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Tretinoin (Topical )


VA CLASSIFICATION
Oil-in-water cream
Primary: DE752
Secondary: DE500

Water-in-oil cream
Primary: DE900

Gel
Primary: DE752
Secondary: DE500

Solution
Primary: DE752
Secondary: DE500


Commonly used brand name(s): Avita; Renova; Retin-A; Retin-A MICRO; Retisol-A; Stieva-A; Stieva-A Forte; Vitamin A Acid; Vitinoin.

Some commonly used names are
retinoic acid , all- trans-retinoic acid, and vitamin A acid .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antiacne agent (topical)—Cream (oil-in-water); Gel; Solution—

Keratolytic (topical)—Cream (oil-in-water); Gel; Solution—

Hypopigmenting agent (topical)—Cream (water-in-oil)—

Photoaging mitigative agent (topical)—Cream (water-in-oil)—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Acne vulgaris(treatment)—Tretinoin cream (oil-in-water formulation), gel, and topical solution are indicated in the topical treatment of acne vulgaris {03} {04} {05} {06} {07} {08}. Although use of tretinoin alone is effective in the topical treatment of mild acne vulgaris (Grades I to III), the therapeutic effect may be increased when tretinoin is used in combination with topical antibiotics {15} or benzoyl peroxide when acne consists predominately of comedones, papules, and pustules {12} {13} {16}. Tretinoin may be used with systemic antibiotics for treatment of all grades of acne, including severe (Grade IV) acne conglobata {04}; however, tretinoin is not effective when used alone for severe acne conglobata {08} {12} {14} {16}. The water-in-oil formulation of the cream is not indicated for treatment of acne vulgaris.

Hyperpigmentation, mottled, facial, due to photoaging (treatment adjunct) or
Skin roughness, facial, due to photoaging (treatment adjunct) or
Wrinkling, fine facial, due to photoaging (treatment adjunct) —The water-in-oil formulation of tretinoin cream is indicated as palliative or adjunctive treatment to skin care and sun avoidance programs to lessen the roughness of facial skin, reduce hyperpigmentation, and decrease the number and severity of fine facial wrinkles caused by photoaging {17} {19} {20} {23} {24} {25} {26} {28} {29} {49}. Although studies to prevent photoaging were conducted with the water-in-oil formulation, there is no reason to expect other formulations to be inactive. Patients who have been compliant but unsuccessful when using skin care and sun avoidance programs alone may benefit by adding tretinoin to the regimen. Skin care and sun avoidance programs include use of sunscreens, protective clothing, and moisturizing lotions or creams {17}. Tretinoin improves the histological process of photoaging but cannot completely repair sun-damaged skin or eliminate all wrinkles {01} {02}.
—There are insufficient data to show tretinoin to be safe and effective for daily use longer than 48 weeks when used as a photoaging mitigative agent {01}. Although the clinical significance is not known, some patients using the water-in-oil formulation of tretinoin cream 0.05% for longer than 48 weeks have experienced adverse effects, such as increased dermal elastosis and atypical changes in melanocytes and keratinocytes {01}. Safety and efficacy have not been established for patients 50 years of age and older {26} {47}, for patients with a history of skin cancer {01} {46}, or for patients who have moderately to heavily pigmented skin {17} {47}.

[Keratosis follicularis (treatment) ]1or
[Verruca plana (treatment)]1—Tretinoin as an oil-in-water cream, a gel, or a solution is used to treat disorders of keratinization, such as keratosis follicularis (Darier"s disease, Darier-White disease) , and verruca plana (flat warts) {03} {34} {35} {36} {37} {38} {39} {40} {41} {42} {43} {55} .

Acceptance not established
The safety and efficacy of topical tretinoin for the treatment or prevention of actinic keratoses {29} {47} {48} or skin neoplasms {01} {30} {46} have not been established.

Unaccepted
Tretinoin is not indicated for and does not reduce coarse or deep wrinkling, skin yellowing, telangiectasia, skin laxity, melanocytic atypia, or dermal elastosis {01} {22} {23} {27} {28} {31} {32} {33} {46} .

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    300.44 {11}


Chemical names
    Retinoic acid {11} or all- trans-retinoic acid {11}.


Description
    Aqueous gel formulation: Tretinoin is adsorbed on an acrylate copolymer, rendering the active ingredient water-soluble. May be referred to as a microsphere or microsponge system by the manufacturer. {54}

Mechanism of action/Effect:

The exact mechanism of tretinoin, a hormone and vitamin A analog, is not known. One possible explanation is altered gene expression causing changes in protein synthesis. {01} {21} {26} {47} {49} Tretinoin diffuses across cell membranes and complexes with specific cytoplasmic receptors, which can then enter the cell's nucleus and bind to DNA. Depending on the tissue, either a transcription process begins—messenger RNA (mRNA) increases and results in subsequent protein synthesis—or transrepression occurs. Transrepression results when the hormone-receptor complex (i.e., cytoplasmic tretinoin receptor) cannot activate the gene transcription factors or the hormone-response element. When gene expression is suppressed, protein synthesis cannot occur. {09} {23} {29} {34} Transrepression is thought to contribute to the photoaging mitigative and hypopigmenting effects.


Antiacne agent or keratolytic agent:

By stimulating the transcription process, tretinoin increases epidermal cell mitosis and epidermal cell turnover. The increased permeability of the skin causes water loss and weakens the horny cell layer, {23} {29} making it less cohesive and easier to peel {15} {26}. This action facilitates the removal of existing comedones and may inhibit the formation of new comedones {13} {14} {15}. It has been proposed that increased turnover in the follicular epithelium prevents formation of keratinous plugs. {13} {15} Tretinoin has also been reported to suppress keratin synthesis {13} {16} {26} {29}.



Photoaging mitigative agent:

Pretreatment of the skin with tretinoin inhibits a sun-induced effect of stimulating the gene transcription factor, AP-I. This transrepression effect stops the sun-induced production of the metalloproteinase enzymes, which responsively remove cells that potentially may be harmed by ultraviolet light from the skin's matrix {09} {10} {21}. Tretinoin does not appreciably absorb ultraviolet light, cannot be regarded as a sunscreen, and will not protect the skin from redness {09}. In addition, tretinoin is thought to increase the growth and differentiation of various epithelial cells, increase the glycosaminoglycan-like substance in the compacted stratum corneum, increase the number of anchoring fibrils, and improve epidermal dysplastic changes {23}. Some studies showed no appreciable change in collagen or elastin tissue content in human skin; {01} {19} {21} {23} {49} other studies did show an increase in collagen content {26} {49}.

Whether tretinoin reverses, partially reverses, or only helps to mitigate the damage associated with ultraviolet light exposure is still considered controversial. {09} {10} {19} {21} {46} This is partly because attentive skin care measures (sunscreens, protective clothing, moisturizers, mild soaps, and sun avoidance programs) used in the protocol of these studies also contributed to the overall efficacy against photoaging {19} {21}; even the placebo cream contributed positive effects. The long-term effects of suppressing the removal of potentially harmed DNA by the metalloproteinase enzymes within human skin are not known. {09} {10}

In a placebo-controlled study in which the water-in-oil formulation of 0.05% tretinoin cream was applied for 24 weeks, patients averaged a 27.1% reduction in fine wrinkling, 37% decrease in mottled hyperpigmentation, and 29.3% decrease in roughness of skin. Total improvement of severity was considered mild and averaged only 1 to 2 units based on a scale of 0 to 9 units. {22} {24}



Hypopigmenting agent:

Tretinoin inhibits melanogenesis {17}. Lightening occurs because tretinoin reduces the melanin content in the epidermis, compacts the stratum corneum {17} {19} {20} {21} {46}, and thickens the epidermis {25}; it is not a result of a change of number or size of melanocytes {20}. Tretinoin may improve but not clearly resolve hyperpigmented skin {20}.



Other actions/effects:

Tretinoin has shown some activity for increased wound healing, hair growth, and some antitumor effects that still need to be established. These actions may be due to increased rates of epidermal cell turnover {46}, angiogenesis {46} {47}, protein synthesis, and increased cell differentiation {46}.

Absorption:

Systemic absorption—Up to 8% of the administered dose of the nonaqueous formulations may be absorbed systemically with repeated application for 10 days {04}; only 1.41% of the administered dose was absorbed with the aqueous formulations {54}. Absorption may be increased when medication is applied to large surface areas, or for long periods of time in chronic extensive dermatoses. {04} {44} {45}



Duration of action:

Although gradual, most patients will show some improvement in skin condition within the first 6 to 7 weeks for the treatment of acne {01} and within 24 weeks for the treatment of photoaging {54}.

Elimination:
    
    Renal—4.45% of applied dose {04} {06}.
    Biliary—1.58% of applied dose {04} {06}.


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to acitretin, etretinate, isotretinoin, or other vitamin A derivatives may be sensitive to tretinoin also, since it is a vitamin A derivative.

Carcinogenicity/Tumorigenicity

A lifetime study in CD-1 mice receiving a topical tretinoin dose of 100 and 200 times the average recommended human dose resulted in a few skin tumors in female mice and liver tumors in male mice. These tumors occurred at a rate similar to that of the untreated mice. The clinical significance of this study as related to humans is not known. {01}

In animal (hairless albino mice) studies, tretinoin has been shown to increase the rate of cutaneous tumor formation induced by ultraviolet radiation. However, the results have not been consistently reproduced in mouse skin in vivo or yeast cells in vitro {04} and the significance of these studies as related to humans is unknown. {01} {04}

Dermal carcinogenicity studies for tretinoin aqueous gel, including the copolymer component, have not been done {54}.

Mutagenicity

The micronucleus assay in mice and the Ames assay are negative for tretinoin {01}.

The Ames assay for the copolymer used in the tretinoin aqueous gel is negative. The copolymer's components, when individually evaluated, were not mutagenic in one study. Other studies show the copolymer to be potentially mutagenic and teratogenic if given long-term at doses several times greater than the recommended human dose. The copolymer is not considered a significant risk to humans when used topically at recommended doses, since the tretinoin aqueous gel contains less than 25 parts per million of the copolymer. {54}

Pregnancy/Reproduction

Pregnancy—
Adequate and well-controlled studies in humans have not been done. Although not clearly associated, 30 cases of congenital malformations have been reported for topical tretinoin during 2 decades of clinical use. Five cases showed a rare defect of incomplete midline development of the forebrain, called holoprosencephaly {49}. It is recommended that topical tretinoin not be used during pregnancy. {01} {49} {51}

Rat, mouse, and rabbit studies have not shown tretinoin to be toxic or teratogenic when subchronic topical doses were used. {52} Topical tretinoin has been shown to be fetotoxic in rabbits given 100 times the usual topical human dose {01}. Teratogenicity studies in Wistar rabbits given 200 times the usual topical human dose showed evidence of a shortened or kinked tail. Doses 80 times the usual human topical dose resulted in domed head and hydrocephaly in the offspring of New Zealand white rabbits {01}. Furthermore, topical tretinoin has caused delayed ossification in a number of bones in the offspring of rats and rabbits given 100 to 320 times the usual topical human dose, respectively. However, the delayed ossification is usually corrected after weaning {04}.

FDA Pregnancy Category C. {01} {03}

Breast-feeding

It is not known whether tretinoin is distributed into breast milk. Risk-benefit should be considered.

Pediatrics

Appropriate studies on the relationship of age to the effects of tretinoin have not been performed in the pediatric population. However, no pediatrics-specific problems have been documented to date in children 12 years of age and older.

Safety and efficacy have not been established for children up to 12 years of age for all uses of tretinoin or for children 12 years of age and older for treatment of photoaging {54}. Problems due to photoaging are unlikely to occur in children or adolescents {01}.


Geriatrics


Appropriate studies on the relationship of age to the effects of tretinoin have not been performed in the geriatric population. However, no geriatrics-specific problems have been documented to date. Significant acne vulgaris is not likely to occur in this age group. Safety and efficacy have not been established for tretinoin's use in treatment of photoaging for adults 50 years of age and older. {01}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Acne products, topical, or topical products containing a peeling agent, such as
Antibiotics, topical, such as
Clindamycin, topical
Erythromycin, topical
Benzoyl peroxide
Resorcinol
Salicylic acid
Sulfur or

Alcohol-containing products, topical, such as
After-shave lotions
Astringents
Cosmetics or soaps with a strong drying effect
Shaving creams or lotions or

Hair products, skin-irritating, such as hair permanents or hair removal products or
Products containing lime or spices, topical or
Soaps or cleansers, abrasive    (concurrent use with tretinoin may cause a cumulative irritant or drying effect, especially with the application of peeling, desquamating, or abrasive agents, resulting in excessive irritation of the skin. If irritation results, the strength or dose of tretinoin may need to be reduced or temporarily discontinued until the skin is less sensitive {01} {12})

    (use of benzoyl peroxide or topical antibiotics with tretinoin on the same area of the skin at the same time is not recommended {16} {17}. A physical incompatibility between the medications or a change in pH may reduce tretinoin's efficacy if used simultaneously. {16} {26} When used together for clinical effect, it is recommended that these medications be used at different times of the day, such as morning and night, to minimize possible skin irritation. If irritation results, tretinoin's strength or dose may need to be reduced or temporarily discontinued until the skin is less sensitive)


Minoxidil, topical    (tretinoin increases the rate and extent of systemic absorption of topical minoxidil and may enhance hair growth according to preliminary studies; however, increased skin irritation may occur. Use of these medications together is not recommended {47} {50})


Photosensitizing medications, such as
Fluoroquinolones
Phenothiazines
Sulfonamides
Thiazide diuretics    (concurrent use with these medications may increase risk of photosensitivity, partly due to tretinoin's ability to induce dryness, peeling, and scaling that is especially prominent during the first several months of use; if skin becomes sunburned or irritated, the strength or dose of tretinoin may need to be reduced or temporarily discontinued until the skin is less sensitive {01})


Retinoids, such as
» Acitretin{53}
» Etretinate{53}
Isotretinoin{53}
» Tretinoin, oral{53}    (retinoids are not used together due to their cumulative mucocutaneous drying or irritative effects. Rarely, isotretinoin has been used together with topical tretinoin to treat acne; however, the strength or dose of one of the retinoids may need to be reduced or one or both retinoids temporarily discontinued if skin irritation results {53})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
Dermatitis, seborrheic or
» Eczema    (tretinoin may cause severe irritation)


Sensitivity to tretinoin{01}
» Sunburn    (irritation may be increased; tretinoin should be discontinued until the skin is less sensitive {01})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Monitoring for side/adverse effects and efficacy during prolonged therapy    (recommended for patients receiving tretinoin for prolonged periods, especially for treatment of photoaging, since long-term safety has not been established beyond 48 weeks)




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Burning or stinging sensation of skin, severe {06}{17}{19}
    
erythema, severe (redness of skin, severe){13}{15}{16}{17}{19}
    
hypopigmentation of treated skin{01}{06}{17}{18}{20} (lightening of treated skin)—may correspond with therapeutic use
    
scaling of skin, severe (severe peeling of skin){06}{13}{15}{16}{19}
    
unusually dry skin, severe {01}{13}{15}{16}{17}{19}

Note: If the retinoid reaction ( erythema, stinging, or burning sensation of skin, and scaling of skin) is severe, tretinoin should be discontinued for 1 to 3 days until the symptoms subside. {17} {29}
Not only does hypopigmentation {06} occur in hyperpigmented skin {20} but lightening of normal pigmented skin also may be statistically significant although clinically minimal. This may be a greater concern for patients with constitutionally dark complexions {18}.


Incidence rare
    
Hyperpigmentation of treated skin{01}{06}{18} (darkening of treated skin)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Burning sensation, stinging, or tingling of skin, mild —transient upon application{06}{17}{19}
    
erythema, mild (redness of skin; unusually warm skin, mild){13}{15}{16}{17}{19}
    
scaling of skin, mild (chapping and slight peeling of skin){06}{13}{15}{16}{19}{28}
    
unusually dry skin, mild {01}{13}{15}{16}{17}{19}

Note: A mild to moderate retinoid reaction ( erythema, mild burning sensation, stinging, or tingling of skin, and mild scaling) occurs within the first few weeks in more than 70 to 90% {26} {28} {29} of patients using therapeutic doses. This reaction peaks within 2 weeks for the 0.05% cream {19} and at 2 months for the 0.1% cream {17} {29}; symptoms may occur less often and be less severe for weaker strengths. Unusually dry skin and mild scaling of skin are more persistent, peaking at 12 to 16 weeks for the 0.05% cream {19}.






Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Tretinoin (Topical) .
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to etretinate, isotretinoin, tretinoin, or vitamin A derivatives

Pregnancy—Not recommended during pregnancy; although not clearly associated, rare cases of fetal problems have occurred with topical use of tretinoin





Breast-feeding—Consulting with physician before breast-feeding.
Other medications, especially acitretin, etretinate, and oral tretinoin
Other medical problems, especially eczema and sunburn

Proper use of this medication
» Importance of not using more medication than the amount prescribed

» Not applying medication to windburned or sunburned skin or on open wounds

» Avoiding contact with the eyes, mouth, and nose

Reading patient directions carefully before use

Proper administration technique
Before applying—Washing skin with mild or nonallergenic soap or cleanser and warm water; gently patting dry; avoid harsh scrubbing of face with washcloth or sponge

» Waiting 20 to 30 minutes for complete drying of skin; applying to wet skin can cause skin irritation

For cream or gel dosage form
Applying very sparingly to affected areas and rubbing in gently but well; a pea-sized amount is sufficient to cover the face

For solution dosage form
Using fingertips, gauze pad, or cotton swab and applying very sparingly to affected areas

Not oversaturating gauze pad or cotton swab to prevent medication from running into areas not intended for treatment
Washing hands afterwards to remove any lingering medication

» Proper dosing
Missed dose: Applying next dose at regularly scheduled time; not doubling doses

» Proper storage

Precautions while using this medication
Possibility that skin will become irritated or that acne may appear to worsen during the first 3 weeks of therapy; checking with health care professional at any time that skin irritation becomes severe or if acne does not improve within 8 to 12 weeks

Not washing the areas of the skin treated with tretinoin for at least 1 hour after application

» Avoiding use of any topical product on the same area within 1 hour before or after application of tretinoin to avoid physical incompatibilities or excessive skin irritation; applying tretinoin at bedtime helps to avoid this when other topical products are used during the day

» Either checking with health care professional before using or avoiding use of other topical acne or skin products containing a peeling agent (benzoyl peroxide, resorcinol, salicylic acid, or sulfur), irritating hair products (permanents or hair removal products), sun-sensitizing skin products (could contain limes or spices), alcohol-containing skin products, or drying or abrasive skin products (some cosmetics or soaps or skin cleansers); sometimes benzoyl peroxide is used with tretinoin for acne treatment but is applied at different times of the day to lessen skin irritation

» Minimizing exposure of treated areas to sunlight, wind, and cold temperatures to avoid sunburn, dryness, or irritation, especially during the first 6 months of treatment with tretinoin. Also, avoiding use of artificial sunlight or sunlamp

Using sunscreen preparations (minimum sun protection factor [SPF] of 15) or wearing protective clothing over treated areas when sunlight exposure cannot be avoided

» Checking with doctor at any time skin becomes too dry or irritated; choosing proper skin product to reduce skin dryness or irritation

For patients using tretinoin to treat acne
Using light water-based skin products, especially regular use of moisturizers, to help reduce skin irritation or dryness

For patients using tretinoin to treat photoaging, hyperpigmentation, or fine wrinkling
» Complying continually with sun avoidance measures

» Using oil-based skin products, especially regular use of moisturizers, to help reduce any skin irritation or dryness resulting from weather or tretinoin


Side/adverse effects
The side/adverse effects of tretinoin are reversible upon discontinuation of therapy; however, hyperpigmentation or hypopigmentation may persist for months

Signs of potential side effects, especially burning or stinging sensation of skin (severe); erythema (severe); hypopigmentation of treated skin—may correspond with therapeutic effect; scaling of skin (severe); unusually dry skin (mild or severe); hyperpigmentation of treated skin


General Dosing Information
Since tretinoin potentially can cause severe irritation and peeling, therapy may be initiated or maintained {47} {49} on an alternate-day or, occasionally, every-third-day regimen {47} {49}, preferably with the less irritating and low-concentration cream or gel dosage form {16}. If tolerated, the more potent liquid or higher-concentration cream or gel preparation may then be used {16} {24}. Alcohol-containing gels and solutions are considered more potent because of the dryness produced from the volatility of their vehicles, an effect appropriate for hot, wet climates and summer months {48}.

If severe irritation occurs, tretinoin should not be applied until the skin is healed or less irritated. Tretinoin should not be applied to mucous membranes; contact near the eyes, lips, or nose should be avoided {01} {26}.

Patients should be counseled on the importance of protecting the skin from the sun, wind, cold temperatures, and excessive dryness by using sunscreens of at least SPF 15, moisturizers {47}, and protective clothing. Artificial sunlight, such as sunlamps, should be avoided. {12} {47}

Any topical products, medications, or agents should not be applied simultaneously but should be delayed at least 1 hour after the application of tretinoin. {26} {49} Topical acne products, such as antibiotics or benzoyl peroxide, are used therapeutically with tretinoin to treat acne but can increase the risk of skin irritation.

The areas to be treated should be cleansed thoroughly before the medication is applied. Using the fingertips when washing the skin helps clean the skin and remove resulting scales and peeling of skin; harsh scrubbing of skin with sponges or cloths should be avoided {17} {47}. Tretinoin should be applied to dry skin (20 to 30 minutes should be allowed after washing) to reduce possible skin irritation that worsens or occurs more often if tretinoin is applied any earlier to nondry skin. {12} {16} Treated areas of skin should not be washed for at least 1 hour after applying tretinoin. {17}When considering dosage adjustments, a pea-sized amount (0.4 inch or 1 centimeter) is enough to cover the entire face.

For the treatment of acne
Within the first few weeks, acne can worsen because of exacerbation of deep, previously unseen lesions {13}. Therapeutic results may be noticeable after 2 to 3 weeks of therapy, but more so after 6 weeks, with optimal results achieved after 3 months of therapy for most patients {12} {13} {14} {15}.

For the treatment of photoaging, hyperpigmentation, or fine wrinkling
In a dose-response study of water-in-oil tretinoin cream, the 0.01% strength was marginally effective, the 0.001% strength showed no difference from the vehicle, and the 0.05% strength provided the best clinical response {21} {25} {28} {29}. Improvement persists for at least 2 months post-therapy, followed by partial and gradual regression {23} {25} {29}.

For the treatment of keratosis follicularis
Irritation caused by tretinoin may be minimized by use of adequate, yet threshold, concentrations of tretinoin or by concurrent use of topical steroids.

For treatment of verruca plana
In the treatment of flat warts, therapy is initiated with a weak concentration of tretinoin. If there is no response, the concentration of the tretinoin preparation and/or frequency of application should be increased.


Topical Dosage Forms

Note: Bracketed information in the Dosage Forms section refers to categories of use and/or indications that are not included in U.S. product labeling.

TRETINOIN CREAM (Oil-in-water) USP

Usual adult and adolescent dose
Acne vulgaris
Initial: Topical, to the skin of affected areas, once a day at bedtime {03} {04} {08}. After the first seven to ten days of use, dose may be increased to two times a day if excessive drying of skin has not occurred {04}.

Maintenance: Topical, to the skin of affected areas, once a day at bedtime {03} {04} or less often as needed {07} {08}.

[Keratosis follicularis]1 or
[Verruca plana]1
Topical, to the skin of affected areas, one or two times a day {55}.


Strength(s) usually available
U.S.—


0.025% (Rx) [Retin-A (stearyl alcohol){03}] [Avita (stearyl alcohol){56}]


0.05% (Rx) [Retin-A (stearyl alcohol){03}]


0.1% (Rx) [Retin-A (stearyl alcohol){03}]

Canada—


0.01% (Rx) [Retin-A{04}] [Retisol-A{05}] [Stieva-A (cetyl alcohol) (edetate disodium) (methylparaben) (propylparaben) (stearyl alcohol){06}] [Vitamin A Acid{07}]


0.025% (Rx) [Retin-A{04}] [Retisol-A (light mineral oil) (Parsol MCX 7.5%) (Parsol 1789 2%) (sodium hydroxide) (stearyl alcohol){05}] [Stieva-A (cetyl alcohol) (edetate disodium) (methylparaben) (propylparaben) (stearyl alcohol){06}] [Vitamin A Acid{07}] [Vitinoin{08}]


0.05% (Rx) [Retin-A{04}] [Retisol-A (light mineral oil) (Parsol MCX 7.5%) (Parsol 1789 2%) (sodium hydroxide) (stearyl alcohol){05}] [Stieva-A (cetyl alcohol) (edetate disodium) (methylparaben) (propylparaben) (stearyl alcohol){06}] [Vitamin A Acid{07}] [Vitinoin{08}]


0.1% (Rx) [Retin-A{04}] [Retisol-A (light mineral oil) (Parsol MCX 7.5%) (Parsol 1789 2%) (sodium hydroxide) (stearyl alcohol){05}] [Stieva-A Forte (cetyl alcohol) (edetate disodium) (methylparaben) (propylparaben) (stearyl alcohol) (titanium dioxide){06}] [Vitamin A Acid{07}] [Vitinoin{08}]

Note: Retisol-A contains sunscreens with a sun protection factor (SPF) of 15 {05} {06}.


Packaging and storage:
Store between 15 and 27 °C (59 and 81 °F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container. Protect from freezing. {03} {05} {06} {07}

Incompatibilities:
Tretinoin and benzoyl peroxide should not be extemporaneously combined, since there is a physical incompatibility between the two medications.

Auxiliary labeling:
   • For external use only.
   • Avoid prolonged or excessive exposure to direct and/or artificial sunlight while using this medication {01}.

Note: Include patient instructions when dispensing.



TRETINOIN CREAM (Water-in-oil) USP

Usual adult and adolescent dose
Hyperpigmentation, mottled, facial, due to photoaging (treatment adjunct) {17} {18} or
Skin roughness, facial, due to photoaging (treatment adjunct) {19} or
Wrinkling, fine facial, due to photoaging (treatment adjunct) {20} {23} {24} {25} {26} {28} {29} {49}
Adults up to 50 years of age: Topical, to the skin of the face, a thin film once a day, usually at bedtime. {01}

Adults 50 years of age and older: Safety and efficacy have not been established. {01}

Note: Dosing is individualized to minimize irritation while maintaining efficacy. Alternate-day dosing, a smaller volume, or a weaker strength can be used initially or when skin becomes too irritated. If irritation becomes severe, tretinoin should be discontinued until irritation substantially lessens or heals. {20} {23} {24} {25} {26} {28} {29} {49}
Safety and efficacy have not been established for daily use for more than forty-eight weeks. {01} Some clinicians recommend only two or three applications per week following use for eight to twelve months to maintain effects. {46}



Usual geriatric dose
Hyperpigmentation, mottled, facial, due to photoaging (treatment adjunct) {01} {02} or
Skin roughness, facial, due to photoaging (treatment adjunct) {01} {02} or
Wrinkling, fine facial, due to photoaging (treatment adjunct) {01} {02}
Adults 50 years of age and older: Safety and efficacy have not been established.


Strength(s) usually available
U.S.—


0.05% (Rx) [Renova (edetate disodium) (light mineral oil) (methylparaben) (purified water) (sorbital solution) (stearyl alcohol){01}]

Canada—


0.05% (Rx) [Renova (edetate disodium) (light mineral oil) (methylparaben) (purified water) (sorbital solution) (stearyl alcohol){02}]

Packaging and storage:
Store between 15 and 27 °C (59 and 81 °F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container. Protect from freezing {03} {05} {06} {07}.

Incompatibilities:
Tretinoin and benzoyl peroxide should not be extemporaneously combined, since there is a physical incompatibility between the two medications.

Insoluble in water, mineral oil, and glycerin. {01}

Auxiliary labeling:
   • For external use only.
   • Avoid prolonged or excessive exposure to direct and/or artificial sunlight while using this medication {01}.

Note: 

• Include patient instructions when dispensing.


• For facial use only.




TRETINOIN GEL USP

Usual adult and adolescent dose
Acne vulgaris or
[Keratosis follicularis]1 or
[Verruca plana]1
See Tretinoin Cream USP (Oil-in-water) {55}.


Strength(s) usually available
U.S.—


0.01% (alcohol-based) (Rx) [Retin-A (butyl alcohol 90% w/w){03}]


0.025% (alcohol-based) (Rx) [Retin-A (butyl alcohol 90% w/w){03}] [Avita (ethanol 83% w/w){57}]


0.1% (aqueous-based) (Rx) [Retin-A MICRO (benzyl alcohol) (butylated hydroxytoluene) (carbomer 934P) (cyclomethicone and dimethicone copolyol) (disodium EDTA) (glycerin) (PPG-20 methyl glucose ether distearate) (propylene glycol) (purified water) (sorbic acid){03}]

Canada—


0.01% (alcohol-based) (Rx) [Retin-A{04}] [Stieva-A (alcohol){06}] [Vitamin A Acid (methylparaben) (propylparaben){07}]


0.025% (alcohol-based) (Rx) [Retin-A{04}] [Stieva-A (alcohol){06}] [Vitamin A Acid (methylparaben) (propylparaben){07}] [Vitinoin{08}]


0.05% (alcohol-based) (Rx) [Stieva-A (alcohol){06}] [Vitamin A Acid (methylparaben) (propylparaben){07}]

Note: Vitinoin gel contains moisturizers {08}.


Packaging and storage:
Store between 15 and 25 °C (59 and 77 °F) {04} unless otherwise specified by manufacturer {03}. Store in a tight container. Protect from light.

Incompatibilities:
Tretinoin and benzoyl peroxide should not be extemporaneously combined, since there is a physical incompatibility between the two medications. {30}

Auxiliary labeling:
   • For external use only.
   • Avoid prolonged or excessive exposure to direct and/or artificial sunlight while using this medication. {01}

Note: 

• Include patient instructions when dispensing.


• Protect from heat and flame {03}.




TRETINOIN TOPICAL SOLUTION USP

Usual adult and adolescent dose
Acne vulgaris or
[Keratosis follicularis]1 or
[Verruca plana]1
See Tretinoin Cream USP (Oil-in-water) {55}.


Strength(s) usually available
U.S.—


0.05% (Rx) [Retin-A (alcohol 55% w/w){03}]

Canada—


0.025% (Rx) [Stieva-A{06}]


0.05% (Rx) [Stieva-A{06}]

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), {03} {06} unless otherwise specified by manufacturer. {03} Store in a tight, light-resistant container.

Incompatibilities:
Tretinoin and benzoyl peroxide should not be extemporaneously combined, since there is a physical incompatibility between the two medications. {30}

Auxiliary labeling:
   • For external use only.
   • Keep container tightly closed.
   • Avoid prolonged or excessive exposure to direct and/or artificial sunlight while using this medication. {01}

Note: Include patient instructions when dispensing.




Revised: 04/24/1998



References
  1. Renova package insert (Ortho—US), Rev 1995, Rec 1/96.
  1. Renova product monograph (Ortho—Canada), Rev 12/95, Rec 2/96.
  1. Retin-A package insert (Ortho—US), Rev 9/93, Rec 2/96.
  1. Retin-A product monograph (McNeil—Canada), Rev 4/94, Rec 2/96.
  1. Retisol-A product monograph (McNeil—Canada), Rev 9/92, Rec 5/96.
  1. Stieva-A product monograph (Stiefel—Canada), Rev 4/94, Rec 5/96.
  1. Vitamin A acid product monograph (Rhone-Poulenc Rorer Canada—Canada), Rev 6/91, Rec 5/96.
  1. Vitinoin product monograph (Pharmascience). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 31st ed. Ottawa: Canadian Pharmaceutical Association; 1996. p. 1596-7.
  1. Fisher GJ, Datta SC, Talwar HS, et al. Molecular basis of sun-induced premature skin aging and retinoid antagonism. Nature 1996 Jan 25; 379: 335-9.
  1. Brash DE, Gilchrest BA. Wrinkles waiting for Godot. Nature 1996 Jan 25; 379: 301-2.
  1. Fleeger CA, editor. USP dictionary of USAN and international drug names 1997. Rockville, MD: The United States Pharmacopeial Convention, Inc.; 1996. p. 734.
  1. Swinyer LJ, Swinyer TA, Britt MR. Topical agents alone in acne. JAMA 1980 Apr 25; 243(16): 1604-13.
  1. Belkap BS. Treatment of acne with 5 percent benzoyl peroxide gel or 0.05 percent retinoic acid cream. Cutis 1979 Jun; 23(6): 856-9.
  1. Gould DJ, Ead R, Cunliffe WJ. Oral tetracycline and retinoic acid gel in acne. Practioner 1978 Aug; 221(1322): 268-71.
  1. Mills OH, Kligman AM. Treatment of acne vulgaris with topically applied erythromycin and tretinoin. Acta Derm Venereol 1978; 58(6): 555-7.
  1. Hurwitz S. The combined effect of vitamin A acid and benzoyl peroxide in the treatment of acne. Cutis 1976 Mar; 17(3): 585-90.
  1. Griffiths CE, Goldfarb MT, Finkel LJ, et al. Topical tretinoin (retinoic acid) treatment of hyperpigmented lesions associated with photoaging in Chinese and Japanese patients: A vehicle-controlled trial. J Am Acad Dermatol 1994 Jan; 30(1): 76-84.
  1. Bulengo-Ransby SM, Griffiths CEM, Kimbrough-Green CK, et al. Topical tretinoin (retinoic acid) therapy for hyperpigmented lesions caused by inflammation of the skin in black patients. N Engl J Med 1993 May 20; 328(20): 1438-43.
  1. Olsen EA, Katz I, Levine N, et al. Tretinoin moisturizers cream: a new therapy for photodamaged skin. J Am Acad Dermatol 1992 Feb; 26(2Pt1): 283-4.
  1. Rafal ES, Griffiths CEM, Ditre CM, et al. Topical tretinoin (retinoic acid) treatment for liver spots associated with photodamage. N Engl J Med 1992 Feb 6; 326(6): 368-74.
  1. Bhawan J, Gonzalez-Serva A, Kishwer N, et al. Effects of tretinoin on photodamaged skin. Arch Dermatol 1991 May; 127(5): 666-72.
  1. Weinstein GD, Nigra TP, Pochi PE, et al. Topical tretinoin for treatment of photodamaged skin. Arch Dermatol 1991 May; 127(5): 659-65.
  1. Ellis CN, Weiss JS, Hamilton TA, et al. Sustained improvement with prolonged topical tretinoin (retinoic acid) for photoaged skin. J Am Acad Dermatol 1990 Oct; 4(Pt 1): 624-37.
  1. Monti M, Caputo R. Clinical efficacy and patient tolerance of topical tretinoin therapy in photo-ageing. J Int Med Res 1990; 18(Suppl 3): 35c-40c.
  1. Lever L, Kumar P, Marks R. Topical retinoic acid for treatment of solar damage. Br J Dermatol 1990; 122(1): 91-8.
  1. Goldfarb MT, Ellis CN, Weiss JS, et al. Topical tretinoin therapy: Its use in photoaged skin. J Am Acad Dermatol 1989; 21: 645-50.
  1. Panel comments, sent 9/7/88.
  1. Leyden JJ, Grove GL, Grove MJ, et al. Treatment of photodamaged facial skin with topical tretinoin. J Am Acad Dermatol 1989 Sep; 21(3 Pt 2): 638-44.
  1. Weiss JS, Ellis CN, Headington JT. Topical tretinoin improves photoaged skin: a double-blind vehicle-controlled study. JAMA 1988 Jan 22/29; 259(4): 527-32.
  1. Roberts L. Questions raised about anti-wrinkle cream. Science 239(4840): 564.
  1. Marks R, Black D, Pearse AD, et al. Techniques for assessing the activity of topically applied retinoids. J Am Acad Dermatol 1986 Oct; 15 (4 Pt 2): 810-6.
  1. Muller SA, Belcher RW, Esterly NB. Keratinizing dermatoses. Arch Dermatol 1977 Aug; 113(8): 1052-4.
  1. Chung J-C, Law MYL, Elliott ST, et al. Dizacholesterol-induced ichthyosis in the hairless mouse. Arch Dermatol 1984 Mar; 120(3): 342-7.
  1. Steijlen PM, Happle R, Van Muijen GNP, et al. Topical treatment with 13–cis-retinoic acid improves Darier's disease and induces the expression of a unique keratin pattern. Dermatologica 1991; 182: 178-83.
  1. Thomas I, Shockman J, Epstein JD. Linear keratosis follicularis: a specific entity? Report of a case responding to combined topical retinoid and alpha-hydroxy acid therapy. J Am Acad Dermatol 1989 Jun; 20(6): 1122-3.
  1. Moore JA, Schosser RH. Unilateral keratosis follicularis. Cutis 1985 May; 35(5): 459-61.
  1. Berger RS. Reactive perforating collagenosis of renal failure/diabetes responsive to topical retinoic acid. Cutis 1989 Jun; 43(6): 540-2.
  1. Brand A, Brody N. Keratotic papules in chronic renal disease. Cutis 1981 Dec; 28(6): 637-9.
  1. Moss HV. Kyrle's disease. Cutis 1979 Apr; 23(4): 463-6.
  1. Al Aboosi M. Treatment of plane warts by tretinoin-induced irritant reaction. Int J Dermatol 1994 Nov; 33(11): 826-7.
  1. Handley J, Dinsmore W. Topical tretinoin in the treatment of anogenital warts. Sex Transm Dis 1992 May-Jun; 19(3): 181.
  1. Sanders BB Jr, Stretcher GS. Warts: diagnosis and treatment. JAMA 1976 Jun 28; 235(26): 2859-61.
  1. Bersaques J. Vitamin A acid in the topic treatment of plantar warts. Dermatologica 1975; 150(6): 369-71.
  1. Willhite CC, Sharma RP, Allen PV. Percutaneous retinoid absorption and embryotoxicity [see comments]. J Invest Dermatol 1990 Nov; 95(5): 516-22. Comment in: J Invest Dermatol 1991: 150-60.
  1. Nau H. Percutaneous retinoid absorption and embryotoxicity [comment]. J Invest Dermatol 1991: 150-60. Comment on: J Invest Dermatol 1990 Nov; 95(5): 516-22.
  1. Kligman AM. Therapeutic aspects of retinoic acid in photoaging. Semin Dermatol 1987 Jun; 6(2): 136-40.
  1. Bazzano GS, Terezakis N, Galen W. Topical tretinoin for hair growth promotion. J Am Acad Dermatol 1986 Oct; 15(4 Pt 2): 810-6.
  1. Kligman AM. Guidelines for the use of topical tretinoin (Retin-A) for photoaged skin. J Am Acad Dermatol 1989 Sep; 21(3 Pt 2): 650-4.
  1. Goldfarb MT, Ellis CN, Voorhees JJ. Topical tretinoin: its use in daily practice to reverse photoaging. Br J Dermatol 1990 122; 35(Suppl): 87-91.
  1. Ferry JJ, Forbes KK, VanderLugt JT, et al. Influence of tretinoin on the percutaneous absorption of minoxidil from an aqueous topical solution. Clin Pharmacol Ther 1990; 47: 439-46.
  1. Retin-A creams have trivial birth-defect hazards. Dickinson's FDA, 1988 Nov 18: 4.
  1. Panel comment, 2/24/97.
  1. Panel comment, 2/24/97.
  1. Retin-A MICRO package insert (Ortho—US), Rev 2/97, Rec 4/97.
  1. Panel comment, 6/24/97.
  1. Avita cream package insert (Penederm—US), Rev 2/97, Rec 6/97.
  1. Avita gel package insert (Penederm—US), Rev 12/97, Rec 3/98.
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