0 μg/mL (106.6 μM) for

high-dose males and 17.4 μg/mL (77.2 μM) for high-dose females when determined

1 hour after the third dose on day 1 of the study). When measured on day 15, plasma

levels of acyclovir in high-dose dogs (150 mg/kg/day) were still very high but they

decreased later when the dosages were decreased. Values for plasma levels after

12 months of treatment were generally comparable to values recorded after 1, 3 and

6 months of treatment. Thus, there was no indication of enhanced metabolism of

acyclovir as a result of chronic treatment.

During the 13th week, some male and female dogs at both the mid- and high-dosage

levels had the following signs: tenderness in forepaws, erosion of footpads, and breaking

and loosening of nails. Regeneration of lost nails began a few weeks later. Nails

regenerated by 6 months (when 3 males and 3 females from each group were killed for an

interim sacrifice) and by the end of the study were of generally good quality. There were

never any signs of an effect on paws or nails in dogs in the low dose group

(15 mg/kg/day).

It is accepted that injury of the corial epithelium that produces nail keratin can result in

arrested production of keratin and production of abnormal keratin. The transient

toxicosis induced by the large doses (45 and 150 mg/kg/day) of acyclovir given during

the first two weeks of the study may have affected the corial epithelium. If there was a

transient effect on the corial epithelium (possibly related to direct effects or secondary to

drug-induced illness during the first two weeks of the study) later loss of the nail could be

a sequella. No discernible effects upon other keratin-producing or keratin-containing

tissues were observed. It should be emphasized that the alterations in the nails appeared

to be related to the transient toxicosis induced by dose levels of 50 and 150 mg/kg/day

tested during the first two weeks of the study and not to the 30 and 60 mg/kg/day dose

levels tested subsequently.

There were no important drug-induced alterations in values for serum biochemical tests,

urinalyses and electrocardiographic tests done at appropriate intervals during this study.

Values for serum albumin and total protein were slightly decreased in dogs treated at 30

and 60 mg/kg/day for 6 and 12 months. However, all values for these parameters

remained within limits accepted as normal.

With the exception of residual alterations in old keratin at the tips of the claws, there

were no signs of treatment-related effects in any of the tissues examined by light

microscopy. Nor were there meaningful alterations in values for the organs weighed at

necropsy. Thus, dose levels up to 60 mg/kg/day were well tolerated for one year. The

"no dose effect" dose level of acyclovir was 15 mg/kg/day (5 mg/kg t.i.d.); however, the

only adverse effects at 30 or 60 mg/kg/day were changes in nails and footpads (30 and

60 mg/kg/day) and mild gastrointestinal signs (60 mg/kg/day).

Page 23 of 39

Reproduction Studies

Teratology – Rats: Acyclovir was administered to pregnant A.R.S. Sprague-Dawley

female rats by subcutaneous injection during the period of organogenesis (day 6 through

day 15 of gestation) at dose levels of 0.0, 6.0, 12.5 and 25.0 mg/kg body weight twice

daily.

Criteria evaluated for compound effect included maternal body weights, weight gains,

appearance and behaviour, survival rates, eye changes, pregnancy rates, and reproduction

data. Offspring viability and development were also evaluated.

In addition to the above measurements, designated animals were sacrificed 1 hour after

the first dose on day 15 in order to collect samples of maternal blood, amniotic fluid and

fetuses for measurements of drug concentration. Mean values from these samples are

listed in Table 8.

Table 8

Acyclovir Concentrations in a Teratology Study in Rats

Dose mg/kg

b.i.d., s.c.

Plasma

(μg/mL)

Acyclovir Concentrations

Amniotic Fluid

(μg/mL)

Fetal Homogenate

μg/mL

(nmoles/g wet wt)

0.26±0.09

0.39±0.06

0.70

(3.13±0.50)

12.5

0.69±0.20

1.13±0.22

0.96

(4.28±0.67)

1.59±0.55

2.0 ±0.53

1.95

(8.64±2.33)

The values obtained for plasma would represent about 30% of initial plasma levels as

judged by the plasma half-life in rodents.

No effects attributable to the administration of acyclovir were noted in comparisons of

maternal body weight values, appearance and behaviour, survival rates, pregnancy rates,

or implantation efficiencies. In addition, no compound-related differences were noted in

evaluations of fetal size, sex and development.

Although the incidences of resorption and fetal viability were within the range of normal

variability in all of the groups, slightly greater incidences of resorptions were noted in the

high-dose animals sacrificed on days 15 and 19 of gestation; however, clear dose-related

trends did not eventuate.

Therefore, acyclovir was not considered teratogenic or embryotoxic when administered

to rats at levels up to 50.0 mg/kg of body weight per day during organogenesis.

Teratology – Rabbits: A teratology study was done in New Zealand White rabbits using

essentially the same experimental design as in the rat, except that dosing was from day 6

through day 18 of gestation. Also, collection of fetuses, amniotic fluid and samples of

maternal blood occurred on day 18 rather than day 15.

Page 24 of 39

No signs of maternal toxicity were observed at any dose, but there was a statistically

significant (p<0.05) lower implantation efficiency in the high-dose group. While there

were a few terata observed in the study (in both control and treated animals), there was

no apparent association with drug treatment. There was, however, an apparent dose-

related response in the number of fetuses having supernumerary ribs. No similar effect

was noted in the rat teratology study (see above) or in a reproduction-fertility experiment

in mice.

Concentrations of acyclovir were detected in plasma and amniotic fluid samples, as well

as in homogenates of fetal tissues. All samples were taken one hour after the first dose

on day 18 of gestation. Drug concentrations in amniotic fluid were substantially higher

than that of plasma (see Table 9).

Table 9

Acyclovir Concentrations in a Teratology Study in Rabbits

Dose mg/kg

b.i.d., s.c.

Plasma

(μg/mL)

Acyclovir Concentrations (Mean and S.E.)

Amniotic Fluid

(μg/mL)

Fetal Homogenate

μg/mL

(nmoles/g wet wt)

0.25±0.03

0.89±0.18

0.16

(0.69±0.13)

12.5

0.25±0.05

8.03±6.37

0.21

(0.92±0.14)

0.39±0.12*

6.16±4.25

0.32

(1.40±0.19)

*N=5

Reproduction – Fertility: Acyclovir was shown not to impair fertility or reproduction

in groups of 15 male and 30 female mice in a two-generation fertility study. The mice in

this study were given acyclovir by gastric intubation at dosage levels of 50, 150 and

450 mg/kg/day. Males were dosed for 64 consecutive days prior to mating and females

for 21 days prior to mating.

In a rat fertility study where groups of 20 male and 20 female rats were given 0, 12.5,

25.0 and 50.0 mg/kg/day by subcutaneous injection, acyclovir was shown not to have an

effect on mating or fertility. The males were dosed for 60 days prior to mating and until

their mating schedule was completed. Female rats were dosed for 14 days prior to mating

and until day 7 of pregnancy. At 50 mg/kg/day s.c. there was a statistically significant

increase in post-implantation loss, but no concomitant decrease in litter size.

In 25 female rabbits treated subcutaneously with 50 mg/kg/day acyclovir on days 6 to 18

of gestation, there was a statistically significant decrease in implantation efficiency but

no concomitant decrease in litter size. There was also a dose-related increase in the

number of fetuses with supernumerary ribs in all drug-treated groups. This increase was

not dose-related when the incidence of supernumerary ribs per litter was examined.

In 15 female rabbits treated intravenously with 50 mg/kg/day acyclovir on days 6 to 18 of

gestation, there was no effect on either implantation efficiency or litter size.

Page 25 of 39

In a rat peri- and postnatal study (20 female rats per group), acyclovir was given

subcutaneously at 0, 12.5, 25 and 50 mg/kg/day from 17 days of gestation to 21 days

postpartum. At 50 mg/kg/day s.c. there was a statistically significant decrease in the

group mean numbers of corpora lutea, total implantation sites and live fetuses in the F1

generation. Although not statistically significant, there was also a dose-related decrease

in group mean numbers of live fetuses and implantation sites at 12.5 mg/kg/day and

25 mg/kg/day s.c.

In a dose-range finding study with 5 female rabbits the intravenous administration of

acyclovir at a dose of 100 mg/kg/day from days 6 to 8 of pregnancy, a dose known to

cause obstructive nephropathy, caused a significant increase in fetal resorptions and a

corresponding decrease in litter size. At a maximum tolerated intravenous dose of

50 mg/kg/day in rabbits there were no drug-related reproductive effects.

In a subchronic toxicity study where groups of 20 male and 20 female rats were given

intraperitoneal doses of acyclovir at 0, 20, 80 or 320 mg/kg/day for one month, and

followed for a one-month postdose period, there was testicular atrophy. Some histologic

evidence of recovery of sperm production was evident 30 days postdose, but this was

insufficient time to demonstrate full reversibility.

Groups of 25 male and 25 female rats were administered intraperitoneal doses of

acyclovir at 0, 5, 20 or 80 mg/kg/day for 6 months. Ten male and 10 female rats in each

group were continued undosed for 13 weeks. Testicular atrophy was limited to high-dose

rats given 80 mg/kg/day for 6 months. Organ weight data and light microscopy defined

full reversibility of the testicular atrophy by the end of the postdose recovery period.

In a 31-day dog study (16 males and 16 females per group) where acyclovir was

administered intravenously at levels of 50, 100 and 200 mg/kg/day, testicles were normal

in dogs at 50 mg/kg. Doses of 100 or 200 mg/kg/day caused death of some dogs due to

cytostatic effects (bone marrow and gastrointestinal epithelium) and aspermic testes or

testes with scattered aspermic tubules. It cannot be ruled out that the testicular change

may have been primary, however, similar changes can be observed secondary to severe

stress in moribund dogs.

Page 26 of 39

Developmental Toxicity Studies

Neonatal Rats - Subchronic Study: Acyclovir dissolved in 0.4% sterile saline was

given by subcutaneous injection to Charles River CD (Sprague-Dawley) neonatal rats for

19 consecutive days, beginning on the 3rd post-partum day. The dose levels tested were

0, 5, 20 and 80 mg/kg body weight. There were 12 litters (each consisting of 5 male and

5 female neonates nursing the natural dam) at each dose level. The dams were not

treated. Neonates were removed from each group for necropsy and microscopic

evaluation of a wide variety of tissues, including eyes and multiple sections of brain, after

they had been treated for 5, 12 or 19 days and after a 3-week postdose drug-free period

(at which time they were 45 days of age). Hematologic (hemoglobin, packed cell

volume, RBC, WBC and differential cell counts) and clinical chemistry (BUN) tests were

done after 16 days of treatment and repeated 18 days after the last (19th) dose was given.

Blood was collected from some neonates 30 minutes after treatment on day 1, on day 9

and at the end of the dose period for the determination of concentrations of acyclovir in

plasma. The largest concentration of acyclovir in plasma was 99.1 μg/mL (440.5 μM)

found in pooled plasma collected from 6 female high-dose (80 mg/kg) neonates

30 minutes after the first dose was given. Treatment with acyclovir did not increase

mortality in the neonatal period.

Rats in the low-dose group gained as much body weight as the respective control rats.

Significant (p<0.05) reductions in mean body weight values were observed in mid- and

high-dose group male and female neonates during the treatment period. Rats in the high-

dose group partially compensated by gaining significantly more body weight than the

controls during the postdose recovery period. There was a minimal but significant

increase in BUN for male (p<0.01) and female (p<0.05) neonates in the high-dose group

on dose day 16. This finding may be of biological importance because there were

minimal accumulations of nuclear debris in renal collecting ducts and loops of Henle in

kidney sections taken from high-dose neonates after 19 days of treatment and examined

by light microscopy. This was the only time period (and the kidney was the only organ)

in which minimal effects on developing organ systems were detected. Thus, 5 mg/kg was

clearly a no effect dose level and 20 mg/kg caused only minimal decreases in body

weight gain.

Eye examinations and light microscopy did not reveal adverse effects on ocular

development. It should be emphasized that there was no morphologic or functional

evidence of adverse effects on developing brain or other portions of the central nervous

system. Thus, acyclovir is distinctly different than cytosine arabinoside which was

reported to produce prominent cerebellar and retinal dysplasia in neonatal rats.

Mutagenicity and Other Short-Term Studies

Acyclovir has been tested for mutagenic potential in a number of in vitro and in vivo

systems:

Page 27 of 39

Microbial: Acyclovir was tested for mutagenic activity in the Ames Salmonella plate

assay; in a preincubation modification of the Ames assay; in the Rosenkrantz E. coli

polA

/polA

DNA repair assay; and in the eukaryote S. cerevisiae, D-4. All studies were

performed both in the presence and absence of exogenous mammalian metabolic

activation. Acyclovir gave no positive responses in any of these systems.

The previous Salmonella studies were extended to extremely high concentrations in order

to achieve toxicity. No positive effects were observed either in the presence or absence

of exogenous mammalian metabolic activation, at concentrations of acyclovir up to

300 mg/plate or 80 mg/mL.

Mammalian Systems: Acyclovir was tested for mutagenic activity in cultured L5178Y

mouse lymphoma cells, heterozygous at the thymidine kinase (TK) locus, by measuring

the forward mutation rate to TK-deficiency (TK

→ TK

; additional studies were

performed at the HGPRT locus and at the Ouabain-resistance marker in these same cells.

All studies were performed in the presence and in the absence of exogenous mammalian

metabolic activation. The test compound was mutagenic at the TK locus at high

concentrations (400 -2,400 μg/mL). (By comparison, the upper limit of acyclovir peak

plasma levels following oral dosing of 200 mg q4h is 0.9 μg/mL). It was negative at the

HGPRT locus and Ouabain-resistance marker. Identical results were obtained with and

without metabolic activation.

Inconclusive results with no apparent dose-related response were obtained when

acyclovir mutagenicity was studied at each of 3 loci (APRT, HGPRT and Ouabain-

resistance) in Chinese hamster ovary (CHO) cells, both in the presence and absence of

exogenous metabolic activation.

Acyclovir, at a concentration of 50 μg/mL (222 μM) for a 72-hour exposure, has been

shown to cause a statistically significant increase in the incidence of morphologically-

transformed foci resulting from treating BALB/C-3T3 cells in vitro in the absence of

exogenous metabolic activation. The morphologically transformed foci have been shown

to grow as tumours following transplantation into immunosuppressed, syngeneic,

weanling mice. Tumour tissues were diagnosed as being either undifferentiated sarcomas

or lymphosarcomas.

Acyclovir, at concentrations between 8 and 64 μg/mL for 18 hours' exposure, did not

induce any morphologically-transformed foci among C3H/10T 1/2 cells treated in vitro in

the absence of exogenous metabolic activation.

Acyclovir, at concentrations of 62.5 and 125 μg/mL for a 48-hour exposure, did not

induce any chromosome aberrations in cultured human lymphocytes in the absence of

exogenous metabolic activation. At higher concentrations, 250 and 500 μg/mL for

48 hours exposure, acyclovir caused a significant increase in the incidence of

chromosome breakage. There was also a significant dose-related decrease in mitotic

index with exposure to acyclovir.

Page 28 of 39

Acyclovir, at doses of 25 and 50 mg/kg/day i.p. for 5 consecutive days, did not produce a

dominant lethal effect in male BKA (CPLP) mice. Further, there was no evidence of a

dominant lethal effect on Charles River CD-1 (ICR) male and female mice treated orally

at dose levels of 50, 150 and 450 mg/kg/day as summarized for the Two Generation

Reproduction/ Fertility Study.

Acyclovir, at single intraperitoneal doses of 25, 50 and 100 mg/kg, failed to induce

chromosome aberrations in bone marrow cells of Chinese hamsters when examined

24 hours after dosing. At higher nephrotoxic doses (500 and 1,000 mg/kg), a blastogenic

effect was seen. (An intraperitoneal dose of 500 mg/kg produces mean peak plasma

levels in Chinese hamsters of 611 μg/mL (2.72 mM) which is 680 times higher than the

upper limit of human peak plasma levels during oral dosing of 200 mg q4h).

Acyclovir, at single intravenous doses of 25, 50 and 100 mg/kg, failed to induce

chromosome aberrations in bone marrow cells of male and female rats when examined at

6, 24 and 48 hours after treatment.

Thus, all these studies showed that acyclovir does not cause single-gene mutations but is

capable of breaking chromosomes.

Immunotoxicology Studies

Acyclovir was subjected to a number of in vitro and in vivo immunological tests.

In two in vivo tests, lymphocyte-mediated cytotoxicity and neutrophil chemotaxis,

acyclovir showed no inhibitory effects at concentrations as high as 135 μg/mL (600 μM).

The compound inhibited rosette formation approximately 50% at 0.9 μg/mL (4 μM).

In four in vivo tests in mice which measured cell-mediated immunity (complement-

dependent cellular cytotoxicity, complement-independent cellular cytotoxicity, delayed

hypersensitivity and graft vs. host reaction) acyclovir showed no inhibitory effects at

single doses up to 200 mg/kg given on day 2 after antigenic stimulation.

Four daily doses of 100 mg/kg/day had no significant effect on Jerne hemolysin plaques

or circulating antibody on day 7 after antigenic stimulation. When the Jerne hemolysin

plaques and antibody titers were examined four days after antigenic challenge and one

day after the last drug dose, 100 mg/kg showed only a slight suppressive effect.

However, 200 mg/kg produced some weight loss (-2.2 g), a moderate reduction in the

number of Jerne hemolysin plaques (PFC/spleen were reduced to 33% of control,

PFC/107 WBC to 46.5% of control). However, there was only a small reduction in the

circulating hemagglutinin titer (from 8.3 to 6.5) and the circulating hemolysin titer (from

9.5 to 8.3) at 200 mg/kg.

Page 29 of 39

In experiments in mice designed to test whether acyclovir would potentiate the

immunosuppressive effect of azathioprine on antibody formation, it was found that the

effects of the two drugs were no more than additive. Only the 200 mg/kg dose of

acyclovir showed an increased suppression of antibody response when given in

combination with azathioprine at doses above 25 mg/kg.

Studies were carried out to evaluate the influence of acyclovir in vitro on human

lymphocyte function. Inhibitory effects on blastogenesis were seen only in assays

examining peak concentrations of potent mitogens, phytohemagglutinin (PHA) and

concanavalin A (Con A), and only at concentrations of drug above 50 μg/mL (222 μM)

and were much less with monilia and tetanus toxoid antigens, where the blastogenic

response is characteristically less vigorous. There was very little effect on cytotoxicity or

LIF production except at concentrations of 200 μg/mL (890 μM) where there has already

been demonstrated to be a direct cytotoxic effect. These inhibitory concentrations are far

in excess of anticipated levels from doses selected for clinical application and over 1,000-

fold higher than the concentration required to inhibit herpesvirus multiplication in vitro.

The effect of acyclovir on human cells was measured. A concentration of 11.2 -

22.5 μg/mL (50-100 μM) inhibits the division of fibroblasts to a variable extent,

depending on the experimental design and the confluency of the monolayer. The

magnitude of this effect was less than that caused by adenine arabinoside or human

leukocyte interferon when these three antiviral agents were compared at clinically

relevant concentrations. Acyclovir also inhibited thymidine incorporation by peripheral

blood mononuclear cells stimulated by PHA or three different herpesvirus antigens. A

linear dose-response curve was observed with these cells, and their proliferation was 50%

inhibited by 22.5 μg/mL (100 μM) acyclovir. Inhibition was exerted on T-cell

proliferation without apparent effect on the release of lymphokines or on monocyte

function.

It should also be mentioned that there was no evidence of adverse effects on the immune

system in the detailed subchronic and chronic animal tests covered earlier in this

summary except at excessively high doses (50 to 100 mg/kg b.i.d.) in dogs where marked

lymphoid hypoplasia occurred.

Page 30 of 39

REFERENCES

Balfour HH, Jr., Kelly JM, Suarez CS, Heussner RC, Englund JA, Crane DD et al.

Acyclovir treatment of varicella in otherwise healthy children. J Pediatr 1990;

116(4):633-639.

Balfour HH, Jr., Rotbart HA, Feldman S, Dunkle LM, Feder HM, Jr., Prober CG

et al. Acyclovir treatment of varicella in otherwise healthy adolescents. The

Collaborative Acyclovir Varicella Study Group. J Pediatr 1992; 120(4 Pt 1):627-

633.

Barry DW, Blum MR. Antiviral drugs: acyclovir, in Recent Advances in Clinical

Pharmacology. Turner P, Shand DG (eds) Churchill Livingstone, Edinburgh

1983.

Barry DW, Nusinoff-Lehrman S. Viral resistance in clinical practice: summary of

five years experience with acyclovir. Pharmacological and Clinical Approaches to

Herpesviruses and Virus Chemotherapy, Aiso, Japan, September 10-13 1984.

Barry DW, Nusinoff-Lehrman S, Ellis MN, Biron KK, Furman PA. Viral

resistance, clinical experience. Scand J Infect Dis Suppl 1985; 47:155-164.

Barry DW, Nusinoff-Lehrman S. Viral resistance in clinical practice: summary of

five years experience with acyclovir. Proceedings of the International Symposium

on Pharmacological and Clinical Approches to Herpes Viruses and Virus

Chemotherapy, Elsever, Amsterdam 1985;269-270.

Biron KK, Elion GB. Effect of acyclovir combined with other antiherpetic agents

on varicella zoster virus in vitro. Am J Med 1982; 73(1A):54-57.

Boelaert J, Schurgers M, Daneels R, Van Landuyt HW, Weatherley BC. Multiple

dose pharmacokinetics of intravenous acyclovir in patients on continuous

ambulatory peritoneal dialysis. J Antimicrob Chemother 1987; 20(1):69-76.

Bryson YJ, Dillon M, Lovett M, Acuna G, Taylor S, Cherry JD et al. Treatment

of first episodes of genital herpes simplex virus infection with oral acyclovir. A

randomized double-blind controlled trial in normal subjects. N Engl J Med 1983;

308(16):916-921.

Burns WH, Saral R, Santos GW, Laskin OL, Lietman PS, McLaren C et al.

Isolation and characterisation of resistant Herpes simplex virus after acyclovir

therapy. Lancet 1982; 1(8269):421-423.

Christophers J, Sutton RN. Characterisation of acyclovir-resistant and -sensitive

clinical herpes simplex virus isolates from an immunocompromised patient. J

Antimicrob Chemother 1987; 20(3):389-398.

Page 31 of 39

Cole NL, Balfour HH, Jr. Varicella-Zoster virus does not become more resistant

to acyclovir during therapy. J Infect Dis 1986; 153(3):605-608.

Collins P, Bauer DJ. The activity in vitro against herpes virus of 9-(2-

hydroxyethoxymethyl)guanine (acycloguanosine), a new antiviral agent. J

Antimicrob Chemother 1979; 5(4):431-436.

Collins P, Oliver NM. Sensitivity monitoring of herpes simplex virus isolates

from patients receiving acyclovir. J Antimicrob Chemother 1986; 18 Suppl

B:103-112.

Collins P. Viral sensitivity following the introduction of acyclovir. Am J Med

1988; 85(2A):129-134.

Collins P, Larder BA, Oliver NM, Kemp S, Smith IW, Darby G. Characterization

of a DNA polymerase mutant of herpes simplex virus from a severely

immunocompromised patient receiving acyclovir. J Gen Virol 1989; 70 ( Pt

2):375-382.

Crumpacker CS, Schnipper LE, Zaia JA, Levin MJ. Growth inhibition by

acycloguanosine of herpesviruses isolated from human infections. Antimicrob

Agents Chemother 1979; 15(5):642-645.

Crumpacker CS, Schnipper LE, Marlowe SI, Kowalsky PN, Hershey BJ, Levin

MJ. Resistance to antiviral drugs of herpes simplex virus isolated from a patient

treated with acyclovir. N Engl J Med 1982; 306(6):343-346.

Darby G, Inglis MM, Larder BA. Mechanisms of resistance to nucleoside

analogue inhibitors of herpes simplex virus. 6th Int Congr Virol 1984;(Abstract

#W34-5).

De Clercq E, Descamps J, Verhelst G, Walker RT, Jones AS, Torrence PF et al.

Comparative efficacy of antiherpes drugs against different strains of herpes

simplex virus. J Infect Dis 1980; 141(5):563-574.

De Clercq E. Comparative efficacy of antiherpes drugs in different cell lines.

Antimicrob Agents Chemother 1982; 21(4):661-663.

Dekker C, Ellis MN, McLaren C, Hunter G, Rogers J, Barry DW. Virus resistance

in clinical practice. J Antimicrob Chemother 1983; 12 Suppl B:137-152.

Douglas JM, Davis LG, Remington ML, Paulsen CA, Perrin EB, Goodman P et

al. A double-blind, placebo-controlled trial to the effect of chronically

administered oral acyclovir on sperm production in men with frequently recurrent

genital herpes. J Infect Dis 1988 Mar; 157:588-93.

Page 32 of 39

Douglas JM, Critchlow C, Benedetti J, Mertz GJ, Connor JD, Hintz MA et al. A

double-blind study of oral acyclovir for suppression of recurrences of genital

herpes simplex virus infection. N Engl J Med 1984; 310(24):1551-1556.

Dunkle LM, Arvin AM, Whitley RJ, Rotbart HA, Feder HM, Jr., Feldman S et al.

A controlled trial of acyclovir for chickenpox in normal children. N Engl J Med

1991; 325(22):1539-1544.

Ellis MN, Keller PM, Martin JL, Strauss SE, Nusinoff-Lehrman S etal.

Characterization of an HSV-2 clinical isolate containing an ACV-resistant mutant

which produces a thymidine kinase with altered substrate specificity. Ninth Int

Herpesvirus Workshop, Seattle, Washington, August 24-29 1984.

Ellis MN, Keller PM, Fyfe JA, Martin JL, Rooney JF, Straus SE et al. Clinical

isolate of herpes simplex virus type 2 that induces a thymidine kinase with altered

substrate specificity. Antimicrob Agents Chemother 1987; 31(7):1117-1125.

Englund JA, Zimmerman ME, Swierkosz EM, Goodman JL, Scholl DR, Balfour

HH, Jr. Herpes simplex virus resistant to acyclovir. A study in a tertiary care

center. Ann Intern Med 1990; 112(6):416-422.

Erlich KS, Jacobson MA, Koehler JE, Follansbee SE, Drennan DP, Gooze L et al.

Foscarnet therapy for severe acyclovir-resistant herpes simplex virus type-2

infections in patients with the acquired immunodeficiency syndrome (AIDS). An

uncontrolled trial. Ann Intern Med 1989; 110(9):710-713.

Erlich KS, Mills J, Chatis P, Mertz GJ, Busch DF, Follansbee SE et al. Acyclovir-

resistant herpes simplex virus infections in patients with the acquired

immunodeficiency syndrome. N Engl J Med 1989; 320(5):293-296.

Field HJ, Darby G, Wildy P. Isolation and characterization of acyclovir-resistant

mutants of herpes simplex virus. J Gen Virol 1980; 49(1):115-124.

Field HJ. The problem of drug-induced resistance in viruses, in Problems of

Antiviral Therapy. Stuart-Harris CH, Oxford J (Eds) Academic Press, London

1983.

Fyfe K. Recurrence patterns of genital herpes after cessation of more then 5 years

of chronic acyclovir suppression. VIII Int Conf AIDS/III Std Wrld Cong

1992;(B240).

Huff JC, Bean B, Balfour HH, Jr., Laskin OL, Connor JD, Corey L et al. Therapy

of herpes zoster with oral acyclovir. Am J Med 1988; 85(2A):84-89.

Jacobson MA, Berger TG, Fikrig S, Becherer P, Moohr JW, Stanat SC et al.

Acyclovir-resistant varicella zoster virus infection after chronic oral acyclovir

Page 33 of 39

therapy in patients with the acquired immunodeficiency syndrome (AIDS). Ann

Intern Med 1990; 112(3):187-191.

Kaplowitz LG, Baker D, Gelb L, Blythe J, Hale R, Frost P et al. Prolonged

continuous acyclovir treatment of normal adults with frequently recurring genital

herpes simplex virus infection. The Acyclovir Study Group. JAMA 1991;

265(6):747-751.

Krasny HC, Liao SH, de Miranda P, Laskin OL, Whelton A, Lietman PS.

Influence of hemodialysis on acyclovir pharmacokinetics in patients with chronic

renal failure. Am J Med 1982; 73(1A):202-204.

Kurtz T. Safety and efficacy of long-term suppressive cyclovir treatment of

frequently recurring genital herpes: year 5 results. 30th Intersci Conf Antimicrob

Agents Chemother 1990;270.

Laskin OL, Longstreth JA, Whelton A, Krasny HC, Keeney RE, Rocco L et al.

Effect of renal failure on the pharmacokinetics of acyclovir. Am J Med 1982;

73(1A):197-201.

Lau RJ, Emery MG, Galinsky RE. Unexpected accumulation of acyclovir in

breast milk with estimation of infant exposure. Obstet Gynecol 1987; 69(3 Pt

2):468-471.

Lehrman SN, Douglas JM, Corey L, Barry DW. Recurrent genital herpes and

suppressive oral acyclovir therapy. Relation between clinical outcome and in-vitro

drug sensitivity. Ann Intern Med 1986; 104(6):786-790.

Marlowe S, Douglas J, Corey L, Schnipper L, Crumpacker C. Sensitivity of HSV

genital isolates after oral acyclovir. 24th Interscience Conf Antimicrob Ag

Chemother, Washington, DC, October 8-10 1984.

Mattison HR, Reichman RC, Benedetti J, Bolgiano D, Davis LG, Bailey-

Farchione A et al. Double-blind, placebo-controlled trial comparing long-term

suppressive with short-term oral acyclovir therapy for management of recurrent

genital herpes. Am J Med 1988; 85(2A):20-25.

McLaren C, Sibrack CD, Barry DW. Spectrum of sensitivity of acyclovir of

herpes simplex virus clinical isolates. Am J Med 1982; 73(1A):376-379.

McLaren C, Ellis MN, Hunter GA. A colorimetric assay for the measurement of

the sensitivity of herpes simplex viruses to antiviral agents. Antiviral Res 1983;

3(4):223-234.

McLaren C, Corey L, Dekket C, Barry DW. In vitro sensitivity to acyclovir in

genital herpes simplex viruses from acyclovir-treated patients. J Infect Dis 1983;

Page 34 of 39

148(5):868-875.

Mertz GJ, Critchlow CW, Benedetti J, Reichman RC, Dolin R, Connor J et al.

Double-blind placebo-controlled trial of oral acyclovir in first-episode genital

herpes simplex virus infection. JAMA 1984; 252(9):1147-1151.

Mertz GJ, Jones CC, Mills J, Fife KH, Lemon SM, Stapleton JT et al. Long-term

acyclovir suppression of frequently recurring genital herpes simplex virus

infection. A multicenter double-blind trial. JAMA 1988; 260(2):201-206.

Mertz GJ, Eron L, Kaufman R, Goldberg L, Raab B, Conant M et al. Prolonged

continuous versus intermittent oral acyclovir treatment in normal adults with

frequently recurring genital herpes simplex virus infection. Am J Med 1988;

85(2A):14-19.

Meyer LJ, de Miranda P, Sheth N, Spruance S. Acyclovir in human breast milk.

Am J Obstet Gynecol 1988; 158(3 Pt 1):586-588.

Mindel A, Weller IV, Faherty A, Sutherland S, Hindley D, Fiddian AP et al.

Prophylactic oral acyclovir in recurrent genital herpes. Lancet 1984; 2(8394):57-

Morton P, Thomson AN. Oral acyclovir in the treatment of herpes zoster in

general practice. N Z Med J 1989; 102(863):93-95.

Naib ZM, Nahmias AJ, Josey WE, Zaki SA. Relation of cytohistopathology of

genital herpesvirus infection to cervical anaplasia. Cancer Res 1973; 33(6):1452-

1463.

Nilsen AE, Aasen T, Halsos AM, Kinge BR, Tjotta EA, Wikstrom K et al.

Efficacy of oral acyclovir in the treatment of initial and recurrent genital herpes.

Lancet 1982; 2(8298):571-573.

Nusinoff-Lehrman S, Hunter G, Rogers J, Corey L, Davis G. The in vitro

acyclovir sensitivity of herpesvirus shed by patients receiving suppressive oral

therapy. 24th Interscience Conf Antimicrob Ag Chemother, Washington, DC,

October 8-10 1984;(Abstract #1015).

O'Brien JJ, Campoli-Richards DM. Acyclovir. An updated review of its antiviral

activity, pharmacokinetic properties and therapeutic efficacy. Drugs 1989;

37(3):233-309.

Pahwa S, Biron K, Lim W, Swenson P, Kaplan MH, Sadick N et al. Continuous

varicella-zoster infection associated with acyclovir resistance in a child with

AIDS. JAMA 1988; 260(19):2879-2882.

Page 35 of 39

Parker AC, Craig JI, Collins P, Oliver N, Smith I. Acyclovir-resistant herpes

simplex virus infection due to altered DNA polymerase. Lancet 1987;

2(8573):1461.

Parris DS, Harrington JE. Herpes simplex virus variants restraint to high

concentrations of acyclovir exist in clinical isolates. Antimicrob Agents

Chemother 1982; 22(1):71-77.

Preblud SR, Arbeter AM, Proctor EA, Starr SE, Plotkin SA. Susceptibility of

vaccine strains of varicella-zoster virus to antiviral compounds. Antimicrob

Agents Chemother 1984; 25(4):417-421.

Reichman RC, Badger GJ, Mertz GJ, Corey L, Richman DD, Connor JD et al.

Treatment of recurrent genital herpes simplex infections with oral acyclovir. A

controlled trial. JAMA 1984; 251(16):2103-2107.

Shah GM, Winer RL, Krasny HC. Acyclovir pharmacokinetics in a patient on

continuous ambulatory peritoneal dialysis. Am J Kidney Dis 1986; 7(6):507-510.

Sibrack CD, Gutman LT, Wilfert CM, McLaren C, St Clair MH, Keller PM et al.

Pathogenicity of acyclovir-resistant herpes simplex virus type 1 from an

immunodeficient child. J Infect Dis 1982; 146(5):673-682.

Straus SE, Seidlin M, Takiff H, Jacobs D, Bowen D, Smith HA. Oral acyclovir to

suppress recurring herpes simplex virus infections in immunodeficient patients.

Ann Intern Med 1984; 100(4):522-524.

Straus SE, Takiff HE, Seidlin M, Bachrach S, Lininger L, DiGiovanna JJ et al.

Suppression of frequently recurring genital herpes. A placebo-controlled double-

blind trial of oral acyclovir. N Engl J Med 1984; 310(24):1545-1550.

Straus SE, Croen KD, Sawyer MH, Freifeld AG, Felser JM, Dale JK et al.

Acyclovir suppression of frequently recurring genital herpes. Efficacy and

diminishing need during successive years of treatment. JAMA 1988;

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in an immunocompromised patient: report of a case. J Oral Maxillofac Surg 1987;

45(8):723-728.

Wade JC, Newton B, McLaren C, Flournoy N, Keeney RE, Meyers JD.

Intravenous acyclovir to treat mucocutaneous herpes simplex virus infection after

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Page 36 of 39

resistant herpes simplex virus isolated from marrow transplant patients receiving

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1082.

IMPORTANT: PLEASE READ

Page 37 of 39

PART III: CONSUMER INFORMATION

Pr

ZOVIRAX

®

(acyclovir)

This leaflet is Part III of a three-part "Product Monograph"

published when ZOVIRAX

(acyclovir) was approved for

sale in Canada and is designed specifically for Consumers.

This leaflet is a summary and will not tell you everything

about ZOVIRAX

. Contact your doctor or pharmacist if you

have any questions about the drug.

ABOUT THIS MEDICATION

What the medication is used for and what it does:

ZOVIRAX

(acyclovir) is an antiviral medicine.

Treatment of shingles (herpes zoster)

ZOVIRAX

is used to treat shingles (herpes zoster)

infections. Shingles is caused by the varicella-zoster virus.

The virus multiplies in and eventually destroys affected skin

cells. ZOVIRAX

stops the virus from multiplying and

therefore from spreading to neighbouring healthy cells. It

cannot replace a cell which has been damaged by the

multiplying virus, but it will facilitate the process of healing.

Treatment of chickenpox (varicella)

ZOVIRAX

is used to treat chickenpox (varicella) which is

caused by the varicella-zoster virus and is highly contagious.

The disease is most contagious shortly before the rash

appears, through the early stages of the rash and until all the

blisters have dried. A patient is not contagious once all the

blisters have become scabs.

Treatment and suppression of genital herpes

ZOVIRAX

is used to treat initial episodes of genital herpes.

Genital herpes is a sexually transmitted infection caused by

the herpes simplex virus (HSV). HSV causes small, fluid-

filled blisters in the genital area which break down into

ulcers/sores which may be itchy or painful. The fluid in these

blisters contains the virus which causes the disease. It is a

feature of all herpes viruses that once in the body, they stay

there throughout life alternating between active (outbreak) and

inactive states.

When taken on a daily basis, ZOVIRAX

can also be used to

prevent the HSV infection from coming back. This type of

treatment is called suppressive therapy.

When it should not be used:

You should not use ZOVIRAX

if you are allergic to or react

badly to acyclovir or valacyclovir or any other components of

ZOVIRAX

(see “What the non-medicinal ingredients are”

section). Tell your doctor if you have ever had an allergic

reaction to any of these ingredients.

What the medicinal ingredient is:

ZOVIRAX

Suspension contains the active ingredient

acyclovir.

What the non-medicinal ingredients are:

ZOVIRAX

Suspension contains the non-medicinal ingredients

banana flavour, cellulose, glycerin, methylparaben,

propylparaben, sorbitol, vanillin, and water.

What dosage forms it comes in:

ZOVIRAX

is available in oral suspension containing 200 mg

of acyclovir per 5 mL.

WARNINGS AND PRECAUTIONS

Before using ZOVIRAX

, tell your doctor if:

You have kidney problems or if you are 65 years of

age or older. Your doctor may give you a lower dose

of ZOVIRAX

and/or

ask you to stay hydrated.

You are severely immunocompromised (e.g. suffering

a severe disease or have recently undergone an organ

transplant, and are taking immunosuppressant drugs

for either of these conditions).

You are pregnant, planning to become pregnant,

breastfeeding or planning to breastfeed.

The safety and effectiveness in children less than 2 years of age

are not known.

You must make sure you drink plenty of liquids such as

water while you are being given ZOVIRAX

Feeling drowsy or sleepy may impair your ability to

concentrate and react. Make sure you are not affected before

you drive or operate machinery.

When using ZOVIRAX

for suppression of genital herpes,

your doctor may periodically stop your drug therapy in order to

reassess your need for continuous treatment. The effect of

long-term use in humans has not been fully assessed. Prudence

is therefore suggested when choosing continuous, long term

therapy with ZOVIRAX

. Suppression of recurrent genital

herpes is therefore, only recommended in those who are

severely affected. Some patients experience increased severity

of the first episode of genital herpes after stopping treatment.

Genital herpes is passed from one person to another through

direct intimate contact. To reduce the risk of transmission,

wash your hands immediately if you touch your skin sores, and

do not touch other parts of your body until you have done so.

IMPORTANT: PLEASE READ

Page 38 of 39

Especially avoid intimate contact with others when the disease

is visible. Herpes virus particles may also be released when

you do not have blisters or sores. For this reason, it is safest

to believe that you can spread the infection to your partner

even when sores are not present.

Although decreased sperm counts were observed in animals

treated with high doses, these effects did not occur in humans.

PROPER USE OF THIS MEDICATION

Medication should not be shared with others. The prescribed

dosage should not be exceeded.

Suspension (liquid) bottle should be shaken before use.

Usual dose for shingles:

For the treatment of shingles (herpes zoster), the usual dose of

ZOVIRAX

is 800 mg every 4 hours, 5 times daily for 7 to 10

days. ZOVIRAX

must be taken as early as possible within

72 hours of the onset of lesions.

Usual dose for chickenpox:

For the treatment of chickenpox (varicella), the usual dose of

ZOVIRAX

is 20 mg/kg (not to exceed 800 mg) 4 times daily

for 5 days. ZOVIRAX

must be taken as early as possible

within 24 hours of the appearance of rash.

Usual dose for genital herpes:

For the treatment of an initial episode of genital herpes, the

usual dose of ZOVIRAX

is 200 mg every 4 hours, 5 times

daily (maximum 1 g daily) for 10 days. ZOVIRAX

must be

taken as early as possible following onset of signs and

symptoms.

For the suppression of genital herpes, the usual dose of

ZOVIRAX

is 200 mg 3 to 5 times daily or 400 mg twice

daily. You should follow dosing instructions carefully. The

objective is to keep enough of the drug in the body at all times

to prevent the herpes virus from multiplying. Your doctor

will try to prescribe the minimum dose required to do this in

your case and may therefore increase or decrease your dose

during the first few weeks. Follow your doctor's instruction

carefully to ensure that you get the best possible response to

treatment.

For the treatment of recurrent episodes of genital herpes, the

usual dose of ZOVIRAX

is 200 mg every 4 hours 5 times

daily for 5 days. ZOVIRAX

must be taken at the earliest

sign or symptom (prodrome) of recurrence.

Overdose:

Missed dose:

If you forget to take a dose, take it as soon as you remember.

Then continue with the next dose at the proper time interval.

Do not double doses.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

As with any widely prescribed medication, adverse events in

association with the use of ZOVIRAX

are reported from time

to time.

Common side effects may affect up to 1 in 10 people:

Headache

Nausea, diarrhea, upset stomach, vomiting

Feeling unwell

Weakness, lack of energy

Skin tingling, itching

Other side effects include: dizziness; high temperature (fever);

itchy, bumpy rash; skin reaction after exposure to light

(photosensitivity); hair loss; unusual bruising or bleeding;

shortness of breath; effects on blood and urine tests; swelling of

the face, lips, mouth, tongue or throat; increases in the enzymes

that work in the liver; feeling agitated or confused; feeling

shaky, unsteady and a lack of co-ordination; difficulty speaking

or hoarseness; seeing or hearing things that are not really there;

feeling drowsy or sleepy; inability to think or judge clearly or

concentrate; disturbances of behaviour, speech and eye

movements; unconsciousness; yellowing of the skin and whites

of the eyes, inflammation of the liver; and changes to blood test

results (reduced numbers of red blood cells, white blood cells,

or blood platelets).

In case of drug overdose, contact a health care practitioner,

hospital emergency department or regional Poison Control

Centre immediately, even if there are no symptoms.

IMPORTANT: PLEASE READ

Page 39 of 39

SERIOUS SIDE EFFECTS, HOW OFTEN THEY

HAPPEN AND WHAT TO DO ABOUT THEM

Frequency

Symptom /

effect

Talk with your

doctor or

pharmacist

Stop taking

drug and call

your doctor

or

pharmacist

Only

if

severe

In all

cases

Unknown

Severe allergic

reaction: itchy,

bumpy rash;

swelling,

sometimes of

the face or

mouth causing

difficulty in

breathing;

collapse

Kidney failure:

pain in the side

(between ribs

and hip) or

kidney area of

your back

Blood

disorders:

unusual bruising

or bleeding

This is not a complete list of side effects. For any unexpected

effects while taking ZOVIRAX

, contact your doctor or

pharmacist.

HOW TO STORE IT

Store ZOVIRAX

Suspension at room temperature (15° to

25°C).

Keep your ZOVIRAX

Suspension in a safe place where

children cannot reach them or see them.

REPORTING SUSPECTED SIDE EFFECTS

You can report any suspected adverse reactions

associated with the use of health products to the Canada

Vigilance Program by one of the following 3 ways:

Report online at www.healthcanada.gc.ca/medeffect

Call toll-free at 1-866-234-2345

Complete a Canada Vigilance Reporting Form and:

- Fax toll-free to 1-866-678-6789, or

- Mail to: Canada Vigilance Program

Health Canada

Postal Locator 0701E

Ottawa, ON K1A 0K9

Postage paid labels, Canada Vigilance Reporting Form

and the adverse reaction reporting guidelines are

available on the MedEffect™ Canada Web site at

www.healthcanada.gc.ca/medeffect.

NOTE: Should you require information related to the

management of side effects, contact your health

professional. The Canada Vigilance Program does not

provide medical advice.

MORE INFORMATION

This document plus the full product monograph, prepared for

health professionals can be found at:

http://www.gsk.ca or by contacting the sponsor,

GlaxoSmithKline Inc.

7333 Mississauga Road

Mississauga, Ontario

L5N 6L4

1-800-387-7374

This leaflet was prepared by GlaxoSmithKline Inc.

Last revised: May 30, 2016

2016 GlaxoSmithKline Inc. All Rights Reserved

ZOVIRAX is a registered trademark of GlaxoSmithKline Inc.

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