RETIN-A CREAM

Canada - English - Health Canada

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Active ingredient:
TRETINOIN
Available from:
BAUSCH HEALTH, CANADA INC.
ATC code:
D10AD01
INN (International Name):
TRETINOIN
Dosage:
0.1%
Pharmaceutical form:
CREAM
Composition:
TRETINOIN 0.1%
Administration route:
TOPICAL
Units in package:
30 G
Prescription type:
Prescription
Therapeutic area:
CELL STIMULANTS AND PROLIFERANTS
Product summary:
Active ingredient group (AIG) number: 0112395004; AHFS: 84:16.00
Authorization status:
APPROVED
Authorization number:
00870021
Authorization date:
1999-02-02

Documents in other languages

PRODUCT MONOGRAPH

Pr

RETIN-A

®

Tretinoin Cream and Gel, Manufacturer’s

Standard

Gel 0.025% and 0.01%

Cream 0.1%, 0.05%, 0.025% and 0.01%

Comedolytic Agent

Bausch Health, Canada Inc.

Date of Revision:

2150 St-Elzear Blvd West

December 12, 2019

Laval, Quebec

H7L 4A8

Submission Control No.: 233627

Registered Trademark used under license

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Product Monograph Page 2 of 19

PRODUCT MONOGRAPH

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RETIN-A

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Tretinoin Cream and Gel, Manufacturer’s

Standard

CLINICAL PHARMACOLOGY

Studies in animals have shown that tretinoin supplies all the physiologic requirements of Vitamin A

except those needed for vision and reproduction. When animals were fed a diet in which Vitamin A

was replaced by Vitamin A acid, there was no storage in the liver. This suggests that the acid may be

the tissue-active form which is important for epithelial growth and general health, while the alcohol

or ester form is necessary for vision and reproduction.

Repeated skin applications of Vitamin A acid over a period of days have produced detectable

changes in the skin. Initially, the change is mild erythema, followed by flaking or peeling of the stratum

corneum, which in itself is associated with a marked thinning of the stratum corneum and increased

cellular turnover in the skin.

Local application of Vitamin A has been reported to have reduced abnormal cornification in

follicular orifices, and Vitamin A acid was reported to be more potent than Vitamin A alcohol or its

esters when applied locally in ointments to human skin.

Although the exact mode of action of tretinoin is unknown, current evidence suggests that topical

tretinoin decreases cohesiveness of follicular cells with decreased microcomedo formation.

Additionally, tretinoin stimulates mitotic activity and increased turnover of follicular epithelial cells,

causing extrusion of the comedomes.

INDICATIONS AND CLINICAL USE

RETIN-A tretinoin is indicated for topical application in the treatment of acne vulgaris.

CONTRAINDICATIONS

RETIN-A tretinoin is contraindicated in patients who have demonstrated a hypersensitivity to the

drug.

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WARNINGS

General Warnings

Excessive use of RETIN-A tretinoin should be avoided. In order to minimize the potential for

additional skin irritation, care should be taken to avoid contact with the eyes, eyelids, angles of the nose,

mouth, mucous membranes or other areas where treatment is not intended. Tretinoin may cause

irritation of circumoral and other sensitive skin areas. Tretinoin should not be applied to severely

inflamed skin or to open lesions.

Simultaneous use of harsh abrasives and other skin treatments, including sun lamp, should be

avoided if possible.

In some patients temporary skin irritation may occur, especially in early weeks of treatment. Should

these reactions occur to an excessive degree, and the skin becomes extremely red, swollen and

crusted, use of tretinoin should be discontinued immediately.

An apparent exacerbation may develop due to the drug effect on previously seen deep lesions. This is

an anticipated part of the therapeutic effect. Therapy should be continued.

Use in Pregnancy:

Topical tretinoin should be used by women of childbearing years only after contraceptive

counselling. It is recommended that topical tretinoin should not be used by pregnant women.

There have been a few reports of birth defects among babies born to women exposed to topical

tretinoin during pregnancy. To date, there have been no adequate and well-controlled prospective

studies performed in pregnant women and the teratogenic blood level of tretinoin is not clear.

However, a well-conducted retrospective cohort study of babies born to women exposed to topical

tretinoin during the first trimester of pregnancy found no excess birth defects among these babies

when compared with babies born to women in the same cohort who were not similarly exposed.

Oral tretinoin has been shown to be teratogenic and fetotoxic in rats when given in doses 1000

and 500 times the topical human dose, respectively.

In nine (9) out of ten (10) topical teratology studies of tretinoin conducted in rats and rabbits

using several formulations, there has been no evidence of teratogenicity. In one (1) out of ten (10)

studies there was an increase in fetal malformations; however, a clear causal relationship of

topical tretinoin in these findings could not be established. In a repeat of this study, there were

no fetal malformations. Topical tretinoin can produce treatment-related fetal effects (delayed

ossification of bones and an increase in supernumerary ribs). The fetal no- effect dose is

1.0 mg/kg/day (200 times the recommended clinical dose). [See TOXICOLOGY - Reproduction

and Teratology subsection.]

Nursing Mothers:

It is not known whether RETIN-A tretinoin is excreted in human milk. Nevertheless, a decision should

be made whether

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to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to

the mother. Since many drugs are excreted in human milk, caution should be exercised when

RETIN-A tretinoin is administered to a nursing mother.

PRECAUTIONS

General Precautions

RETIN-A tretinoin is for external use only.

Cosmetics may be used, but the areas to be treated should be cleansed thoroughly before the

medication is applied. Astringent toiletries should be avoided.

Patients will be able to remove hair as usual (e.g. plucking, electrolysis, depilatories) but should avoid

these procedures at night before applying RETIN-A tretinoin as they might result in skin irritation.

Permanent wave solutions, waxing preparations, medicated soaps and shampoos can sometimes irritate

even normal skin. Caution should be used so that these products do not come into contact with skin

treated with RETIN-A tretinoin.

Exposure to sunlight, including ultraviolet sunlamps, may provoke additional irritation. Therefore,

exposure should be avoided or minimized during the use of tretinoin. A patient experiencing

considerable sun exposure due to occupational duties, and/or any patient inherently sensitive to the

sun, should exercise particular caution. When exposure to sunlight cannot be avoided, use of

sunscreen products and protective clothing over treated areas is recommended.

Hyper- or hypopigmentation has occasionally been reported when the product is used to the point of

producing severe irritation. This is reversible when the medication is stopped.

Safety and effectiveness have not been established in children.

GELS ARE FLAMMABLE. Note: Keep away from heat and flame. Keep tube tightly closed. Local

Irritation

It is not recommended to initiate treatment with RETIN-A tretinoin or continue its use in the presence

of skin irritation (e.g. erythema, peeling, pruritus, sunburn, etc.) until these symptoms subside.

In certain sensitive individuals, RETIN-A tretinoin may induce severe local erythema, swelling,

pruritus, warmth, burning or stinging, blistering, crusting and/or peeling at the site of application. If

the degree of local irritation warrants, the patient should be instructed to either apply the medication

less frequently or discontinue its use temporarily.

Tretinoin has been reported to cause severe irritation on eczematous skin and should be used with

utmost caution in patients with this condition. If a patient experiences severe or persistent irritation,

the patient should be advised to discontinue application of RETIN-A tretinoin completely, and if

necessary, consult a physician.

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Weather extremes, such as wind, cold and low humidity may be irritating to skin treated with

RETIN-A tretinoin and may increase its dryness.

Drug Interactions

Concomitant topical medication, medicated or abrasive soaps and cleansers, soaps and cosmetics

that have a strong drying effect, and products with high concentrations of alcohol, astringents, spices

or lime should be used with caution because of possible interaction with tretinoin. Particular caution

should be exercised in using preparations containing sulfur, resorcinol, or salicylic acid with

tretinoin. It is also advisable to "rest" a patient's skin until the effects of such preparations subside

before use of tretinoin is begun.

ADVERSE REACTIONS

Some degree of local irritation is expected. The most commonly reported undesirable effects are dry

skin, burning, stinging, warmth, erythema, pruritus, rash, peeling and temporary hypo- and

hyperpigmentation. Rarely reported undesirable effects are blistering and crusting of the skin, eye

irritation and edema. These reactions were usually mild to moderate in severity, generally well-

tolerated and self-limiting, occurred early during the course of therapy and generally decreased over

time with the exception of dry skin, which tended to persist.

True contact allergy to topical tretinoin is rarely encountered.

Changes in the skin may be anticipated, indicating an active effect of the medication. Expected

changes include mild erythema and flaking or peeling of the stratum corneum. In certain very

sensitive patients, the skin may become very erythematous, edematous, blistered or crusted. In such

cases, application of tretinoin should be discontinued until the skin has fully recovered. Further

applications should be at a level that the individual can tolerate. All adverse reactions observed are

reversible when treatment is discontinued.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

If medication is applied excessively, no more rapid or better results will be obtained and marked

redness, peeling, or discomfort may occur. RETIN-A tretinoin is intended for topical use only. In the

event of accidental ingestion, if the ingestion is recent, the stomach should be emptied immediately

by gastric lavage or by induction of emesis. All other treatment should be appropriately supportive.

Oral ingestion of the drug may lead to the same side 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. Reduce amount or

frequency of application if undesirable reactions occur.

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DOSAGE AND ADMINISTRATION

Excessive use of RETIN-A tretinoin should be avoided.

Adults

Apply daily to the affected areas, preferably at bedtime, after cleansing with a mild, non-medicated

soap and water. The treated area should be washed no more than twice per day. After washing, the skin

should be dried gently and completely without rubbing it. Allow at least 20 to 30 minutes to dry

before applying medication. Only a sufficient quantity of medication should be applied to cover the

affected areas lightly, using a gauze swab, cotton wool or the tips of clean fingers. Over-saturation

should be avoided since excess medication could run into the eyes, angles of the nose or other areas

where treatment is not intended.

Discontinue treatment if a severe local inflammatory response is experienced. Reinstitute therapy

when the reaction has subsided and apply preparation every other day or less frequently. Should

discomfort still be experienced, stop treatment completely.

Maintenance dose should be the least number of applications that will prevent recurrence of the

condition. Maintenance therapy should be administered daily for best results.

Application of RETIN-A tretinoin may cause a transitory feeling of warmth or slight stinging. When

administered according to recommended guidelines, RETIN-A tretinoin may produce a slight erythema

similar to that of mild sunburn. In cases where it is necessary to temporarily discontinue therapy or

reduce the frequency of application, therapy should be resumed, or the frequency of application

increased when the patient becomes able to tolerate the treatment.

Excess application of RETIN-A tretinoin does not provide more rapid or better results. In fact, marked

redness, peeling or discomfort can occur. If excess application occurs accidentally or through over-

enthusiastic use, RETIN-A tretinoin should be discontinued for several days before resuming

therapy.

Therapeutic effects may be noticed after two to three weeks of use, but more than six weeks of therapy

may be required before definite beneficial effects are seen. During the early weeks of treatment, an

apparent exacerbation of inflammatory lesions may occur. This is due to the action of the medication

on deep, previously unseen lesions and should not be considered a reason to discontinue therapy.

Once a satisfactory response has been obtained, it may be possible to maintain this improvement

with less frequent applications.

Safety and effectiveness have not been established in children.

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PHARMACEUTICAL INFORMATION

Drug Substance:

Common Name:

tretinoin

Chemical Name:

3,7-dimethyl-9-(2,6,6-trimethyl-i-cyclo-hexen-1-yl)-2,4,6,8, -

nonatetraenoic acid.

Structural Formula:

Molecular Formula:

Molecular Weight: 300.44 g/mol

Description:

Tretinoin is a yellow to light-orange, crystalline powder which is

extremely light- and oxygen- sensitive. It is insoluble in water, slightly

soluble in alcohol and in chloroform. Chemically, tretinoin is related to

Vitamin A, differing only in having a carboxyl as the end group on the

side chain.

STABILITY AND STORAGE RECOMMENDATIONS

Keep container closed when not in use. Store between 15°C - 25°C.

AVAILABILITY OF DOSAGE FORMS

RETIN-A tretinoin Gel 0.025% and 0.01% is supplied in tubes containing 30 g.

RETIN-A tretinoin Cream 0.1%, 0.05%, 0.025% and 0.01% is supplied in 30 g tubes in a bland,

hydrophilic base.

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INFORMATION FOR THE CONSUMER

WHAT IS ACNE?

Acne Vulgaris is a common disease. It affects 90% of the population to some degree at some point in

their lifetime.

Acne is not just a teenage disease. In some people it may start for the first time in the twenties or even

later. In some, it lasts through the adult years. However, in most people, acne clears with time.

Acne is a disease of the oil gland. The face, chest and back have the largest number of oil glands and

thus acne may involve any or all of these areas.

Acne begins with the formation of a plug in the oil gland. The plug is made up of surface skin, oil, and

bacteria. It is not due to dirt or lack of washing. The plug is seen in the skin as a blackhead or

whitehead.

MICROCOMEDO

After formation of the plug, some of the oil in the gland escapes into the surrounding skin. It causes

inflammation which is seen in the skin as a red swelling, namely papules, pustules, or cysts.

PAPULE

WHAT CAUSES ACNE?

Acne is due to many different factors.

Heredity is most important. Although your parents may or may not have had acne, you still can inherit

oil glands which are susceptible to acne.

Acne is not due to an imbalance of hormones. Your normal hormones stimulate the oil glands and

contribute to acne.

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Bacteria are also important. Acne is not an infection. However, bacteria in the oil glands produce

substances which in turn cause the inflammation of acne.

Further information about the causes of acne may be obtained from your doctor.

HOW TO HELP YOURSELF

Diet

Most dermatologists agree that acne is not due to diet. However, it is wise to avoid iodides (excess

salt, kelp, seaweed) which can aggravate acne.

Cosmetics

Oil-based cosmetic creams, moisturizing creams, suntan oils, and makeup should be avoided. They

all can make acne worse. Use oil-free, water-based liquid makeup or powder.

Washing

Avoid excess washing or harsh scrubbing which can make acne worse. Wash gently and frequently

enough to keep the skin dry but not irritated.

Hands Off

Avoid picking or touching affected areas as this makes acne worse.

FACTS ABOUT RETIN-A CREAM AND GEL

WHAT IS IT?

RETIN-A Cream or Gel contains Vitamin A Acid. RETIN-A Cream or Gel is effective against

blackheads, whiteheads, and minor inflammatory lesions of acne such as papules and pustules.

ADVERSE REACTIONS

Peeling, burning, itching, stinging, redness and eye irritation may occur with some people during the

first one or two weeks of therapy. These reactions can easily be minimized by following the

instructions carefully. Should the effects become excessively troublesome, discontinue use and

consult your doctor.

SAFETY

Topical tretinoin should be used by women of childbearing years only after contraceptive

counselling. Pregnant women should discontinue use of topical tretinoin.

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RETIN-A Cream or Gel has been prescribed by your physician for your use only. Do not allow

other people to use it.

RETIN-A Cream or Gel is for topical use only.

Do not apply RETIN-A Cream or Gel to areas of skin where you have other problems such as

eczema, severely inflamed skin or open lesions.

RETIN-A Cream or Gel can make your skin more sensitive and increase the possibility of

sunburn. Minimize exposure of areas treated with RETIN-A Cream or Gel to sunlight or

sunlamps during treatment. Wear protective clothing whenever you have to go out in the sun,

even on hazy days. Also use a sunscreen on areas treated with RETIN-A Cream or Gel.

Avoid excessive exposure to wind or cold as skin treated with RETIN-A Cream or Gel may be

more vulnerable to these extremes.

Use other acne medication only on your physician's advice and follow the physician's

instructions carefully.

Try to avoid using topical products with a high concentration of alcohol, spices, or lime as they

cause needless stinging and burning on treated skin.

Excessive medication will not produce better results and marked redness, peeling and

discomfort may occur. It is recommended that you apply a moisturizer or a moisturizer with

sunscreen that will not aggravate your acne (non-comedogenic) every morning after you

wash.

GELS ARE FLAMMABLE. Note: Keep away from heat and flame. Keep tube tightly closed.

HOW TO USE

Wash with a mild soap and dry skin gently.

Wait twenty minutes before applying medication so that your skin is completely dry.

Apply RETIN-A Cream or Gel once daily before bedtime (or as directed by your doctor).

Squeeze a small amount (about the size of a pea) on your fingertip. Spread on the skin where

acne lesions appear, using enough to cover the entire affected area lightly.

Keep the medication away from the corners of the nose, mouth, eyes and mucous membranes

or other areas where treatment is not intended. Spread away from these areas when applying.

Keep container closed when not in use.

The medication should become invisible almost immediately. If it is still visible or if dry

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flaking occurs within a minute or so, you are using too much.

If your doctor has prescribed another topical acne treatment (i.e. benzoyl peroxide or topical

antibiotic), do not apply RETIN-A Cream or Gel at the same time of day as the other

products.

After 3 to 6 weeks of therapy some patients notice new blemishes. At this stage it is very

important to continue using RETIN-A Cream or Gel. Do not expect an overnight cure. With

the use of RETIN-A Cream or Gel, you will notice a gradual improvement over eight to

twelve weeks.

PHARMACOLOGY

Radioactive Vitamin A and retinoic acid were introduced into the duodenum of rats.

-tagged Vitamin A was found largely in the lymph, while C

-tagged retinoic acid was found

mostly in the bile.

After hydrolysis of the ester, retinol is partially transported to other tissues, partially conjugated to the ß-

glucosidaronate, and partially oxidized to retinoic acid. The retinoic acid may be partly

decarboxylated and further degraded, or may form a ß-glucuronide, which is secreted in the bile. A

portion of the glucuronides is returned to the liver by enterohepatic circulation, but the major portion

is excreted in the feces, some also being excreted in the urine.

Johnson conducted a study to measure the extent of percutaneous absorption of topically applied

radioactive retinoic acid by normal individuals, and by patients with psoriasis or acne. The extent of

absorption was judged by measuring the amount of radioactivity in (a) urine, (b) feces, (c) plasma,

(d)respiratory carbon dioxide, and (e) remaining at the site of application. The urine data were felt to

be the most reliable indicator of absorption because of the low levels of radioactivity obtained in the

other samples examined. Two formulations were evaluated. One formulation consisted of 0.11%

retinoic acid in a petrolatum base. The second formulation consisted of 0.11% retinoic acid in

solution in a polyethylene glycol-ethanol vehicle. Both formulations were the same as those prepared

for non-radioactive clinical evaluations.

The urinary excretion of radioactivity following application of retinoic acid ointment or solution was

compared to that seen with the ointment in normal subjects. In addition, the total absorption was

calculated using the data of Maibach following i.v. administration of retinoic acid. The results

suggest that after a single administration of the ointment, absorption is greater (4x) in psoriatics than

in normal. On repeated application for 10 days absorption may increase as much as 12 x (relative to

normal) to an average maximum of 8% of the administered dose.

TOXICOLOGY

NOTE: The term "active Vitamin A acid acne preparation" will be substituted by the term retinoic

acid solution.

Acute oral toxicity studies were carried out in dogs, rats and mice to determine the effects of

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0.1% (w/w) retinoic acid solution when compared with the Vitamin A acid acne preparation vehicle.

In rats, for example, the 0.1% retinoic acid solution had an acute oral LD

of 20.3 mL/kg while the

vehicle had an LD

of 20.3 mL/kg.

The LD

values of the product and its vehicle, following 0.10% i.v. administration, were 5.2 ml/kg

and 5.0 mL/kg in mice, respectively, and 8.7 mL/kg and 8.8 mg/kg in rats. Apparently retinoic acid

does not contribute to the lethal potential of the product.

When 0.1% doses of 5 and 10 mL/kg of either formulation were administered to dogs, pronounced

emetic effects were produced.

Emesis was inconsistent at doses of 1 mL/kg, and the dogs that retained this dose subsequently

exhibited no untoward effects.

Both the active preparation and the vehicle caused slight to moderate conjunctival irritation when

instilled into the eyes of rabbits. No corneal or iritic effects were noted.

A primary skin irritation was carried out in rabbits, employing a standard patch test technique as

described in "Principles and Procedures for Evaluating the Toxicity of Household Substances".

Retinoic acid solution (0.1%) had a primary irritation rating of 1.40 and thus would be classified as a

mild primary irritant.

An acute dermal toxicity study was carried out in which single doses of up to 9.4 mL/kg of the

retinoic acid solution (0.1%) were applied for 24-hour exposures to the intact and abraded skin of

rabbits. No evidence of systemic toxicity was found during or after the test.

A six-week subacute dermal toxicity study was performed in rabbits. Within this period, dosage levels of

0.1, 0.5 and 1.0 mL/kg/day of retinoic acid solution (0.1%) were applied to the abraded and intact

skin of the animals. These daily doses were estimated to be 3-30 times the calculated maximum

clinical dose. Locally there was marked erythema, hyperkeratosis, mummification, loss of elasticity

and cracking of the skin. These responses were dose-related and reached their maximum in about

three weeks. The washed high-dose group had less local reaction than the unwashed high-dose

group. In those animals studied four weeks after application of retinoic acid was discontinued, the

local reactions subsided. Little evidence of irritation remained at the end of the observation period.

Other findings were considered to be indirectly attributable to the irritation produced by the test

materials. These dose-related effects include impaired growth, depression of the erythrocyte-

hemoglobin-hematocrit system, and accelerated sedimentation rates. An increased frequency of gross

lesions in all treated groups was observed at necropsy. Ophthalmologic and radiologic examinations,

and the chemistry assays gave no indication of toxicity. Tissue histopathology only revealed changes

in the skin. There was no evidence found of systemic toxicity directly attributable

to topical application of the retinoic acid solution. Those changes that did occur were considered

related to the known local irritant properties of retinoic acid.

Studies in hairless albino mice suggest that tretinoin may accelerate the tumorigenic potential of

ultraviolet radiation. The significance to men is not clear.

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Four groups of 60 hairless mice each were used in the 18-month study. Groups II, III and IV were

treated daily with simulated solar ultraviolet radiation (UVR). The mice were exposed for 2 hours on

each of 196 consecutive days to 180 J/M

/day erythema effective energy (approximately one-half

human skin erythema dose of UVR). After each UVR exposure, the groups were painted topically

with 100 mL of either vehicle alone (methanol) or 0.001% retinoic acid (RA) or 0.01% RA, in

methanol. Group I received vehicle alone without UVR. Beginning at 20 weeks, the two groups III and

IV receiving UVR plus RA developed a substantial number of tumors; there were no tumors in

Group I. The mean latent period for tumor appearance in the vehicle plus UVR Group II was longer

than the mean latent periods of the RA-treated groups. The mechanism of the RA-enhanced

photocarcinogenesis is not yet known.

In separate tests, the investigators found no evidence of RA phototoxicity in either mouse skin in vivo

or in yeast cells in vitro.

Dermal toxicity studies in humans have shown that the retinoic acid solution (0.1%) did not cause

contact sensitization, of the subjects phototoxicity or photosensitization in any of the subjects

investigated. Further studies have shown the expected local effects of erythema, tenderness and

pooling. However, there was no evidence of systemic toxicity.

Kligman, et al. studied the histology of normal skin treated with 0.1% vitamin A acid in an alcoholic

vehicle, and reported "As initial clinical inflammation developed, the epidermis thickened (acanthosis)

and the cornified cells retained their nuclei (parakeratosis). A quite characteristic change was the

intercellular accumulation of fluid causing the cell membranes to be pushed apart.

This prominent intercellular edema was not usually accompanied by evidence of cell damage.

Surprisingly, little inflammatory cell infiltrate was seen in the dermis; these changes related to mild

inflammation.

With high concentrations, there may be severe epidermal damage with vesiculation. In the chronic

phase, after weeks or months of application, the characteristic findings were moderate acanthosis, a

decidedly thickened and conspicuous granular cell layer, and a thin, loose stratum corneum which

was frequently lost in sectioning. Again, dermal inflammatory changes were scarcely discernible."

Studies of retinoic acid in topical application to human skin have produced no evidence of toxic

effects other than local irritation. One investigator who applied 0.1% retinoic acid in fatty cream

topically to 53 patients for as long as a year of continuous therapy reported occasional skin irritation

"which disappears quickly".

Studies have been conducted to determine the amount of tretinoin that can penetrate human skin

when it is applied topically. These studies involved application of

-tagged tretinoin topically to volunteers with normal skin, and others with psoriasis or acne whose

skin was irritated by repeated applications of tretinoin before the studies with radioactive material

were conducted.

In normal, absorption of the solution was greater (1.8 x) than with the ointment. Absorption after

single administration was increased 6 x in subjects with acne, and increased 37 x in these subjects,

on repeated (10 day) application, to an average maximum absorption of 26% of the administered

dose.

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Based on the recovery of radioactivity from the site of application, the average maximum absorption

with the ointment was 4% in normal subjects, 6% in subjects with psoriasis following single

administration, and 14% in the same subjects following repeated (10 day) administration. The

average maximum absorption with the solution was 14% in normal subjects, 20% in subjects with

acne following single administration, and 1% following repeated 10-day administration. These figures

are reasonable estimates for maximum possible absorption; however, they may tend to overestimate

the actual extent of absorption because of the technical problems associated with quantitative removal

of the applied dose 6 hours after application.

This study has shown that, under the time limits stated, the average maximum extent of absorption of

retinoic acid from a petrolatum base ointment in subjects with psoriasis is approximately 8% of the

dose and does not exceed 14% of the administered dose. The average maximum extent of absorption

of retinoic acid from a solution in subjects with acne is approximately 26% of the administered dose

and does not exceed 31% (on the average) of the administered dose. Knowing the greatest amount

absorbed in one individual (58%), the "high average" absorption (31%), and the maximum amount

applied topically (rounded off to 1.6 g), it is possible to calculate a "safety index" as follows:

Dose Applied

1.6 g

1.6 g

Patients Weight

50 kg

50 kg

Concentration of Drug

0.05%

0.05%

Extent of Absorption

Amounts absorbed

0.005 mg/kg

0.009 mg/kg

No effect dose (in rats) *

1.0 mg/kg

1.0 mg/kg

Safety Index

200:1

111:1

* Species most sensitive to teratogenic effects.

Although the foregoing figures are based on the most extensive application that might occur (entire

face, back and chest) and the highest absorptions determined experimentally, it is worth noting that

even if 100% were absorbed, the safety factor would still be in excess of 62-fold, based on the 1

mg/kg systemic dose determined to be safe in pregnant rats. If the concentration of tretinoin were

doubled to 0.1%, the safety factor would still be more than 31-fold with 100% absorption. At 0.1%

concentration the safety factor would be 55:1 when calculated in relation to the tested maximum

absorption through damaged skin.

Reproduction and Teratology

In a dermal rat teratogenicity study, animals received 0.1 or 1.0 mL/kg/day of 0.05% tretinoin gel

which corresponds to 0.05 or 0.5 mg/kg/day pure drug applied topically throughout organogenesis.

There was no evidence of maternal, embryo or fetal toxicity or teratogenicity. In the high dose, there

was an increase in the anatomical variations of incomplete ossification of parietal, interparietal and

supraoccipital bones of the skull. These effects are not considered to be teratogenic responses.

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Topical administration of all-trans retinoic acid to pregnant rats at dose levels of 1, 2.5, or 5 mg/kg/day

during the period of organogenesis (days 6 - 16 of gestation) was not teratogenic even at maternally

toxic doses (> 2.5 mg/kg). There was evidence of fetal toxicity at 5 mg/kg; an increase in the

incidence of supernumerary ribs was noted as was a decrease in body weight.

A dermal rabbit study was conducted to evaluate the teratogenic and/or embryotoxic potential of

three 0.1% tretinoin formulations, ointment, cream and alcoholic solution. Drug was applied to a

shaven area of the backs of animals in the following amounts: 150 and 600 mg/kg for the ointment,

50 and 200 mg/kg for the cream, 0.4 and 1.6 mL/kg for the solution. Well defined erythema was

recorded in all the animals receiving the high dose levels of both the ointment and cream from the

second to the last day of treatment. A milder degree of erythema was seen in the animals treated with

1.6 mL/kg of the solution. Slight edema was noted only in the high dose ointment animals on

examination at the end of the treatment period. In all cases the adverse reaction quickly regressed and

was no longer visible by the end of gestation. Dose levels of up to 600 mg/kg tretinoic acid ointment,

200 mg/kg retinoic acid cream and 1.6 mL/kg retinoic acid solution had no teratogenic activity or

adverse effects on weaning when injuncted onto the backs of New Zealand White rabbits daily from

Day 6 to Day 18 of gestation. The cream and solution at the high dose levels did produce a slight

increase in embryotoxicity, but it was thought unlikely that this would be reproduced in clinical

practice.

In a separate dermal rabbit teratogenicity study, animals received 0.1 or 1.0 mL/kg/day of 0.05%

tretinoin gel which corresponds to 0.05 or 0.5 mg/kg/day pure drug applied topically throughout

organogenesis. Dose related moderate to severe dermal irritation was observed in the dams. There

was a slight increase in resorption in the high dose group and a treatment-related increase in incomplete

ossification of parietal bones as was previously reported in rats. No evidence of

teratogenicity was found.

A rabbit study utilizing topically applied dosages of 0.05 and 0.5 mg/kg/day of tretinoin

(1 mL/kg/day of 0.005% and 0.05% RENOVA formulation, respectively) was conducted to assess

embryo-fetal toxicity and teratogenic potential. The RENOVA formulation was not teratogenic at

maternally toxic dosages of up to 0.5 mg/kg (100 times the clinical dose). Marked maternal toxicity

(severe dermal irritation, decreased body weight) was observed at 0.05 and 0.5 mg/kg/day. At the high

dose (0.5 mg/kg/day of tretinoin) increased incidence of spontaneous abortions and fetal toxicity

(decreased body weight and increased resorptions probably secondary to maternal toxicity) were

observed.

A rat study using an investigational topical formulation of tretinoin at dosages of 0.2, 0.5, and

1.0 mg/kg/day was conducted to assess embryo-fetal toxicity and teratogenic potential. Maternal

toxicity was observed in all treated groups. No adverse effects on embryo-fetal viability, fetal body

weights, or fetal morphology were observed at the doses tested.

A rabbit study utilizing topically-applied dosages of the same investigational formulation of tretinoin

in dosages of 0.2, 0.5, and 1.0 mg/kg/day was conducted to assess embryo-fetal toxicity and

teratogenic potential. Rabbits wore Elizabethan collars during the treatment period. Maternal toxicity

was observed in all treated groups. Evaluation of the incidence of specific fetal findings revealed an

association with the 0.5 and 1.0 mg/kg/day dosages. These included slight-to-moderate dilations of

the lateral and/or third ventricles of the brain, and hydrocephaly, and, in these fetuses, cleft palate,

hemorrhagic brain, or deformations of limb and/or rib. A causal relationship of topical treatment and

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these findings could not be established because the fetal observations were not consistently dose-

dependent, oral and/or inhalation exposure could not be ruled out and, hydrocephaly is known to

occur spontaneously in rabbits. Therefore, a follow-up study was designed to clarify the etiology of

the fetal alterations.

In the follow-up rabbit study, animals were exposed to topically applied dosages of 0.5 and

1.0 mg/kg/day of the investigational formulation of tretinoin for 6 hours/day, or 1.0 mg/kg/day for

24 hours/day. Animals exposed for 6 hours/day were restrained during the exposure period. Animals

exposed for 24 hours/day were not restrained. Maternal toxicity was observed in all treated groups.

No fetal abnormalities were observed in either group exposed. Therefore, the fetal alterations in the

previous study may have been spontaneous events or the result of possible oral ingestion during the

study.

Oral administration of tretinoin to pregnant rats at doses of either 1.0 or 2.5 mg/kg/day throughout

organogenesis produced no maternal toxicity. The higher dose produced only a modest increase in

intrauterine death. There was a treatment-related, but not dose-related increase in the anatomical

variations of increased thoracic rib or sternebrae. Tretinoin at either dose did not interfere with

implantation or fetal weight, nor did it produce a teratogenic response.

In another study, pregnant rats received a suspension of all-trans retinoic acid orally at doses of 1,

2.5, 5, or 10 mg/kg/day on days 6 through 15 of gestation. At 10 mg/kg an increase in the production

of cleft palate was observed.

Orally administered tretinoin during pregnancy produces dose-dependent and stage-dependent fetal

anomalies in several species. In Segment II oral and dermal teratology studies in Wistar rats, frank

fetal malformations were observed only after oral administration of 10 mg/kg tretinoin where one

fetus in each of 3 litters showed cleft palate. No fetal malformations resulted after oral or dermal

application of tretinoin at 1, 2.5, or 5 mg/kg doses.

Oral and dermal doses of >2.5 mg/kg tretinoin produced an increased incidence of fetuses with

skeletal variations (greater in oral), e.g., vestigial ribs. Skeletal variations, while treatment-related,

are not categorized as teratogenic outcomes, but as segmental variations of embryonic pattern

formation, and as such are not incompatible with normal development. While oral tretinoin produced

a higher incidence of fetal effects than dermal tretinoin, the overall fetal no-observable-effect-level by

either dosage route is 1 mg/kg (200 times the estimated clinical dose). The findings in the two above-

mentioned studies are consistent with results reported from numerous earlier studies.

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Mills Jr OH, Kligman AM. Assay of Comedolytic Activity in Acne Patients. Acta Derm

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Thomas III JR, Doyle JA. The therapeutic uses of topical vitamin A acid. J Am Acad

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Frost P, Weinstein GD. Topical Vitamin A Acid for scaling dermatoses. Clin Res (National

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tract of animals fed a diet deficient in Vitamin A alcohol but containing Vitamin A acid. 1. The

male rat. J Reprod Fertil 1963; 5:159.

Beer P. Investigations on the effect of Vitamin A acid. Dermatologica 1962 124:192.

Murray TK. Potency of Vitamin A acid in the vaginal smear assay. Proc Soc Exptl Biol Med

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Fulton J, Gross PR, Cornelius CE, Kligman AM. Darier's disease - Treatment with topical

Vitamin A acid. Dept. of Dermatology, Hospital of the University of Pennsylvania, Duhring

Laboratories, Philadelphia, Pa.

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