VITAMIN A ACID 0.05% GEL

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Active ingredient:
TRETINOIN
Available from:
VALEANT CANADA LP/VALEANT CANADA S.E.C.
ATC code:
D10AD01
INN (International Name):
TRETINOIN
Dosage:
0.05%
Pharmaceutical form:
GEL
Composition:
TRETINOIN 0.05%
Administration route:
TOPICAL
Units in package:
25G
Prescription type:
Prescription
Therapeutic area:
CELL STIMULANTS AND PROLIFERANTS
Product summary:
Active ingredient group (AIG) number: 0112395001; AHFS: 84:16.00
Authorization status:
APPROVED
Authorization number:
01926489
Authorization date:
2002-03-11

Documents

PRODUCT MONOGRAPH

VITAMIN A ACID

(tretinoin gel, Manufacturer’s Standard)

0.01% or 0.025% or 0.05% Gel

TOPICAL ACNE THERAPY

Valeant Canada LP / Valeant Canada S.E.C.

4787 Levy St.

Montreal, QC

H4R 2P9

Date of Preparation:

February 20, 2012

Submission Control No.: 153418

Page 2 of 12

NAME OF DRUG

VITAMIN A ACID

(tretinoin gel, Manufacturer’s Standard)

0.01% or 0.025% or 0.05% Gel

THERAPEUTIC CLASSIFICATION

Topical Acne Therapy

ACTIONS, CLINICAL PHARMACOLOGY

The interest in oral Vitamin A in the treatment of acne started some 30 years ago following

publication of a report by Straumfjord

and theoretical support for the use of the vitamin in the

reduction of hyperkeratosis came from basic science investigations. Hunter and Pinkus

showed

a reduction in the number of keratinocytes in the human stratum corneum during oral Vitamin A

therapy. Fell and Mellanby

noticed a suppression of keratinization by excessive Vitamin A in

tissue culture. This led to the opinion that Vitamin A is antikeratinizing.

Topical use of Vitamin A was suggested as a means of reducing systemic toxicity from Vitamin

A taken orally and a number of topical forms of Vitamin A were tried. Vitamin A acid was found

to be the most potent because of its greater peeling action.

Vitamin A Acid has a very pronounced keratolytic action according to both Von Beer

and Von

Stuttgen

. This action has led to its use in a number of dermatological conditions. It was tried

successfully by Kligman et al

in the treatment of acne vulgaris since follicular hyperkeratosis is

considered as being an initial stage of acne.

INDICATIONS and CLINICAL USES

Vitamin A Acid Gel is indicated for topical application in the treatment of acne vulgaris,

primarily Grades I, II and III in which comedones, papules and pustules predominate.

CONTRAINDICATIONS

Use of the gel should be discontinued if hypersensitivity to any of the ingredients is noted.

Page 3 of 12

WARNINGS

Use in Pregnancy: Topical Vitamin A Acid should be used by women of childbearing years

only after contraceptive counseling. It is recommended that topical Vitamin A Acid not be

used by pregnant women. There have been rare reports of birth defects among babies born to

women exposed to topical tretinoin during pregnancy. However, there are no well controlled

prospective studies of the use of topical tretinoin in pregnant women. A retrospective study of

mothers exposed to topical tretinoin during the first trimester of pregnancy found no increase in

the incidence of birth defects. Topical retinoid teratology studies in rats and rabbits have been

inconclusive. As with all retinoids, tretinoin administered orally at high doses is teratogenic.

When applying Vitamin A Acid, care should be taken not to apply near the eyes, mouth, angles

of the nose and mucous membranes. Topical use may cause severe local redness and peeling at

the site of the application. If the degree of local irritation warrants, use the medication less

frequently, discontinue use temporarily, or discontinue use completely, and consult your

physician.

PRECAUTIONS

Concomitant topical medications and particularly other peeling agents should be used with

caution. In case of a change of medications to Vitamin A Acid, it would be advisable to wait

until peeling from previous medications has subsided.

Because of an increased susceptibility to sunlight in patients with sunburn the use of Vitamin A

Acid is not advisable until the skin has fully recovered. Exposure to sunlight and sunlamps

should be avoided or minimized during treatment with Vitamin A Acid, because of heightened

susceptibility to UV radiation as a result of the use of tretinoin.

Use of sunburn protectant products with a sun protection factor (SPF) of at least 15 and

protective clothing over treated areas is recommended when exposure cannot be avoided.

ADVERSE REACTIONS

In certain very sensitive patients the skin may get to be very erythematous, edematous, blistered

or crusted. In such cases, application of Vitamin A Acid should be discontinued until the skin

has fully recovered; further application should be at a level that the individual can tolerate.

Temporary hyper- or hypo-pigmentation can occur with repeated application of Vitamin A Acid.

Increased susceptibility to sunlight has been reported. All adverse reactions seem to be reversible

when treatment is discontinued.

Page 4 of 12

SYMPTOMS and TREATMENT of OVERDOSAGE

Vitamin A Acid if used excessively may cause marked erythema, severe peeling of the skin,

discomfort; on the other hand, excessive application may not bring more rapid or better results.

Amount or frequency of application should be reduced if undesirable reactions occur.

Inadvertent oral ingestion of Vitamin A Acid may lead to the same adverse effects as those

associated with excessive oral intake of Vitamin A including teratogenesis in women of

childbearing years. Therefore, in such cases, pregnancy testing should be carried out in women

of childbearing years.

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

DOSAGE and ADMINISTRATION

Vitamin A Acid should be applied daily, preferably before retiring where acne lesions are

present, using enough of the non-oily gel to lightly cover the affected area. An exacerbation of

the inflammatory lesions may take place during the early weeks of application. These result from

the action of the Vitamin A Acid on deep and previously unseen comedones and papules.

Therapeutic results should be seen after 2 - 4 weeks of treatment. Results may take 6 - 8 weeks

before reaching optimal degree. Once acne lesions have responded satisfactorily, improvement

can be maintained with less frequent application.

In cases of severe erythema at an early stage of treatment, the frequency of application and

amount may be reduced at the beginning of treatment and then increased progressively.

Page 5 of 12

PHARMACEUTICAL INFORMATION

Drug Substance

Tretinoin

Molecular Formula:

Molecular Weight:

300.44

Chemical Name:

3, 7-Dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-

2,4,6,8 nonatetraenoic acid

Description: Tretinoin is a yellow to light orange crystalline powder. Tretinoin is also known as

retinoic acid or as Vitamin A Acid.

COMPOSITION

VITAMIN A ACID Gel contains either 0.01%, 0.025% or 0.05% Tretinoin, USP.

Preservative: Methylparaben & Propylparaben

Non-Medicinal Ingredients: Alcohol 95%, Carboxyvinyl Polymer Carbopol 980, Isopropyl

Alcohol, Propylene Glycol, Purified Water, Solulan 98, Tetrasodium Edetate Tetrahydrate and

Trolamine.

STABILITY and STORAGE RECOMMENDATIONS

VITAMIN A ACID Gels should be stored at controlled room temperature (15-30

DOSAGE FORM

VITAMIN A ACID GEL 0.01%, 0.025% and 0.05% is supplied in tubes of 25 grams.

Page 6 of 12

INFORMATION FOR THE PATIENT

WHAT YOU SHOULD EXPECT

Your doctor has recommended VITAMIN A ACID Gel for topical application in the treatment

of acne.

VITAMIN A ACID is a highly effective medication, but it is important to recognize that it is not

a quick cure. It is valuable to view the treatment as a 6-12 week program that will take time

before the best results are seen.

Since VITAMIN A ACID works from beneath the skin surface, clearing usually takes from

6-12 weeks.

For most patients excellent results are achieved. During the early weeks, the primary objective is

to allow your skin to slowly build up a tolerance to this medication as it is potentially irritating.

Later your skin will adapt and clearing will occur. Keeping a long-term perspective, following

your doctor’s instruction, and maintaining your commitment over a 6-12 week time period will

help you to get the most from your treatment program.

If you are a female of childbearing years, you should use VITAMIN A ACID only after

consulting your doctor and seeking his advice for contraceptive counseling. If you are

pregnant, you should discontinue use of VITAMIN A ACID.

Your doctor has given you VITAMIN A ACID for your use only. Do not allow anyone

else to use it.

PLEASE REVIEW THE USAGE GUIDELINES.

1.

Getting Started:

Before starting therapy with VITAMIN A ACID products, it is advisable to

discontinue previous topical acne medications, unless otherwise specified by your

doctor. It is also advisable to discontinue medicated or abrasive soaps and

cleaners, soaps that have a strong drying effect and products with a high

concentration of alcohol or astringents, such as shaving lotions during VITAMIN

A ACID therapy.

2.

Application:

The affected area should be washed with lukewarm water and patted dry. Wait at

least 20 minutes before applying medication. Apply VITAMIN A ACID sparingly

with the fingertips to the affected area once daily just prior to bedtime. Smooth in

lightly with the fingertips and avoid “rubbing” into the skin. Care must be taken

not to apply near the eyes, lips, nostrils or open sores, as these are most sensitive

to irritation.

Page 7 of 12

3.

Caution:

If medication is applied excessively, more rapid or better results will not be

obtained, and marked redness, peeling or discomfort may occur. It is better to

start out with a light application, building this up rather than vice versa. A light,

even application will bring positive results over time.

4.

Sensitivity:

As your skin may be more sensitive to the sun’s rays, wind and cold, avoid or

minimize direct or prolonged exposure to the sun’s rays and use of sunlamps

because VITAMIN A ACID heightens the susceptibility of your skin to the

adverse effects of the sun. If exposure to sun’s rays is unavoidable, the use of

sunburn protectant products with a sun protection factor (SPF) of at least 15 and

protective clothing over treated areas is recommended.

5.

Considerations:

Some redness, burning or peeling may occur during the first few weeks of use

until your skin adapts to the medication. Your acne condition may also appear to

worsen after a week or two as VITAMIN A ACID works to unseat previously

unseen acne lesions. This is expected and indicates that the medication is working.

Inform your doctor of these changes.

Should the redness, burning or peeling worsen or persist, reduce the frequency of

application as advised by your doctor.

The use of the product should be discontinued if any unusual reaction occurs;

keep your doctor informed.

After noticeable improvement occurs, VITAMIN A ACID can be used on a

reduced schedule with your doctor’s approval, to prevent new acne blemishes

from developing.

Page 8 of 12

PHARMACOLOGY

Interest in oral Vitamin A in the treatment of acne stems from a paper by Straumfjord in which it

was stated that the primary histologic changes seen in acne were not different in any important

way from the follicular lesions attributed to Vitamin A deficiency. He used large doses of oral

Vitamin A in the hope of reducing the primary pathological change seen in acne; i.e., the

hyperkeratosis of the sebaceous follicles. Such a theory was supported by basic science

investigation which showed:

reduction of keratinocytes in the human stratum corneum during oral

Vitamin A therapy

suppression of keratinization by excessive Vitamin A in tissue culture

Such basic findings plus hair loss from oral high doses of Vitamin A had led to the view that

Vitamin A is antikeratinizing or keratolytic.

Topical use of Vitamin A Acid was suggested as a means of reducing systemic toxicity of

Vitamin A. Kligman tried it successfully in the treatment of acne because of its great peeling

action and also because of its keratolytic properties since follicular hyperkeratosis is considered

to be an early stage of the condition.

There is considerable evidence to indicate that Vitamin A Acid prevents the formation and

appearance of comedones and unseats the comedones already present. Mill, Leyden and

Kligman

say of this action, and we quote:

“The action of the drug that best explains this effect is interference with the

cohesiveness of horny cells. A comedone forms because the horny cells produced

by the follicular epithelium do not desquamate as they normally do. Instead they

stick tightly together to create an expanding impaction of horny material in the

follicular canal. Tretinoin promotes dehiscence and the keratinized cells fall

apart.”

“Other disorders centering about follicular hyperkeratosis in which tretinoin has

been shown to be beneficial include pseudo-folliculitis of the beard, senile

comedones, pomade acne, acne cosmetica, trichostasis spinulosa, nevus

comedonicus, and Darier disease. In all, the key effect is sloughing of impacted

horn by dehiscence of horny cells”.

Kaidbey and Kligman

have found Vitamin A Acid to be the most comedolytic and by far of five

commonly used peeling agents including salicylic acid, sulfur-resorcinol, and benzoyl peroxide.

Page 9 of 12

TOXICOLOGY

Acute toxicity studies of VITAMIN A ACID were carried out in the mouse and rat. The

intraperitoneal LD

was found to be 640 and 600 mg/kg in the mouse and rat respectively.

When VITAMIN A ACID was administered orally it was found to be almost non-toxic; in the rat

no mortality occurred with a maximal dose if 2000 mg/kg while in the mouse a dose of

5000 mg/kg produced only 20% mortality. (In both the mouse and rat, signs of acute intoxication

included tip-toe gait, mild emprosthotonus, severe body tremors, intermittent tonic-clonic

convulsions, marked central nervous system depression, lacrimation, ptosis and severe diarrhea).

A ninety-day study of the subacute toxicity of VITAMIN A ACID was carried out on the rabbit

through the dermal route at dose levels of 2x, 10x and 20x the maximum human dose level of

0.01 mg/kg of body weight.

Animals receiving VITAMIN A ACID showed erythema and eschar formation, the severity of

which increased with increasing dose levels of the topically applied material. Hemograms and

blood biochemical parameters revealed no treatment related changes. There were no

abnormalities in bone growth. A histopathological study of the treated skin showed acute

inflammation of the upper dermis producing micro-abscesses and in some cases folliculitis

which may have been responsible for atrophic changes and some destruction of hair follicles. In

addition, changes to the epithelium were observed which included acanthosis, parakeratosis and

basal hyperplasia. These results are explained by the well known keratolytic effects of

VITAMIN A ACID.

The dermal absorption of VITAMIN A ACID was investigated in the rat and rabbit. Results

showed that dermal absorption occurred in the rabbit and possibly in the rat.

Teratology

Tretinoin has been used as a standard compound for the experimental induction of malformations

in various species. The mechanism of action has not been elucidated; there are indications that

tretinoin and its analogues act directly on gene expression. It has been shown in vitro that

tretinoin inhibits chondrogenic differentiation, reduces matrix synthesis and alters matrix

composition.

A number of published reports have shown that Vitamin A ingested orally in large doses has

teratogenic effects in animals. The same teratogenic activity has also been reported with

VITAMIN A ACID. Since dermal absorption takes place, it became necessary to check the

teratogenic activity of VITAMIN A ACID following topical application. Studies of the

teratogenic effects of VITAMIN A ACID applied topically were carried out in the rat and the

rabbit at doses equivalent up to 20x the maximum human dose. In these two species, no

teratogenic effects were observed in the experimental groups which received topical application

of VITAMIN A ACID.

Page 10 of 12

Any comedogenic effect of a formulation topically applied for the treatment of acne vulgaris is

likely to worsen the condition instead of curing or preventing it. It establishes a vicious circle:

VITAMIN A ACID may hasten the resolution of papulo-pustules but any comedogenic

ingredients in the formulation may insidiously promote the formation of new comedones from

which inflammatory lesions spring. The comedogenicity of VITAMIN A ACID gel was tested in

the rabbit. Results showed the non-oily gel to be non-comedogenic.

Page 11 of 12

REFERENCES

STRAUMFJORD JV. Vitamin A: Its effects on acne. Northwest Med 1943; 42:210-225

HUNTER R, PINKUS H. The effects of oral Vitamin A on the number of keratin cells of

human epidermis. J Invest Derm 1961; 37:459-460

FELL HB, MELLANBY E. Metaplasia produced in cultures of chick ectoderms by high

Vitamin A. J Physiol 1953; 119:470-488

Von BEER P. Untersuchungen uber die wirking der Vitamin A saure. Dermatologica

1962; 124:65-80

Von STUTTGEN C. Zer lokalbehandling von keratosen mit Vitamin A saure. Dermatol

1962; 124:65-80

KLIGMAN AM et al. Topical Vitamin A acid in acne vulgaris. Arch Dermatol 1969;

99:459-476

MILLS OH, LEYDEN JJ, KLIGMAN AM. Tretinoin treatment of steroid acne. Arch

Dermatol 1973; 108:381-384

MILLS OH, KLIGMAN AM. Topically applied tretinoin in the treatment of trichostasis

spinulosa. Arch Dermatol 1973; 108:378-380

KAIDBEY KH, KLIGMAN AM. Effectiveness of peeling agents on experimental open

comedones. Curtis 1975; 16:53-56

CHIZ J, MacFARLAND NH. The acute oral and intraperitoneal toxicities of retinoic acid

in the mouse and rat. Bio-Research Laboratories, Project 5914, Report No. 1, July 13,

1974.

LEVINSKY HV, DUSSAULT P, KAHN DS, MacFARLAND NH. A three-month study

of the subacute toxicity of retinoic acid in the albino rabbit. Bio-Research Laboratories,

Project 5914, Report No. 4, March 15, 1974.

LEVINSKY HV, DUSSAULT P, MacFARLAND NH. A study of the dermal absorption

of retinoic acid in the rat and rabbit. Bio-Research Laboratories, Project 5914, Report No.

2, December 18, 1974.

LEVINSKY HV, MACFARLAND NH. A study of the teratological effects of retinoic

acid in the rat. Bio-Research Laboratories, Project 5914, Report No. 3, January 22, 1974.

Page 12 of 12

OWSTON E, PROCTER B, CHAPPEL CI. A study of the teratological effects of retinoic

acid in the rabbit. Bio-Research Laboratories, Project 5914, Report No. 6, December 31,

1975.

Proctor BG, RONA G. A study of the potential comedogenicity of a proposed new acne

medication. Bio-Research Laboratories, Project 5507, Report, August 4, 1976.

PAPA CM. The cutaneous safety of topical tretinoin. Acta Dermatoverner (Stockholm)

1975; Suppl. 74.

ZIMMERMANN B. Effects of all-trans retinoic acid on chondrogenesis and

endochondral mineralization in cartilage organoid culture. Teratology 1995; 51 (6):18A

JICK SJ, TERRIS BZ, JICK H. First trimester topical tretinoin and congenital disorders.

Lancet 1993; 341:1181 - 82

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