NEO-ZOL VAGINAL CREAM 2%

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Active ingredient:
CLOTRIMAZOLE
Available from:
PRESTIGE PHARMA INC
ATC code:
G01AF02
INN (International Name):
CLOTRIMAZOLE
Dosage:
2%
Pharmaceutical form:
CREAM
Composition:
CLOTRIMAZOLE 2%
Administration route:
VAGINAL
Units in package:
25G
Prescription type:
OTC
Therapeutic area:
AZOLES
Product summary:
Active ingredient group (AIG) number: 0110231003; AHFS: 84:04.08.08
Authorization status:
APPROVED
Authorization number:
00874078
Authorization date:
2015-11-16

PRODUCT

MONOGRAPH

NEO-ZOL

VAGINAL

CREAM

Clotrimazole Vaginal Cream USP 1%

NEO-ZOL

VAGINAL

CREAM

Clotrimazole Vaginal Cream USP 2%

Antifungal Agent

Prestige Pharma Inc.

Date of Preparation:

6565 Duncan Street

November 13

, 2015

Montreal, Quebec

H4B 1#8

Control #187895

PRODUCT

MONOGRAPH

NEO-ZOL

VAGINAL

CREAM

Clotrimazole Vaginal Cream USP 1%

NEO-ZOL

VAGINAL

CREAM

Clotrimazole Vaginal Cream USP 2%

THERAPEUTIC

CLASSIFICATION

Antifungal Agent

ACTION

Clotrimazole acts primarily by damaging the permeability barrier in the cell membrane of

fungi. Clotrimazole brings about inhibition of ergosterol biosynthesis, an essential constituent

of fungal cell membranes. If ergosterol synthesis is completely or partially inhibited, the cell is

no longer able to construct an intact cell membrane. This leads to death of the fungus.

Exposure

Candida

albicans

clotrimazole

causes

leakage

intracellular

phosphorus compounds into the ambient medium with a concomitant breakdown of cellular

nucleic acids and potassium eflux. The onset of these events is rapid and extensive after

exposure

organism

to the

drug,

causes

time-dependent

concentration-

dependent inhibition of fungal growth.

INDICATIONS

Neo-Zol

Vaginal

Cream

indicated

6-day

treatment

vaginal

candidiasis

and associated

vulval

candidiasis. Neo-Zol

Vaginal

Cream

indicated

3-day

treatment of vaginal candidiasis and associated vulval candidiasis.

CONTRAINDICATIONS

Neo-Zol Vaginal Cream is contraindicated in patients who are hypersensitive to clotrimazole or

any nonmedicinal ingredients in the formulation of Neo-Zol vaginal cream. For a complete

listing, see the Composition section of the product monograph.

PRECAUTIONS

Neo-Zol Vaginal Cream is not for ophthalmic use. Neo-Zol Vaginal Cream is not for oral use.

with

topical

agents,

skin

sensitization

result.

Neo-Zol

topical

preparations should be discontinued should such reactions occur, and appropriate therapy

instituted.

Treatment

during

menstrual

period

should

performed.

treatment

should

finished before the onset of menstruation. Concomitant medication with vaginal Clotrimazole and

oral tacrolimus (immunosuppressant) might lead to increased tacrolimus plasma levels. Patients

should thus be thoroughly monitored for symptoms of tacrolimus overdosage.

Use in Pregnancy

Although intravaginal application of clotrimazole has shown negligible absorption from both

normal and inflamed human vaginal mucosa, Neo-Zol Vaginal Cream should not be used in the

first trimester of pregnancy unless the physician considers it essential to the welfare of the

patient.

The use of applicators may be undesirable in some pregnant patients and digital insertion of

the vaginal

tablets

considered.

Sanitation

birth

canal

should

ensured

particularly during the last 4 – 6 weeks of pregnancy.

ADVERSE

REACTIONS

Experimental, therapeutic, and large scale clinical studies have shown clotrimazole to be

well tolerated after topical application.

Erythema,

stinging,

blistering,

genital

peeling,

edema,

discomfort

within

reproductive

system

and breasts,

pruritus,

allergic

reaction

(syncope,

hypotension,

dyspnea,

urticaria),

general irritation of the skin, pelvic pain and abdominal pain have been reported infrequently.

Two of 419 (0.5%) patients treated with the 1% vaginal cream experienced adverse reactions

judged to be possibly drug related. These were intercurrent cystitis and vaginal burning. Neither

necessitated discontinuation

treatment.

None

were

serious

consequence

complications occurred.

In clinical trials, 2/217 patients (0.9%) who received 2% clotrimazole vaginal cream experienced

an adverse reaction. 26/796 (3.3%) of patients in clinical trials involving 10% clotrimazole

vaginal cream experienced an adverse reaction. Most adverse reactions involved local itching

and burning. Only rarely was it necessary to discontinue treatment.

DOSAGE

ADMINISTRATION

Vaginal Candidiasis

N

EO

-Z

OL

V

AGINAL

C

REAM

1%

The recommended daily dose is ONE full applicator intravaginally for SIX consecutive days,

preferably at bedtime.

N

EO

-Z

OL

V

AGINAL

C

REAM

2%

recommended

daily

dose

full

applicator

intravaginally for

THREE

consecutive

days, preferably at bedtime.

Vaginal

Candidiasis

accompanied

irritation

vaginal

area.

Therefore,

concomitant local treatment with Neo-Zol Vaginal Cream applied to the irritated vaginal area

and as far as the anal region twice a day is advisable. Neo-Zol Vaginal Cream applied on the

glans penis may prevent reinfection by the partner.

N.B.:

cream

should

inserted

deep

intravaginally

means

applicator

(See WARNING). The plunger should then be depressed slowly.

General hygienic measures such as twice daily tub baths and avoidance of tight underclothing

are important in vaginal infections.

PHARMACEUTICAL

INFORMATION

DRUG

SUBSTANCE

P

ROPER

N

AME

:

clotrimazole

C

HEMICAL

N

AME

:

1-(o-chloro-αα-diphenylbenzyl) imidazole

S

TRUCTURAL

F

ORMULA

:

M

OLECULAR

F

ORMULA

: C

Molecular Weight: 344.84

Description:

Clotrimazole is a white to pale yellow, crystalline, weakly alkaline substance, M.P. 145°C,

soluble in acetone, chloroform and ethanol, and practically insoluble in water. It forms stable

salts with both inorganic and organic acids. It is not photosensitive but slightly hygroscopic and

may be hydrolyzed in acid media.

C

OMPOSITION

Neo-Zol Vaginal Cream 1%

contains 10 mg/g of clotrimazole in a cream base of sorbitan

monostearate, polysorbate 60, cetyl esters wax, cetostearyl alcohol, 2-octyl dodecanol, purified

water, and benzyl alcohol 1% as preservative.

Neo-Zol Vaginal Cream 2%

contains 20 mg/g of clotrimazole in a cream base of sorbitan

monostearate, polysorbate 60, cetyl esters wax, cetostearyl alcohol, 2-octyl dodecanol, purified

water, and benzyl alcohol 1% as preservative.

STABILITY

STORAGE

RECOMMENDATIONS

Neo-Zol Vaginal Cream 1% and 2% must be stored at room temperature between 15oC and

30oC

AVAILABILITY

DOSAGE

FORMS

Neo-Zol Vaginal Cream 1%

is supplied in a 50 g tube of 1% vaginal cream in a carton

containing disposable plastic applicators and patient instructions. 50 g of Neo-Zol Vaginal

Cream 1% is sufficient for 6 intravaginal applications with additional cream for extravaginal use

if required.

Neo-Zol Vaginal Cream 2%

is supplied in a 25 g tube of 2% vaginal cream in a carton

containing disposable plastic applicators and patient instructions. 25 g of Neo-Zol Vaginal

Cream 2% is sufficient for 3 intravaginal applications with additional cream for extravaginal use

if required.

INFORMATION

CONSUMER

EDUCATIONAL

BROCHURE

NEO-ZOL

VAGINAL

CREAM

Clotrimazole Vaginal Cream USP 1%

Antifungal

FOR THE TREATMENT OF VAGINAL YEAST INFECTIONS

READ THIS BEFORE USING

What is a "yeast infection

"?

A "yeast infection" may occur any time there is an overgrowth of yeast organisms in the vagina.

The vagina normally has bacteria and yeast organisms present. Under some conditions, the

number

of yeast organisms rises,

irritating the delicate

tissues

of the

vagina

and vaginal

opening. Conditions that make this more likely to occur are illness and the use of antibiotics

(antibiotics do not affect the yeast organism). Changes in hormone levels may also increase the

risk of a yeast infection. Changes that can occur during pregnancy, with the use of oral

contraceptive pills, or just before a woman's period, may all increase the risk of a vaginal yeast

infection. Some diseases, such as diabetes, can also make a person more susceptible. Even such

things as hot humid weather, continuous use of panty liners, or tight, non-breathing clothing

may increase a woman's chances of developing a yeast infection. These infections are not

usually transmitted through sexual relations, even though a small percentage of male partners

do have infections at the same time.

How do I know if I have a "yeast infection?"

When a "yeast infection" occurs, the body responds with an increase in vaginal secretions.

These secretions are generally thick and sticky, but odourless. These are often referred to as

"cheesy" or "curd-like" because of their similarity to cottage cheese. These secretions are

irritating to the tissues of the vaginal area, causing intense itching, redness, and swelling.

Sometimes red spots or sores may develop, especially if the area has been scratched in

response to the itching. Soreness in the vagina, discomfort when passing urine and pain during

sexual relations is common. 8 Yeast infections do not cause fevers, chills, nausea, vomiting,

diarrhoea, back pain, shoulder pain or vaginal haemorrhaging. If these symptoms are present,

or if the vaginal discharge is foul-smelling, a more serious condition may be present and you

should consult your physician immediately. Even if all of your symptoms point to a yeast

infection, you should not attempt to treat yourself without consulting a physician if it is your

first infection. If you have a second infection in less than 2 months, or experience frequent

infections, contact your physician for evaluation and advice.

How do I cure a "yeast infection"?

To cure a "yeast infection", it is necessary to kill the overgrowth of yeast organisms that

cause

the infection.

Neo-Zol

cure

most

vaginal

yeast

infections.

Even

though the

symptoms of an infection may be relieved in only a few hours or days, you should use Neo-

Zol for a full 6 days. This will decrease the chance of the infection returning. If your

symptoms do not improve after 3 days of treatment or disappear within 7 days, or if they

get worse, discontinue treatment and contact your physician.

How do I use Neo-Zol Vaginal Cream 1%?

Neo-Zol Vaginal Cream 1% is used to treat vaginal yeast infections. Neo-Zol is inserted high into

the vagina once a day (preferably at bedtime) for 6 consecutive days.

Sufficient cream is

provided for 6 intravaginal applications. Extra cream is supplied for use in relieving the external

itching and burning sometimes associated with a vaginal yeast infection. Neo-Zol is only for use

in the vagina and irritated vaginal area and should never be taken by mouth. Treatment during

the menstrual period should not be performed. While you may have sexual relations during

treatment with Neo-Zol, most couples wait until treatment has finished.

Filling the Applicator:

Remove the cap from the tube of Neo-Zol and reverse it to puncture the safety seal over the end

of the tube. To fill the applicator, screw the open end of the applicator on the end of the tube.

Gently squeeze the tube. The plunger will rise as cream enters the applicator. When the

applicator is full, the proper amount of Neo-Zol has been pushed into the applicator and the

applicator may be removed. Replace the cap and roll up the tube from the bottom so that the tube

will be ready for the next use.

Inserting the Medication:

Neo-Zol Vaginal Cream 1% is inserted into the vagina in much the same way as a tampon.

Stand, squat, or lie on your back in a comfortable position. Insert the filled applicator into the

vagina as far as it will comfortably go. Holding the barrel of the applicator steady, gently depress

the plunger until it stops. This will release the medication high in the vagina where it will be

most effective. Remove the applicator. A small additional amount of Neo-Zol Vaginal Cream

may be applied to the opening of the vagina to help provide extra relief.

Using the Cream Externally:

A small amount of Neo-Zol Vaginal Cream may be applied to the opening of the vagina to

help provide extra relief of external symptoms. Squeeze a small amount of cream onto your

finger and gently spread over the irritated vaginal area. Use the cream once or twice a day and

only during the period when external symptoms are present, to a maximum of 7 days.

Disposing of the Applicator:

The Neo-Zol vaginal applicator is recyclable where facilities exist.

ARNINGS

If you are at increased risk for sexually transmitted diseases, have multiple sexual partners or

change partners often, consult a doctor before starting each treatment.

If this is your first yeast infection, it should be evaluated by your physician before you start

any medication.

Do not use Neo-Zol if you have abdominal pain, fever or a foul-smelling vaginal discharge.

If these symptoms are present, you could have a more serious condition and should consult

your physician immediately.

If there is no improvement in your symptoms in 3 days or if they have not disappeared within 7

days, you might not have a vaginal yeast infection. Consult your physician.

you have frequent vaginal

infections, or

if your

yeast infection returns in less than 2

months, consult your physician prior to starting treatment.

Do not use Neo-Zol if you are pregnant, think you are, or are nursing, without first consulting

your physician.

If you experience a rash or new irritation while using the product, discontinue use and contact

your physician.

Concomitant medication with vaginal Clotrimazole and oral tacrolimus (immunosuppressant)

might lead to increased tacrolimus plasma levels.

Neo-Zol may reduce the effectiveness of some birth control methods, such as condoms,

diaphragms, or vaginal spermicides. This effect is temporary and occurs only during treatment.

Do not use tampons, intravaginal douches or other vaginal products while using this product.

Neo-Zol Vaginal Cream is for vaginal use only. Avoid contact with eyes; if this happens,

rinse thoroughly with water.

Neo-Zol

Vaginal

Cream

vaginal

irritated

vaginal

area

only.

Neo-Zol

used externally should not be used for vaginal itching due to causes other than a yeast

infection.

If Neo-Zol is accidentally swallowed, contact your local emergency room or Poison Control

Centre immediately.

Keep Neo-Zol and all other medications out of the reach of children.

Neo-Zol should not be used by girls less than 12 years of age unless advised by a physician.

If you have any questions about Neo-Zol or vaginal infections, contact your pharmacist or

physician.

Medicinal Ingredient: Clotrimazole 1.0%

STORE AT ROOM TEMPERATURE BETWEEN 15

°

C AND 30

°

C.

Prestige Pharma Inc.

6565 Duncan Street

Montreal, Quebec

H4B 1E8

INFORMATION

CONSUMER

EDUCATIONAL

BROCHURE

NEO-ZOL

VAGINAL

CREAM

Clotrimazole Vaginal Cream USP 2%

Antifungal

FOR THE TREATMENT OF VAGINAL YEAST INFECTIONS

READ THIS BEFORE USING

What is a "yeast infection

"?

A "yeast infection" may occur any time there is an overgrowth of yeast organisms in the vagina.

The vagina normally has bacteria and yeast organisms present. Under some conditions, the

number

of yeast organisms rises,

irritating the delicate

tissues

of the

vagina

and vaginal

opening. Conditions that make this more likely to occur are illness and the use of antibiotics

(antibiotics do not affect the yeast organism). Changes in hormone levels may also increase the

risk of a yeast infection. Changes that can occur during pregnancy, with the use of oral

contraceptive pills, or just before a woman's period, may all increase the risk of a vaginal yeast

infection. Some diseases, such as diabetes, can also make a person more susceptible. Even such

things as hot humid weather, continuous use of panty liners, or tight, non-breathing clothing

may increase a woman's chances of developing a yeast infection. These infections are not

usually transmitted through sexual relations, even though a small percentage of male partners

do have infections at the same time.

How do I know if I have a "yeast infection?"

When a "yeast infection" occurs, the body responds with an increase in vaginal secretions.

These secretions are generally thick and sticky, but odourless. These are often referred to as

"cheesy" or "curd-like" because of their similarity to cottage cheese. These secretions are

irritating to the tissues of the vaginal area, causing intense itching, redness, and swelling.

Sometimes red spots or sores may develop, especially if the area has been scratched in

response to the itching. Soreness in the vagina, discomfort when passing urine and pain during

sexual relations is common. 8 Yeast infections do not cause fevers, chills, nausea, vomiting,

diarrhoea, back pain, shoulder pain or vaginal haemorrhaging. If these symptoms are present,

or if the vaginal discharge is foul-smelling, a more serious condition may be present and you

should consult your physician immediately. Even if all of your symptoms point to a yeast

infection, you should not attempt to treat yourself without consulting a physician if it is your

first infection. If you have a second infection in less than 2 months, or experience frequent

infections, contact your physician for evaluation and advice.

How do I cure a "yeast infection"?

To cure a "yeast infection", it is necessary to kill the overgrowth of yeast organisms that

cause

the infection.

Neo-Zol

cure

most

vaginal

yeast

infections.

Even

though the

symptoms of an infection may be relieved in only a few hours or days, you should use Neo-

Zol for a full 6 days. This will decrease the chance of the infection returning. If your

symptoms do not improve after 3 days of treatment or disappear within 7 days, or if they

get worse, discontinue treatment and contact your physician.

How do I use Neo-Zol Vaginal Cream 2%?

Neo-Zol Vaginal Cream 2% is used to treat vaginal yeast infections. Neo-Zol is inserted high into

the vagina once a day (preferably at bedtime)

for 6 consecutive days.

Sufficient cream is

provided for 6 intravaginal applications. Extra cream is supplied for use in relieving the external

itching and burning sometimes associated with a vaginal yeast infection. Neo-Zol is only for use

in the vagina and irritated vaginal area and should never be taken by mouth. Treatment during

the menstrual period should not be performed. While you may have sexual relations during

treatment with Neo-Zol, most couples wait until treatment has finished.

Filling the Applicator:

Remove the cap from the tube of Neo-Zol and reverse it to puncture the safety seal over the

end of the tube. To fill the applicator, screw the open end of the applicator on the end of the

tube. Gently squeeze the tube. The plunger will rise as cream enters the applicator. When the

applicator is full, the proper amount of Neo-Zol has been pushed into the applicator and the

applicator may be removed. Replace the cap and roll up the tube from the bottom so that the

tube will be ready for the next use.

Inserting the Medication:

Neo-Zol Vaginal Cream 2% is inserted into the vagina in much the same way as a tampon.

Stand, squat, or lie on your back in a comfortable position. Insert the filled applicator into the

vagina as far as it will comfortably go. Holding the barrel of the applicator steady, gently

depress the plunger until it stops. This will release the medication high in the vagina where it

will be most effective. Remove the applicator. A small additional amount of Neo-Zol Vaginal

Cream may be applied to the opening of the vagina to help provide extra relief.

Using the Cream Externally:

A small amount of Neo-Zol Vaginal Cream may be applied to the opening of the vagina to

help provide extra relief of external symptoms. Squeeze a small amount of cream onto your

finger and gently spread over the irritated vaginal area. Use the cream once or twice a day and

only during the period when external symptoms are present, to a maximum of 7 days.

Disposing of the Applicator:

The Neo-Zol vaginal applicator is recyclable where facilities exist.

ARNINGS

If you are at increased risk for sexually transmitted diseases, have multiple sexual partners or

change partners often, consult a doctor before starting each treatment.

If this is your first yeast infection, it should be evaluated by your physician before you start

any medication.

Do not use Neo-Zol if you have abdominal pain, fever or a foul-smelling vaginal discharge.

If these symptoms are present, you could have a more serious condition and should consult

your physician immediately.

If there is no improvement in your symptoms in 3 days or if they have not disappeared within 7

days, you might not have a vaginal yeast infection. Consult your physician.

you have frequent vaginal

infections, or

if your

yeast infection returns in less than 2

months, consult your physician prior to starting treatment.

Do not use Neo-Zol if you are pregnant, think you are, or are nursing, without first consulting

your physician.

If you experience a rash or new irritation while using the product, discontinue use and contact

your physician.

Concomitant medication with vaginal Clotrimazole and oral tacrolimus (immunosuppressant)

might lead to increased tacrolimus plasma levels.

Neo-Zol may reduce the effectiveness of some birth control methods, such as condoms,

diaphragms, or vaginal spermicides. This effect is temporary and occurs only during treatment.

Do not use tampons, intravaginal douches or other vaginal products while using this product.

Neo-Zol Vaginal Cream is for vaginal use only. Avoid contact with eyes; if this happens,

rinse thoroughly with water.

Neo-Zol

Vaginal

Cream

vaginal

irritated

vaginal

area

only.

Neo-Zol

used externally should not be used for vaginal itching due to causes other than a yeast

infection.

If Neo-Zol is accidentally swallowed, contact your local emergency room or Poison Control

Centre immediately.

Keep Neo-Zol and all other medications out of the reach of children.

Neo-Zol should not be used by girls less than 12 years of age unless advised by a physician.

If you have any questions about Neo-Zol or vaginal infections, contact your pharmacist or

physician.

Medicinal Ingredient: Clotrimazole 2.0%

STORE AT ROOM TEMPERATURE BETWEEN 15

°

C AND 30

°

C.

Prestige Pharma Inc.

6565 Duncan Street

Montreal, Quebec

H4B 1E8

MICROBIOLOGY

Clotrimazole is an antifungal agent with a broad spectrum of activity. In general, the in vitro

activity of clotrimazole corresponds to that of tolnaftate, griseofulvin, and pyrrolnitrin against

dermatophytes (Trichophyton, Microsporum and Epidermophyton species) and to that of the

polyenes,

amphotericin

B and

nystatin,

against

budding

fungi

(Candida

Histoplasma

species).

In vitro, clotrimazole is fungistatic for most isolates of pathogenic fungi at concentrations of

0.02

to 10

μg/mL.

drug

fungicidal

many

isolates

Trichophyton,

Microsporum, Epidermophyton and Candida species at concentration of 0.1 to 2 μg/mL.

one-step

multiple-step

secondary

resistance

clotrimazole

developed

during

successive passages of C. albicans, C. krusei, C. pseudotropicalis, T. mentagrophytes, T. rubrum,

Cryptococcus neoformans, Aspergillus niger, and A. nidulans. Only a few isolates have been

designated as having primary resistance to clotrimazole: a single isolate of C. guillermondii, six

isolates of C. neoformans, three isolates of Paracoccidioides brasiliensis and two isolates of

Blakeslea trispora.

Topical

application

clotrimazole

been

effective

treatment

skin

infections experimentally

induced

guinea

with

mentagrophytes

quinckeanum. Clinical studies conducted as double-blind trials with mycological control have

shown that clotrimazole is effective in the treatment of tinea cruris, tinea corporis, tinea pedis,

tinea versicolor and cutaneous candidiasis. Mycological examinations have proven its efficacy

against

Trichophyton rubrum,

mentagrophytes,

Malassezia

furfur

Candida

albicans.

Griseofulvin- resistant dermatophytes show no cross resistance to clotrimazole. It may be

assumed,

therefore,

that

site

of action

this

drug

different

from

that

other

antimycotics. Consequently, there is no cross resistance between these agents.

Antifungal Activity in Vitro

Minimum inhibitory concentrations (MICs) of clotrimazole were determined in serial dilution

in broth or agar and in agar diffusion tests using the punched hole procedure. Conventional

culture substrates,

incubation

times,

incubation

temperatures

were

used.

concentrations less than 2 μg/mL, clotrimazole was fungicidal for many isolates of C. albicans,

Trichophyton sp., Microsporum sp., and Epidermophyton sp., tested, and at concentrations less

than 5 μg/mL, clotrimazole was fungistatic for other isolates of these species. Addition of

bovine serum to the culture media at a final concentration of 30% resulted in somewhat higher

MICs of clotrimazole.

vitro

antifungal

activity

clotrimazole

comparable

that

pyrrolnitrin;

either compound

0.78

μg/mL

fungicidal

most

strains

Trichophyton

sp.,

Microsporum sp. and Epidermophyton sp., tested.

The type of action of clotrimazole was determined in the Warburg apparatus by measuring

oxygen consumption of proliferating organisms exposed to varying concentrations of the

drug. Additional studies were performed using a classical subculture technique with organism

counts made after 16, 24 and 48 hours of exposure to the drug. These experiments showed

that the primary action of clotrimazole at concentrations up to 20 μg/mL is fungistatic and

affects only proliferating organisms. At concentrations greater than 20 μg/mL, clotrimazole was

fungicidal for some organisms.

The determinations of MICs of clotrimazole for budding fungi and for biphasic fungi in the

yeast phase have been shown to be dependent on the size of the inoculum and the length of

incubation time. MICs for several isolates of Candida albicans and Torulopsis glabrata were

higher when the inoculum size or incubation time or both were increased.

The effects of inoculum size has been attributed to binding of clotrimazole to the surface of

the fungal cells. This was established in a study of turntable cultures of C. albicans. After 24

hours, the amount of clotrimazole in a nutrient substrate was reduced from 1 μg/mL to 0.7

μg/mL by an inoculum of 1 to 5 x 10

cells/mL.

A larger inoculum, 1 x 10

cells/mL, reduced the drug concentration from 1 μg/mL to 0.3

μg/mL. When

cultures

were

centrifuged

cell

sediment

washed

with

physiological saline solution, the wash solutions contained clotrimazole in concentrations of 0.2

μg/mL to 0.4 μg/mL.

The effect of incubation time on the determination of MIC values is thought to be related to

the mechanism of action of clotrimazole. Initial studies indicated that clotrimazole acted as

an antemetabolite upon the amino acid and protein metabolism of the fungi, causing a gradual

inhibition of fungal growth.

However, recent studies using C. albicans as the test organism have shown that the primary

mode of action of clotrimazole is damage to the permeability of the cell membrane. Exposure

of C. albicans to clotrimazole caused leakage of intracellular phosphorus compounds into the

ambient medium with a concomitant breakdown of cellular nucleic acids. The onset of these

events was rapid and extensive after exposure of C. albicans to the drug and caused a time-

dependent and concentration-dependent inhibition of fungal growth.

Resistance Development

Only a few isolates have been designated as having primary resistance to clotrimazole; a

single isolate of Candida guillermondii, six isolates of Cryptococcus neoformans, three isolates

of Paracoccidioides

brasiliensis,

isolates

Blakeslea

trispora.

potential

development of secondary resistance to clotrimazole was determined for several organisms by

successive passages in a liquid medium, successive passages on a solid medium, or the Warburg

proliferation test. Growth of dermatophytes and yeasts on Szybalski plates was also used as a

method for determining the development of secondary resistance.

No change in sensitivity

was detected for C. albicans in any of the tests for secondary resistance, and no change in

sensitivity

detected

Trichophyton

mentagrophytes,

rubrum,

krusei,

C. pseudotropicalis, C. neoformans, Aspergillus niger, or A. nidulans after successive passages

on liquid and solid media. Possible resistance development was noted in successive passages

of Torulopsis glabrata and other Torulopsis species. Data obtained from Szybalski plate growth

and from other tests indicated that dermatophytes and yeasts do not develop one-step or

oligo-step secondary resistance.

PHARMACOLOGY

Pharmacokinetics

Metabolism studies performed after oral or intravenous administration have shown that in

most species studied, levels of clotrimazole in tissue and serum are low. The majority of the

drug is excreted as metabolites in the feces, with small amounts excreted in the urine. Human

studies indicate

slow

excretion

following

oral

administration

C-labelled

clotrimazole

(greater than 6 days). After intraperitoneal and subcutaneous administration, very low levels

have been observed in the urine. The absorption and organ distribution of the drug is very poor

when administered parenterally.

The pharmacokinetics of topically applied clotrimazole in human subjects have been evaluated

by Duhm et al. who reported on the penetration of radioactive clotrimazole 1% cream and 1%

solution into intact and acutely inflamed skin. Six hours after application of the drug, the

concentration of clotrimazole found in skin layers varied from 100 μg/cm

in the stratum

corneum to 0.5 to 1.0 μg/cm

in the stratum reticulare and <0.1 μg/cm

in the subcutis. No

measurable amount of radioactivity (0.001 μg/mL) was found in the serum within 48 hours

after application of 0.5 mL of the solution or 0.8 g of the cream.

Intravaginal

application

C-labelled

clotrimazole

inserts

containing

active

substance in human subjects has shown that the amount absorbed is less than 1/200 of that

absorbed

after

oral administration

clotrimazole.

maximum

serum

concentration values

were between 0.016

and 0.05

μg/mL from one to three

days after

intravaginal

application.

Intravaginal application

human

subjects

C-labelled

clotrimazole vaginal cream containing 50 mg of active substance has shown that the systemic

absorption of clotrimazole from the Vaginal Cream is quantitatively proportional to that from

the Vaginal Inserts.

animal

experiments,

clotrimazole

exerts

vitro

vivo,

dose-dependent,

stimulating effect on certain microsomal enzyme systems which is approximately equal to that

of phenobarbital in its inductive potential. However, this stimulating effect subsides rapidly

when treatment is discontinued. The enzyme-inductive effect of clotrimazole has been found to

be intact in adrenalectomized animals.

In 8 double-blind studies and one single-blind study involving 432 patients using the 1% cream

7 days, the average mycological cure rate was 72% with a range of 55

-90%. Oral

contraceptives did not significantly alter mycological cure rates and overall success. In a limited

number of pregnant women, the 1 % cream appeared to be effective, although the cure

rates seemed to be somewhat lower. In clinical trials with clotrimazole 2% vaginal cream,

266/303 patients (88%) had a negative culture for Candida sp. four weeks following treatment.

TOXICOLOGY

ACUTE

TOXICITY

(ORAL)

Animal

Species

LD

50

mg/kg

Mouse

761 - 923

708 - 718

Rabbit

> 1000

kg > 1000; vomiting from 100 mg/kg

> 2000; vomiting from 100 mg/

Multidose Local Tolerance

Primary skin irritation (patch test): no detectable reddening on the intact rabbit skin at

either 24

72 hours with 1

% solution or

cream

of clotrimazole. Very slight erythema

formation after 24 hours in the scarified rabbit skin.

Primary

irritation

conjunctival

mucosa:

clotrimazole

solution

cream

produced

a transient

conjunctival

irritation

rabbits,

consisting

low-grade

reddening

slight increase in secretion. No grossly detectable alterations were present in either the cornea

or the iris of any of the treated animals. Both the cream and solution produced a transient,

very slight reddening of the conjunctival mucosa. No alterations occurred on the cornea.

Subacute (up to 13 weeks) dermal tolerance: the application of 1% clotrimazole solution

or 1%

cream

systemically

well

tolerated;

edema

seen

treated

skin,

although mild erythema was observed sporadically. The animals in all groups with abraded

skin manifested a slight healing tendency.

Subacute

(dogs:

days;

monkeys:

weeks)

local

vaginal

tolerance:

repeated application

clotrimazole

vaginal

inserts

showed

satisfactory

local

systemic tolerance. There were no detectable adverse effects, and the cytological examination

in monkeys indicated variations consistent with normal estrus cycles.

Subacute

dogs:

days;

monkeys:

weeks;

healthy

human

volunteers:

days) local

vaginal

tolerance.

repeated

application

Vaginal

Cream

showed

satisfactory local and systemic tolerance without adverse effects or abnormalities in vaginal

cytology in all species.

REPRODUCTION

TERATOLOGY

At dosages up to 100 mg/kg (subcutaneous), clotrimazole was well tolerated by pregnant mice,

rats and rabbits, and it had no embryotoxic or teratogenic effect.

When given to pregnant rats at oral doses up to 100 mg/kg from day 6 through day 15 of

gestation, the number of resorptions was higher and the fetal weights were lower than the

controls, but the number of fetal malformations did not differ significantly from that of the

control group.

Rats treated with clotrimazole for 10 weeks at dosage up to 50 mg/kg/day did not show

any difference from the control group in the duration of estrus, fertility, duration of pregnancy,

or in the number of implantations and resorptions. The dose of 50 mg/kg/day impaired the

development of the young, and dams receiving this dose level raised fewer offspring.

The intravaginal administration of 100 mg/kg clotrimazole from the sixth to the fifteenth day

of gestation was well tolerated by pregnant rats, and there were no harmful effects on the

fertilization rate, the resorption rate, the mean fetal weight, and the frequency of stunted

forms and of fetuses with slight bone alterations. No malformations were produced by this

dose.

Human

cases

under

treatment

which

were

evaluated

with

respect

photosensitivity

and phototoxicity, no reactions were encountered.

Twenty

normal

subjects

were

tested

controlled

study

sensitivity

ultraviolet

radiation. Areas of skin treated with clotrimazole were irradiated for 30 seconds on the first

day, and for one-half minute longer each time on every second day thereafter. One of the 20

subjects was irradiated once only; 9 subjects three times, and 10 subjects four times. One

subject developed papule formation after the first exposure to ultraviolet radiation.

There were undesirable effects in three (0.5%) of 653 patients treated with clotrimazole

vaginal cream which were possibly related to treatment. Discontinuation of treatment was

necessary in a patient with a sensation of vaginal burning and in another patient with a possible

allergic reaction, manifested by vaginal burning, local irritation and erythema. Treatment was,

however, continued in a patient with intercurrent cystitis.

REFERENCES

1) Cartwright, R.Y.: Clotrimazole in the Treatment of Acute and "Resistant" Vaginal Candidiasis.

Postgrad. Med. J. 5O, Suppl. 1, 90-92 (1974).

2) Duhm, B., Maul, W., and Medenwald, H., et al.: Pharmakokinetik nach topischer Anwendung

Bisphenyl-(2-chlorophenyl)-

-imidazolyl-methan

after

topical application).

Arzneimittel-Forschung 22:1276-1280 (1972). English version, Drugs Made in Germany 15:99-

103 (1972).

3) Dunster, G.D.: Vaginal candidiasis in pregnancy - A trial of clotrimazole. Postgrad. Med. J. 50,

Suppl. 1, 86-88 (1974).

Fredriksson,

Topical

treatment

with

5097.

broad

spectrum

antimycotic agent. Brit. J. of Dermatology 866:628-630 (1972).

5) Freis, A.: The tolerance of Clotrimazole on Topical Application. Drugs made in Germany XV.

120-121 (1972).

6) Higton, B.K.: A trial of clotrimazole and nystatin in vaginal candidiasis. Postgrad. Med. J. 50,

Suppl. 1, 95-96 (1974).

Holt,

Studies

broad-spectrum

antimycotic

agent

5097.

Int.

Congress

for Microbiology, Mexico City, August, 1970.

Legal,

H.P.:

treatment

trichomonas

candida

vaginitis

with

clotrimazole

vaginal tablets. Postgrad. Med. J. 50, Suppl. 1, 81-83 (1974).

Lohmeyer,

Treatment

candidiasis

trichomoniasis

female

genital

tract. Postgrad. Med. J. 50, Suppl. 1, 78-79 (1974).

Masterton,

al.:

Six-day

clotrimazole

therapy

vaginal

candidiasis.

Curr.

Med.

Res. Opin., (1975), 3, 83.

Milsom,

Forssman,

Treatment

vaginal

candidiasis

with

single

mg clotrimazole pessary. Br. J. Ven. Dis. 2, 124-126 (1982).

12) Plempel, M., Bartmenn, K., Buchel, K.H., and Regel, E.: BAY b 5097, a New Orally Applicable

Antifungal Substance with Broad-spectrum Activity. Antimicrobial Agents and Chemotherap.

271-274 (1969).

Ritzerfeld,

Venschott,

M.L.:

vitro

Untersuchungen

Antimykotikum

Chlortritylimidazol. Int. J. Clin. Pharmacology, Therapy and Tox. 4, No. 2, 204-

206 (1971).

14) Schnell, J.D.: The incidence of vaginal candida and trichomonas infections and treatment

of trichomonas vaginitis with clotrimazole. Postgrad. Med. J., 50, Suppl. 1, 79-81 (1974).

15) Iwata, K., Yamaguchi, H., Hiratani, T.: Mode of Action of Clotrimazole. Sabouraudia 11:158-

166 (1973).

16) Iwata, K., Kanda, Y., Yamagochi, H. et al.: Electron microscopic studies on the mechanism

of action of clotrimazole. Sabouraudia 11:205-209 (1973).

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