CLOTRIMADERM VAGINAL 6 CREAM

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Active ingredient:
CLOTRIMAZOLE
Available from:
TARO PHARMACEUTICALS INC
ATC code:
G01AF02
INN (International Name):
CLOTRIMAZOLE
Dosage:
1%
Pharmaceutical form:
CREAM
Composition:
CLOTRIMAZOLE 1%
Administration route:
VAGINAL
Units in package:
50GM
Prescription type:
OTC
Therapeutic area:
AZOLES
Product summary:
Active ingredient group (AIG) number: 0110231001; AHFS: 84:04.08.08
Authorization status:
APPROVED
Authorization number:
00812366
Authorization date:
2020-02-21

Page 1 of 22

PRODUCT MONOGRAPH

Clotrimaderm Vaginal 6

(Clotrimazole Vaginal Cream USP 1%

Clotrimaderm Vaginal 3

(Clotrimazole Vaginal Cream USP

Clotrimaderm External Cream

(Clotrimazole Vaginal Cream USP 1%)

Antifungal Agent

Taro Pharmaceuticals Inc. Date of Pr

130 East Drive January 27, 2020

Brampton,

Ontario

Control #232921

Page 2 of 22

Table of Contents

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

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

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

CONTRAINDICATIONS ................................................................................................................. 3

WARNINGS AND PRECAUTIONS ............................................................................................... 3

ADVERSE REACTIONS ................................................................................................................. 4

DRUG INTERACTIONS .................................................................................................................. 5

DOSAGE AND ADMINISTRATION ............................................................................................. 5

OVERDOSAGE ................................................................................................................................. 6

ACTION AND CLINICAL PHARMACOLOGY

....................................................................... 6

STORAGE AND STABILITY .......................................................................................................... 7

DOSAGE FORMS, COMPOSITION AND PACKAGING .............................................................. 7

PART II: SCIENTIFIC INFORMATION ....................................................................................... 9

PHARMACEUTICAL INFORMATION .......................................................................................... 9

CLINICAL TRIALS ........................................................................................................................ 10

GY ........................................................................................................................... 10

TOXICOLOGY ................................................................................................................................ 12

RENC

S ............................................................................................................................... 155

PART III: CONSUMER INFORMATION: Clotrimaderm Vaginal 6 ..................................... 177

PART III: CONSUMER INFORMATION: Clotrimaderm Vaginal 3 ....................................... 19

Page 3 of 22

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

Route of Administration

Dosage Form / Strength

Clinically Relevant Nonmedicinal Ingredients

Vaginal

cream

1%, 2%

For a complete listing see Dosage Forms,

Composition and Packaging section.

INDICATIONS AND CLINICAL USE

Clotrimaderm Vaginal 6 (clotrimazole) is indicated for the 6-day treatment of vaginal candidiasis.

Clotrimaderm Vaginal 3 (clotrimazole) is indicated for the 3-day treatment of vaginal candidiasis.

Clotrimaderm External Cream (Clotrimazole Cream 1%) is indicated for the topical treatment of

external irritation caused by vulvovaginal candidiasis.

CONTRAINDICATIONS

Patients who are hypersensitive to this drug or to any ingredient in the formulation or component

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

section of the product monograph.

WARNINGS AND PRECAUTIONS

General

Clotrimaderm Vaginal cream and Clotrimaderm External Cream are not for ophthalmic use.

Patients should seek medical advice if they have frequent vaginal infections or if their yeast

infection returns in less than 2 months.

Patients should seek medical advice if they suffer from diabetes mellitus, or have underlying

immunodeficiency disease (such as HIV-AIDS).

As with all topical agents, skin sensitization may result. Use of Clotrimaderm External

Cream

ical

preparations should be discontinued should such reactions occur, and

Page 4 of 22

appropriate therapy instituted.

Treatment during the menstrual period should not be performed. The treatment should be finished

before the onset of menstruation.

While sexual relation may be had during treatment with clotrimazole

topical

ons, most

couples wait until treatment has finished as the partner could become infected.

Effects on Fertility:

No human studies of the effects of clotrimazole on fertility have been performed; however, animal

studies have not demonstrated any effects of the drug on fertility.

Special Populations

Pregnant Women:

There are limited amounts of data from the use of clotrimazole in pregnant women. Animal studies

do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see

REPRODUCTION AND TERATOLOGY). Although intravaginal application of clotrimazole

has shown negligible absorption from both normal and inflamed human vaginal mucosa,

Clotrimaderm 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.

Nursing Women:Available pharmacodynamics / toxicological studies in animals have shown

excretion of clotrimazole / metabolites in milk. Breastfeeding should be discontinued during

treatment with clotrimazole.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

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

tolerated after topical application.

For Clotrimazole External Cream:

Immune system disorders: allergic reaction (syncope, hypotension, dyspnea, urticarial)

Skin and subcutaneous skin disorders: blisters, discomfort/pain, edema, erythema, irritation,

peeling/exfoliation, pruritis, rash, stinging/burning.

For Clotrimazole Vaginal cream:

Immune system disorders: allergic reaction (syncope, hypotension, dyspnea, urticaria)

Reproductive system disorders and breast disorders: genital peeling, pruritis, edema, erythema,

stinging, blistering, discomfort, general irritation of the skin and pelvic pain, vaginal hemorrhage

Page 5 of 22

Gastrointestinal disorder: abdominal pain

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 of treatment. None were of serious consequence and no

complications occurred.

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

adverse reaction. Most adverse reactions involved local itching and burning. Only rarely was it

necessary to discontinue treatment.

DRUG INTERACTIONS

Overview

Drug-Drug Interactions

Concomitant medication with vaginal Clotrimazole and oral tacrolimus/sirolimus

(immunosuppressants) might lead to increased tacrolimus/sirolimus plasma levels. Patients should

thus be thoroughly monitored for symptoms of tacrolimus/sirolimus overdosage.

DOSAGE AND ADMINISTRATION

Dosing Considerations

Vaginal

iasi

may be accompanied by irritation in the vaginal area. Therefore, concomitant

local treatment with Clotrimaderm Vaginal cream (or Clotrimazole External Cream) applied to the

irritated vaginal area and as far as the anal region twice a day is advisable. Clotrimazole External

Cream (or Clotrimazole Vaginal cream) applied on the glans penis may prevent re-infection by the

partner.

N.B.: The cream should be inserted deep intravaginally by means of the applicator (See

PRECAUTIONS). 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.

Recommended Dose and Dosage Adjustment

Vaginal Candidiasis

Clotrimaderm

Vaginal 6

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

preferably at bedtime.

Page 6 of 22

Clotrimaderm

Vaginal 3

The recommended daily dose is ONE full applicator intravaginally for THREE consecutive

days, preferably at bedtime.

Clotrimaderm External Cream

The cream should be spread onto the irritated area once or twice daily as needed, for up to seven

consecutive days.

OVERDOSAGE

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

ACTION AND CLINICAL PH

AR

M

AC

OLOG

Y

Mechanism of 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 of Candida albicans to clotrimazole causes leakage of 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 of the

organism to the drug, and causes a time-dependent and concentration-dependent inhibition of

fungal growth.

Pharmacokinetics

Pharmacokinetic investigations after vaginal application have shown that only a small amount

of clotrimazole (3-10%) is absorbed. Due to the rapid hepatic metabolization of absorbed

clotrimazole into pharmacologically active metabolites, the resulting peak plasma

concentrations of clotrimazole after vaginal application of a 500 mg dose were less than 10

ng/mL, suggesting that clotrimazole applied intravaginally is unlikely to lead to measurable

systemic effects or side effects.

Metabolism studies performed after oral or intravenous administration have shown that

most species studies, 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 of

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

Page 7 of 22

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 of

C-labelled clotrimazole

s containing 100 mg of active

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

that

absorbed after the oral administration of 1.5 g of clotrimazole. The maximum serum concentration

values were between 0.016 and 0.05 µg/mL from one to three days after intravaginal application.

Intravaginal application in human subjects of 5 mL

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

In animal experiments, clotrimazole exerts an in vitro and in

vivo,

dose-dependent, stimulating

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

phenobarbital in its

potential.

However,

s stimulating effect subsides rapidly when

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

intact in adrenalectomized animals.

STORAGE AND STABILITY

Clotrimaderm Vaginal 6, Clotrimaderm Vaginal 3, and Clotrimaderm External Cream must be

stored at room temperature between 15°C and 30°C.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Clotrimaderm Vaginal 6 is supplied in

50 g tube of 1% vaginal cream in a carton containing 6

disposable plastic applicators and patient instructions. 50 g of Clotrimaderm Vaginal cream 1%

is sufficient for 6 intravaginal applications with additional cream for extravaginal use if required.

Clotrimaderm Vaginal 3 is supplied in a 25 g tube of 2% vaginal cream in a carton containing 3

disposable plastic applicators and patient instructions. 25 g of Clotrimaderm Vaginal cream 2%

is sufficient for 3 intravaginal

applications

with additional cream for extravaginal use if required.

Composition

Clotrimaderm Vaginal 6 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.

Page 8 of 22

Clotrimaderm Vaginal 3 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.

Clotrimaderm External 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.

Page 9 of 22

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name:

clotrimazole

Chemical name: 1-(o-chloro-αα-diphenylbenzyl) imidazole

Molecular formula and molecular mass: C

344.84 g/mol

Structural formula:

Phisicochemical properties: Clotrimazole is

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.

Page 10 of 22

CLINICAL TRIALS

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

for 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, both the 1% cream and the 100 mg tablet 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.

M

ICR

OB

I

OLO

GY

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 and Histoplasma

species).

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

0.02 to 10 µ g/mL. The drug is fungicidal for many isolates of Trichophyton, Microsporum,

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

No one-step or multiple-step secondary resistance to clotrimazole has developed during successive

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

neoformans, A s p

u s n

r , and A. nidulans. Only a few isolates have been designated as

having primary resistance to clotrimazole:

single isolate of C. guillermondii, six isolates of C.

neoformans, three isolates of Paracoccidioides brasiliensis and two isolates of Blakeslea trispora.

Topical application of clotrimazole has been effective in the treatment of skin infections

experimentally induced in the guinea pig with T. mentagrophytes and T. 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, T. mentagrophytes, Malassezia furfur and Candida albicans. Griseofulvin- resistant

dermatophytes show no cross resistance to clotrimazole.

may be assumed, therefore, that the site of

action of this drug is different from that of other antimycotics. Consequently, there is no cross

resistance between these agents.

Page 11 of 22

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, and incubation temperatures were used. At 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.

The in vitro antifungal activity of clotrimazole was comparable to that of pyrrolnitrin; either

compound at 0.78 µg/mL was fungicidal for most strains of Trichophyton sp., Microsporum sp.

and Epidermophyton sp., tested.

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

oxygen consumption of proliferating organisms exposed to varying concentrations of the drug.

Additional studies were performed using

classical subculture technique

h organism counts

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 the cultures were centrifuged and the cell sediment was 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

antimetabolite upon the amino acid and protein metabolism of the fungi, causing a gradual inhibition

of fungal growth.

Page 12 of 22

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

ry 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, and two isolates of Blakeslea trispora. The potential for

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

of the tests for secondary resistance, and

no change in sensitivity was detected for Trichophyton mentagrophytes, T. rubrum, C. krusei,

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.

TOXICOLOGY

Non-clinical data reveal no special hazards for humans based on conventional studies of safety

pharmacology, genotoxicity and carcinogenic potential. Effects in nonclinical studies, such as the

effects on the liver (elevation of transaminases and alkaline phosphatase, liver cell hypertrophy) in the

repeat-dose toxicity studies, the effects on the survival of the neonate in a rat fertility study, the

species-specific indirect effects on the growth/survival of the fetus in a rat teratology study were

observed with oral administration but only at exposures in excess of the maximum human exposure

indicating little relevance to clinical use. Given the limited absorption of clotrimazole following a

topic application, the potential for toxicity with the occasional use of Clotrimaderm Vaginal 6 is

further limited.

Carcinogenicity of clotrimazole was evaluated in a 78-week oral dosing study in rats and the results

did not show any carcinogenic effect of clotrimazole.

Clotrimazole has been extensively studied in in vitro and in vivo mutagenicity assays, and no

evidence of genotoxic potential was found. In an Ames test, an in vitro biological assay to detect the

Page 13 of 22

mutagenicity of chemical compounds, clotrimazole showed no evidence of mutagenic activity.

Clotrimaozle was found to be non-mutagenic in two additional in vitro studies, a gene

mutati

test

in V79 cell lines and an Unscheduled DNA Synthesis (UDS) in primary rat hepatocytes. Studies

evaluating the mutagenicity of clotrimazole in germ cells did not demonstrate mutagenic effects in a

spermatogonia test in male hamsters, or in a dominant lethal test in male mice. Additionally, in mice,

clotrimazole was not clastogenic in a micronucleus test.

Acute Toxicology

Animal

Species

LD

50

mg/kg

Mouse

761-923

708-718

Rabbit

>1000

>1000; vomiting from 100 mg/kg

>2000; vomiting from 100 mg/ kg

Multidose Local Tolerance

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

either 24 or 72 hours with 1% solution or cream of clotrimazole. Very slight erythema

formation after 24 hours in the scarified rabbit skin.

2. Primary irritation on conjunctival mucosa: clotrimazole solution or cream produced

transient conjunctival irritation in rabbits, consisting in low-grade reddening and a slight

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

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.

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

1% cream was

systemically

well tolerated; no edema was seen on the treated

skin,

although mild erythema was observed

sporadically.

The animals in all groups

with

abraded skin

manifested

a slight healing

tendency.

Subacute (dogs: 14 days; monkeys: 13 weeks) local vaginal tolerance:

repeated

application

clotrimazole

vaginal tablets showed a

satisfactory

local

systemic

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

monkeys indicated variations consistent with normal estrus cycles.

Subacute (5 dogs: 30 days; 4 monkeys: 13 weeks; 10 healthy human volunteers: 28 days)

local vaginal tolerance. The repeated application of vaginal cream showed a satisfactory

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

all species.

Page 14 of 22

Human

In 453 cases under treatment which were evaluated with respect to photosensitivity and

phototoxicity, no reactions were encountered.

Twenty normal subjects were tested in a controlled study for sensitivity to 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.

REPRODUCTION AND TERATOLOGY

At dosages up to 100 mg/kg (oral), 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 of 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.

Page 15 of 22

RE

FE

RENC

E

S

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3, Educational Brochure p. 2), (1998).

Vasquez E.M., Pollak R., Benedetti E. Clotrimazole increases tacrolimus blood levels: a

drug interaction in kidney transplant patients. Clin Transplantation 2001: 15: 95-99.

Vasquez, Eva M., Shin, Grace P., Sifontis, Nicole, Benedetti, Enrico. Concomitant

Clotrimazole Therapy More Than Doubles the Relative Oral Bioavailability of

Tacrolimus. Ther Drug Monit. October 2005:27(5).

CANESTEN® Product Monograph, Bayer Inc. Date of Revision: July 19, 2019.

Control Number 227823.

IMPORTANT: PLEASE READ

Page 17 of 22

PART III: CONSUMER INFORMATION

Clotrimaderm Vaginal 6

Clotrimazole Vaginal Cream USP 1% - Antifungal

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

Monograph" published when Clotrimaderm

Vaginal 6 was approved for sale in Canada and is

designed specifically for Consumers. This leaflet is a

summary and will not tell you everything about

Clotrimaderm Vaginal 6. Contact your doctor or

pharmacist if you have any questions about the

drug.

ABOUT THIS MEDICATION

What the medication is used for:

Clotrimaderm Vaginal 6 is used to treat vaginal yeast

infections. Clotrimazole can 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 Clotrimaderm Vaginal 6 for a full 6 days. This will

decrease the chance of the infection returning.

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.

What it does:

Clotrimazole is an antifungal that kills the overgrowth

of yeast organisms that cause the infection.

When it should not be used:

Do not use Clotrimaderm Vaginal 6:

if you are allergic to clotrimazole or any

ingredient in the formulation.

in girls less than 12 years of age unless advised

by a physician.

What the medicinal ingredient is:

Clotrimazole 1% w/w

What the important non-medicinal ingredients are:

Benzyl alcohol, cetostearyl alcohol, cetyl esters wax,

octyl dodecanol, polysorbate 60, sorbitan monostearate,

water.

What dosage forms it comes in:

vaginal cream: 1%

WARNINGS AND PRECAUTIONS

BEFORE you use Clotrimaderm Vaginal 6 talk to

your doctor or pharmacist if:

you are at increased risk for sexually

transmitted diseases (e.g. HIV-AIDS), have

multiple sexual partners or change partners

often

you have diabetes

this is your first yeast infection

you have frequent vaginal infections, or if your

yeast infection returns in less than 2 months

you are pregnant, think you are, or are nursing

Clotrimaderm Vaginal 6 is for vaginal use only.

Do not use Clotrimaderm Vaginal 6 if you have

abdominal pain, fever or a foul-smelling discharge. If

these symptoms are present, you could have a more

serious condition and should consult your physician

immediately.

IMPORTANT: PLEASE READ

Page 18 of 22

Do not use tampons, intravaginal douches or other

vaginal products while using this product.

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.

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. Discontinue

treatment and contact your physician.

Contact your physician if symptoms worsen.

Avoid contact with eyes; if this happens, rinse

thoroughly with water.

If Clotrimaderm Vaginal 6 is accidentally swallowed,

contact your local emergency room or Poison Control

Centre immediately.

If you have any questions about Clotrimaderm Vaginal

6 or vaginal infections, contact your pharmacist or

physician.

INTERACTIONS WITH THIS MEDICATION

Drugs that may interact with Clotrimaderm Vaginal

6 include:

tacrolimus, sirolimus (immunosuppressant)

Clotrimazole 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.

PROPER USE OF THIS MEDICATION

Usual dose:

Clotrimaderm Vaginal 6 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. Clotrimaderm

Vaginal 6 is only for use in the vagina and should never

be taken by mouth. Treatment during the menstrual

period should not be performed. The treatment should

be finished before the onset of menstruation. While

you may have sexual relations during treatment with

Clotrimaderm Vaginal 6, most couples wait until

treatment has finished as your partner could become

infected.

Filling the Applicator:

Remove the cap from the tube of Clotrimaderm Vaginal

6 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 at the bottom. The plunger will rise as cream

enters the applicator. When the plunger stops, the

proper amount of Clotrimaderm Vaginal 6 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:

Clotrimaderm Vaginal 6 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.

Using the Cream Externally:

A small amount of Clotrimaderm Vaginal 6 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.

IMPORTANT: PLEASE READ

Page 19 of 22

Disposing of the Applicator:

The Clotrimaderm Vaginal 6 vaginal applicator is

recyclable where facilities exist.

Overdose:

SIDE EFFECTS AND WHAT TO DO ABOUT

THEM

If you experience a rash or new irritation while using

the product, discontinue use and contact your doctor.

This is not a complete list of side effects. For any

unexpected effects while taking Clotrimaderm Vaginal

6, contact your doctor or pharmacist.

HOW TO STORE IT

Keep Clotrimaderm Vaginal 6 and all other medications

out of the reach and sight of children.

Store at room temperature between 15°C and 30 °C.

MORE INFORMATION

If you want more information about Clotrimaderm

Vaginal 6:

Talk to your healthcare professional;

Find the full product monograph that is

prepared for healthcare professionals and

includes this Patient Medication Information

by visiting the Health Canada website

(https://www.canada.ca/en/health-

canada.html); the manufacturer’s website

(www.taro.ca), or by calling 1-800-268-1975.

This leaflet was prepared by:

Taro Pharmaceuticals Inc.,

130 East Drive

Brampton, ON, L6T 1C1

Last Revised: January 27, 2020

If you think you have taken too much Clotrimaderm

Vaginal 6, contact your healthcare professional,

hospital emergency department or regional poison

control centre immediately, even if there are no

symptoms.

Reporting Side Effects

You can report any suspected side effects

associated with the use of health products to Health

Canada by:

Visiting the Web page on Adverse

Reaction Reporting

(https://www.canada.ca/en/health-

canada/services/drugs-health-

products/medeffect-canada/adverse-

reaction-reporting.html) for information on

how to report online, by mail or by fax; or

Calling toll-free at 1-866-234-2345.

NOTE: Contact your health professional if you

need information about how to manage your side

effects. The Canada Vigilance Program does not

provide medical advice.

IMPORTANT: PLEASE READ

Page 20 of 22

PART III: CONSUMER INFORMATION

Clotrimaderm Vaginal 3

Clotrimazole Vaginal Cream USP 2% - Antifungal

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

Monograph" published when Clotrimaderm

Vaginal 3 was approved for sale in Canada and is

designed specifically for Consumers. This leaflet is a

summary and will not tell you everything about

Clotrimaderm Vaginal 3. Contact your doctor or

pharmacist if you have any questions about the

drug.

ABOUT THIS MEDICATION

What the medication is used for:

Clotrimaderm Vaginal 3 is used to treat vaginal yeast

infections. Clotrimazole can 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 Clotrimaderm Vaginal 3 for a full 3 days. This will

decrease the chance of the infection returning.

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.

What it does:

Clotrimazole is an antifungal that kills the overgrowth

of yeast organisms that cause the infection.

When it should not be used:

Do not use Clotrimaderm Vaginal 3:

if you are allergic to clotrimazole or any

ingredient in the formulation.

in girls less than 12 years of age unless advised

by a physician.

What the medicinal ingredient is:

Clotrimazole 2% w/w

What the important non-medicinal ingredients are:

Benzyl alcohol, cetostearyl alcohol, cetyl esters wax,

octyl dodecanol, polysorbate 60, sorbitan monostearate,

water.

What dosage forms it comes in:

vaginal cream: 2%

WARNINGS AND PRECAUTIONS

BEFORE you use Clotrimaderm Vaginal 3 talk to

your doctor or pharmacist if:

you are at increased risk for sexually

transmitted diseases (e.g. HIV-AIDS), have

multiple sexual partners or change partners

often

you have diabetes

this is your first yeast infection

you have frequent vaginal infections, or if your

yeast infection returns in less than 2 months

you are pregnant, think you are, or are nursing

Clotrimaderm Vaginal 3 is for vaginal use only.

Do not use Clotrimaderm Vaginal 3 if you have

abdominal pain, fever or a foul-smelling discharge. If

these symptoms are present, you could have a more

serious condition and should consult your physician

immediately.

IMPORTANT: PLEASE READ

Page 21 of 22

Do not use tampons, intravaginal douches or other

vaginal products while using this product.

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.

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. Discontinue

treatment and contact your physician.

Contact your physician if symptoms worsen.

Avoid contact with eyes; if this happens, rinse

thoroughly with water.

If Clotrimaderm Vaginal 3 is accidentally swallowed,

contact your local emergency room or Poison Control

Centre immediately.

If you have any questions about Clotrimaderm Vaginal

3 or vaginal infections, contact your pharmacist or

physician.

INTERACTIONS WITH THIS MEDICATION

Drugs that may interact with Clotrimaderm Vaginal

3 include:

tacrolimus, sirolimus (immunosuppressant)

Clotrimazole 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.

PROPER USE OF THIS MEDICATION

Usual dose:

Clotrimaderm Vaginal 3 is inserted high into the vagina

once a day (preferably at bedtime) for 3 consecutive

days. Sufficient cream is provided for 3 intravaginal

applications. Extra cream is supplied for use in

relieving the external itching and burning sometimes

associated with a vaginal yeast infection. Clotrimaderm

Vaginal 3 is only for use in the vagina and should never

be taken by mouth. Treatment during the menstrual

period should not be performed. The treatment should

be finished before the onset of menstruation. While

you may have sexual relations during treatment with

Clotrimaderm Vaginal 3, most couples wait until

treatment has finished as your partner could become

infected.

Filling the Applicator:

Remove the cap from the tube of Clotrimaderm Vaginal

3 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 at the bottom. The plunger will rise as cream

enters the applicator. When the plunger stops, the

proper amount of Clotrimaderm Vaginal 3 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:

Clotrimaderm Vaginal 3 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.

Using the Cream Externally:

A small amount of Clotrimaderm Vaginal 3 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.

IMPORTANT: PLEASE READ

Page 22 of 22

Disposing of the Applicator:

The Clotrimaderm Vaginal 3 vaginal applicator is

recyclable where facilities exist.

Overdose:

SIDE EFFECTS AND WHAT TO DO ABOUT

THEM

If you experience a rash or new irritation while using

the product, discontinue use and contact your doctor.

This is not a complete list of side effects. For any

unexpected effects while taking Clotrimaderm Vaginal

3, contact your doctor or pharmacist.

HOW TO STORE IT

Keep Clotrimaderm Vaginal 3 and all other medications

out of the reach of children.

Store at room temperature between 15°C and 30 °C.

MORE INFORMATION

If you want more information about Clotrimaderm

Vaginal 3:

Talk to your healthcare professional;

Find the full product monograph that is

prepared for healthcare professionals and

includes this Patient Medication Information

by visiting the Health Canada website

(https://www.canada.ca/en/health-

canada.html); the manufacturer’s website

(www.taro.ca), or by calling 1-800-268-1975.

This leaflet was prepared by:

Taro Pharmaceuticals Inc.,

130 East Drive

Brampton, ON, L6T 1C1

Last Revised: January 27, 2020

If you think you have taken too much Clotrimaderm

Vaginal 3, contact your healthcare professional,

hospital emergency department or regional poison

control centre immediately, even if there are no

symptoms.

Reporting Side Effects

You can report any suspected side effects associated

with the use of health products to Health Canada by:

Visiting the Web page on Adverse Reaction

Reporting (https://www.canada.ca/en/health-

canada/services/drugs-health-

products/medeffect-canada/adverse-reaction-

reporting.html) for information on how to

report online, by mail or by fax; or

Calling toll-free at 1-866-234-2345.

NOTE: Contact your health professional if you need

information about how to manage your side effects.

The Canada Vigilance Program does not provide

medical advice.

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