Retin-A Micro ®is a retinoid indicated for topical application in the treatment of acne vulgaris.

{ "type": "p", "children": [], "text": "Retin-A Micro\n \n ®is a retinoid indicated for topical application in the treatment of acne vulgaris.\n\n " }

For topical use only. Not for ophthalmic, oral, or intravaginal use.

{ "type": "p", "children": [], "text": "For topical use only. Not for ophthalmic, oral, or intravaginal use." }

Retin-A Micro should be applied once a day, in the evening, to the skin where acne lesions appear, using enough to cover the entire affected area in a thin layer. Areas to be treated should be cleansed thoroughly before the medication is applied. If medication is applied excessively, no more rapid or better results will be obtained and marked redness, peeling, or discomfort may occur. A transitory feeling of warmth or slight stinging may be noted on application. In cases where it has been necessary to temporarily discontinue therapy or to reduce the frequency of application, therapy may be resumed or the frequency of application increased as the patient becomes able to tolerate the treatment. Frequency of application should be closely monitored by careful observation of the clinical therapeutic response and skin tolerance. Efficacy has not been established for less than once daily dosing frequencies.

{ "type": "p", "children": [], "text": "Retin-A Micro should be applied once a day, in the evening, to the skin where acne lesions appear, using enough to cover the entire affected area in a thin layer. Areas to be treated should be cleansed thoroughly before the medication is applied. If medication is applied excessively, no more rapid or better results will be obtained and marked redness, peeling, or discomfort may occur. A transitory feeling of warmth or slight stinging may be noted on application. In cases where it has been necessary to temporarily discontinue therapy or to reduce the frequency of application, therapy may be resumed or the frequency of application increased as the patient becomes able to tolerate the treatment. Frequency of application should be closely monitored by careful observation of the clinical therapeutic response and skin tolerance. Efficacy has not been established for less than once daily dosing frequencies." }

During the early weeks of therapy, an apparent exacerbation of inflammatory lesions may occur. If tolerated, this should not be considered a reason to discontinue therapy [see Adverse Reactions (6.1)] .

{ "type": "p", "children": [], "text": "During the early weeks of therapy, an apparent exacerbation of inflammatory lesions may occur. If tolerated, this should not be considered a reason to discontinue therapy\n \n [see\n \n Adverse Reactions (6.1)]\n \n .\n\n " }

Therapeutic results may be noticed after two weeks, but more than seven weeks of therapy are required before consistent beneficial effects are observed.

{ "type": "p", "children": [], "text": "Therapeutic results may be noticed after two weeks, but more than seven weeks of therapy are required before consistent beneficial effects are observed." }

Retin-A Micro should be kept away from the eyes, the mouth, paranasal creases of the nose, and mucous membranes.

{ "type": "p", "children": [], "text": "Retin-A Micro should be kept away from the eyes, the mouth, paranasal creases of the nose, and mucous membranes." }

Patients treated with Retin-A Micro may use cosmetics.

{ "type": "p", "children": [], "text": "Patients treated with Retin-A Micro may use cosmetics." }

Concomitant topical medication, medicated or abrasive soaps and cleansers, products that have a strong drying effect, products with high concentrations of alcohol, astringents, or spices should be used with caution because of possible interaction with tretinoin. Avoid contact with the peel of limes. Particular caution should be exercised with the concomitant use of topical over-the-counter acne preparations containing benzoyl peroxide, sulfur, resorcinol, or salicylic acid with Retin-A Micro. It also is advisable to allow the effects of such preparations to subside before use of Retin-A Micro is begun.

{ "type": "p", "children": [], "text": "Concomitant topical medication, medicated or abrasive soaps and cleansers, products that have a strong drying effect, products with high concentrations of alcohol, astringents, or spices should be used with caution because of possible interaction with tretinoin. Avoid contact with the peel of limes. Particular caution should be exercised with the concomitant use of topical over-the-counter acne preparations containing benzoyl peroxide, sulfur, resorcinol, or salicylic acid with Retin-A Micro. It also is advisable to allow the effects of such preparations to subside before use of Retin-A Micro is begun." }

Retin-A Micro is a white to very pale yellow opaque gel. Retin-A Micro is available in four strengths: 0.1%, 0.08%, 0.06% and 0.04%.

{ "type": "p", "children": [], "text": "Retin-A Micro is a white to very pale yellow opaque gel. Retin-A Micro is available in four strengths: 0.1%, 0.08%, 0.06% and 0.04%." }

Each gram of Retin-A Micro Gel, 0.1%, contains 1 mg of tretinoin.

{ "type": "p", "children": [], "text": "Each gram of Retin-A Micro Gel, 0.1%, contains 1 mg of tretinoin." }

Each gram of Retin-A Micro Gel, 0.08%, contains 0.8 mg of tretinoin.

{ "type": "p", "children": [], "text": "Each gram of Retin-A Micro Gel, 0.08%, contains 0.8 mg of tretinoin." }

Each gram of Retin-A Micro Gel, 0.06%, contains 0.6 mg of tretinoin.

{ "type": "p", "children": [], "text": "Each gram of Retin-A Micro Gel, 0.06%, contains 0.6 mg of tretinoin." }

Each gram of Retin-A Micro Gel, 0.04%, contains 0.4 mg of tretinoin.

{ "type": "p", "children": [], "text": "Each gram of Retin-A Micro Gel, 0.04%, contains 0.4 mg of tretinoin." }

None.

{ "type": "p", "children": [], "text": "None." }

The skin of certain individuals may become excessively dry, red, swollen, or blistered.

Tretinoin has been reported to cause severe irritation on eczematous skin and should be used with utmost caution in patients with this condition.

If the degree of irritation warrants, patients should be directed to temporarily reduce the amount or frequency of application of the medication, discontinue use temporarily, or discontinue use all together. Efficacy at reduced frequencies of application has not been established. If a reaction suggesting sensitivity occurs, use of the medication should be discontinued.

To help limit skin irritation, patients must:

Patients should apply a topical moisturizer if dryness is bothersome.

Unprotected exposure to sunlight, including sunlamps (UV light) should be avoided or minimized during the use of Retin-A Micro and patients with sunburn should be advised not to use the product until fully recovered because of heightened susceptibility to sunlight as a result of the use of tretinoin. Patients who may be required to have extended periods of UV exposure (e.g., due to occupation or sports), or those with inherent sensitivity to the sun, or those using medications that cause photosensitivity, should exercise particular caution. Use of sunscreen products (SPF 15 or higher) and protective clothing over treated areas are recommended when exposure cannot be avoided [ see Nonclinical Toxicology (13.1)].

Weather extremes, such as wind or cold, also may be irritating to tretinoin-treated skin.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical Trials in Subjects with Acne

In separate clinical trials for each concentration, acne subjects treated with Retin-A Micro (tretinoin) Gel microsphere, 0.1% or 0.04%, over the twelve-week period showed that cutaneous irritation scores for erythema, peeling, dryness, burning/stinging, or itching peaked during the initial two weeks of therapy, decreasing thereafter.

Approximately half of the subjects treated with Retin-A Micro, 0.04%, had cutaneous irritation at Week 2. Of those subjects who did experience cutaneous side effects, most had signs or symptoms that were mild in severity (severity was ranked on a 4-point ordinal scale: 0=none, 1=mild, 2=moderate, and 3=severe). Less than 10% of patients experienced moderate cutaneous irritation and there was no severe irritation at Week 2.

In trials of Retin-A Micro (tretinoin) Gel microsphere, 0.04%, throughout the treatment period the majority of subjects experienced some degree of irritation (mild, moderate, or severe) with 1% (2/225) of subjects having scores indicative of a severe irritation; 1.3% (3/225) of subjects treated with Retin-A Micro (tretinoin) Gel microsphere, 0.04%, discontinued treatment due to irritation, which included dryness in one patient and peeling and urticaria in another.

In trials of Retin-A Micro (tretinoin) Gel microsphere, 0.1%, no more than 3% of subjects had cutaneous irritation scores indicative of severe irritation; 6% (14/224) of subjects treated with Retin-A Micro (tretinoin) Gel microsphere, 0.1%, discontinued treatment due to irritation. Of these 14 subjects, four had severe irritation after 3 to 5 days of treatment, with blistering in one subject.

In a double-blind trial with 156 acne subjects comparing 12 weeks of treatment with Retin-A Micro (tretinoin) Gel, 0.04% or 0.1%, (78 subjects each group), the most frequently-reported adverse events affected the skin and subcutaneous tissue (15.4% in the 0.04% group, and 20.5% in the 0.1% group). The most prevalent of the dermatologic adverse events in the 0.04% group was skin irritation (6.4%); and in the 0.1% group skin burning (7.7%), erythema (5.1%), skin irritation (3.8%), and dermatitis (3.8%). Most adverse events were of mild intensity (63.4%), and 34.4% were moderate. One subject in each group had adverse events characterized as severe, neither were dermatologic findings and neither was characterized as related to drug by the investigator.

Trials in Subjects without Acne

In a half-face comparison trial conducted for up to 14 days in women with sensitive skin, but without acne, Retin-A Micro (tretinoin) Gel microsphere, 0.1%, was statistically less irritating than tretinoin cream, 0.1%. In addition, a cumulative 21- day irritation evaluation in subjects with normal skin showed that Retin-A Micro (tretinoin) Gel microsphere, 0.1%, had a lower irritation profile than tretinoin cream, 0.1%. The clinical significance of these irritation studies for patients with acne is not established. Comparable effectiveness of Retin-A Micro (tretinoin) Gel microsphere, 0.1%, and tretinoin cream, 0.1%, has not been established. The lower irritancy of Retin-A Micro (tretinoin) Gel microsphere, 0.1%, in subjects without acne may be attributable to the properties of its vehicle. The contribution of decreased irritancy by the MICROSPONGE ®System has not been established. No irritation trials have been performed to compare Retin-A Micro (tretinoin) Gel microsphere, 0.04%, with either Retin-A Micro (tretinoin) Gel microsphere, 0.1%, or tretinoin cream, 0.1%.

The following adverse reactions have been identified during post-approval use of Retin-A Micro Gel. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Temporary hyper- or hypopigmentation has been reported with repeated application of tretinoin.

Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. Retin-A Micro should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Thirty human cases of temporally associated congenital malformations have been reported during two decades of clinical use of tretinoin products. Although no definite pattern of teratogenicity and no causal association has been established from these cases, five of the reports describe the rare birth defect category holoprosencephaly (defects associated with incomplete midline development of the forebrain). The significance of these spontaneous reports in terms of risk to the fetus is not known.

For purposes of comparison of the animal exposure to systemic human exposure, the MRHD applied topically is defined as 1 gram of Retin-A Micro (tretinoin) Gel microsphere, 0.1%, applied daily to a 60 kg person (0.017 mg tretinoin/kg body weight).

Pregnant rats were treated with Retin-A Micro (tretinoin) Gel microsphere, 0.1%, at daily dermal doses of 0.5 to 1.0 mg/kg/day tretinoin on gestation days 6-15. Alterations were seen in vertebrae and ribs of offspring at 5 to 10 times the MRHD based on the body surface area (BSA) comparison.

Pregnant New Zealand White rabbits were treated with Retin-A Micro (tretinoin) Gel microsphere, 0.1%, at daily dermal doses of 0.2, 0.5, and 1.0 mg/kg/day tretinoin on gestation days 7-19. Doses were administered topically for 24 hours a day while wearing Elizabethan collars to prevent ingestion of the drug. Increased incidences of certain alterations, including domed head and hydrocephaly, typical of retinoid-induced fetal malformations in this species, were observed at 0.5 and 1.0 mg/kg/day. Similar malformations were not observed at 0.2 mg/kg/day, 4 times the MRHD based on BSA comparison. Other pregnant rabbits exposed topically for six hours per day to 0.5 or 1.0 mg/kg/day tretinoin while restrained in stocks to prevent ingestion, did not show any malformations at doses up to 19 times (1.0 mg/kg/day) the MRHD based on BSA comparison, but fetal resorptions were increased at 0.5 mg/kg (10 times the MRHD based on BSA comparison).

Oral tretinoin has been shown to cause malformations in rats, mice, rabbits, hamsters, and nonhuman primates.

Tretinoin induced fetal malformations in Wistar rats when given orally at doses greater than 1 mg/kg/day (10 times the MRHD based on BSA comparison). In the cynomolgus monkey, fetal malformations were reported for doses of 10 mg/kg/day but none were observed at 5 mg/kg/day (95 times the MRHD based on BSA comparison), although increased skeletal variations were observed at all doses. Dose-related increases in embryolethality and abortion also were reported. Similar results have also been reported in pigtail macaques.

In oral peri- and postnatal development studies in rats with tretinoin, decreased survival of neonates and growth retardation were observed at doses in excess of 2 mg/kg/day (19 times the MRHD based on BSA comparison).

Nonteratogenic effects on fetus

Oral tretinoin has been shown to be fetotoxic in rats when administered at doses 24 times the MRHD based on BSA comparison.

Topical tretinoin has been shown to be fetotoxic in rabbits when administered at doses 10 times the MRHD based on BSA comparison.

It is not known whether tretinoin and/or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Retin-A Micro is administered to a nursing woman.

Safety and effectiveness in children below the age of 12 have not been established.

Safety and effectiveness in a geriatric population have not been established. Clinical trials of Retin-A Micro (tretinoin) Gel microsphere, 0.1% and 0.04%, did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger subjects.

Oral ingestion of large amounts of the drug may lead to the same side effects as those associated with excessive oral intake of Vitamin A.

{ "type": "p", "children": [], "text": "Oral ingestion of large amounts of the drug may lead to the same side effects as those associated with excessive oral intake of Vitamin A." }

Retin-A Micro (tretinoin) Gel microsphere, 0.1%, 0.08%, 0.06% and 0.04% is a white to very pale yellow opaque gel for topical treatment of acne vulgaris.

{ "type": "p", "children": [], "text": "Retin-A Micro (tretinoin) Gel microsphere, 0.1%, 0.08%, 0.06% and 0.04% is a white to very pale yellow opaque gel for topical treatment of acne vulgaris." }

Chemically, tretinoin is all-trans-retinoic acid, also known as (all-E)-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoic acid. It is a member of the retinoid class of compounds and a metabolite of naturally occurring Vitamin A. Tretinoin has a molecular weight of 300.44, a molecular formula of C 20H 28O 2and the following chemical structure:

{ "type": "p", "children": [], "text": "Chemically, tretinoin is all-trans-retinoic acid, also known as (all-E)-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoic acid. It is a member of the retinoid class of compounds and a metabolite of naturally occurring Vitamin A. Tretinoin has a molecular weight of 300.44, a molecular formula of C\n \n 20H\n \n 28O\n \n 2and the following chemical structure:\n\n " }

Each gram of Retin-A Micro Gel, 0.1%, contains 1 mg of tretinoin.

{ "type": "p", "children": [], "text": "Each gram of Retin-A Micro Gel, 0.1%, contains 1 mg of tretinoin." }

Each gram of Retin-A Micro Gel, 0.08%, contains 0.8 mg of tretinoin.

{ "type": "p", "children": [], "text": "Each gram of Retin-A Micro Gel, 0.08%, contains 0.8 mg of tretinoin." }

Each gram of Retin-A Micro Gel, 0.06%, contains 0.6 mg of tretinoin.

{ "type": "p", "children": [], "text": "Each gram of Retin-A Micro Gel, 0.06%, contains 0.6 mg of tretinoin." }

Each gram of Retin-A Micro Gel, 0.04%, contains 0.4 mg of tretinoin.

{ "type": "p", "children": [], "text": "Each gram of Retin-A Micro Gel, 0.04%, contains 0.4 mg of tretinoin." }

The formulation contains methyl methacrylate/glycol dimethacrylate crosspolymer (MICROSPONGE ®System), propylene glycol dicaprylate/dicaprate and butylated hydroxytoluene to enable inclusion of the active ingredient, tretinoin, in an aqueous gel. Other components consist of benzyl alcohol, butylated hydroxytoluene, carbomer 974P, cyclomethicone and dimethicone copolyol, disodium EDTA, glycerin, PPG-20 methyl glucose ether distearate, propylene glycol, purified water, sorbic acid, and trolamine.

{ "type": "p", "children": [], "text": "The formulation contains methyl methacrylate/glycol dimethacrylate crosspolymer (MICROSPONGE\n \n ®System), propylene glycol dicaprylate/dicaprate and butylated hydroxytoluene to enable inclusion of the active ingredient, tretinoin, in an aqueous gel. Other components consist of benzyl alcohol, butylated hydroxytoluene, carbomer 974P, cyclomethicone and dimethicone copolyol, disodium EDTA, glycerin, PPG-20 methyl glucose ether distearate, propylene glycol, purified water, sorbic acid, and trolamine.\n\n " }

Although tretinoin activates three members of the retinoic acid (RAR) nuclear receptors (RARα, RARß, and RARγ) which may act to modify gene expression, subsequent protein synthesis, and epithelial cell growth and differentiation, it has not been established whether the clinical effects of tretinoin are mediated through activation of retinoic acid receptors and/or other mechanisms.

The exact mode of action of tretinoin is unknown. Current evidence suggests that topical tretinoin decreases cohesiveness of follicular epithelial cells with decreased microcomedone formation. Additionally, tretinoin stimulates mitotic activity and increased turnover of follicular epithelial cells causing extrusion of the comedones.

Tretinoin is a metabolite of Vitamin A metabolism in man. Percutaneous absorption, as determined by the cumulative excretion of radiolabeled drug into urine and feces, was assessed in 44 healthy men and women after single and repeated daily applications of 500 mg of a 0.1% tretinoin gel formulation. Estimates of in vivobioavailability, mean (SD)%, following both single and multiple daily applications, for a period of 28 days with the 0.1% gel, were 0.82 (0.11)% and 1.41 (0.54)%, respectively. The plasma concentrations of tretinoin and its metabolites, 13- cis-retinoic acid, all- trans-4-oxo-retinoic acid, and 13- cis-4-oxo-retinoic acid, generally ranged from 1 to 3 ng/mL and were essentially unaltered after either single or multiple daily applications of Retin-A Micro (tretinoin) Gel microsphere, 0.1%, relative to baseline levels. Clinical pharmacokinetic studies have not been performed with Retin-A Micro (tretinoin) Gel microsphere, 0.08%, 0.06% and 0.04%.

Dermal carcinogenicity testing has not been performed with Retin-A Micro (tretinoin) Gel microsphere, 0.1%, 0.08%, 0.06% or 0.04%.

In a 91-week dermal study in which CD-1 mice were administered 0.017% and 0.035% formulations of tretinoin, cutaneous squamous cell carcinomas and papillomas in the treatment area were observed in some female mice. These concentrations are near the tretinoin concentration of the 0.04% and 0.1% clinical formulations. A dose-related incidence of liver tumors in male mice was observed at those same doses. The maximum systemic doses associated with the administered 0.017% and 0.035% formulations are 0.5 and 1.0 mg/kg/day tretinoin, respectively. These doses are two and four times the MRHD based on BSA comparison.

The biological significance of these findings is not clear because they occurred at doses that exceeded the dermal maximally tolerated dose of tretinoin and because they were within the background natural occurrence rate for these tumors in this strain of mice.

There was no evidence of carcinogenic potential when 0.025 mg/kg/day of tretinoin was administered topically to mice (0.1 times the MRHD based on BSA comparison).

Studies in hairless albino mice suggest that concurrent exposure to tretinoin may enhance the tumorigenic potential of carcinogenic doses of UVB and UVA light from a solar simulator. This effect has been confirmed in a later study in pigmented mice, and dark pigmentation did not overcome the enhancement of photocarcinogenesis by 0.05% tretinoin. Although the significance of these studies to humans is not clear, patients should minimize exposure to sunlight or artificial ultraviolet irradiation sources [see Warnings and Precautions (5.2)] .

The genotoxic potential of tretinoin was evaluated in the Ames assay and in the in vivo mouse micronucleus assay, both of which were negative.

The components of the microspheres have shown potential for genetic toxicity and fetal malformation. EGDMA, a component of the excipient acrylates copolymer, was positive for induction of structural chromosomal aberrations in the in vitro chromosomal aberration assay in mammalian cells in the absence of metabolic activation, and negative for genetic toxicity in the Ames assay, and the in vivo mouse micronucleus assay.

In oral fertility studies in rats with tretinoin, the no-observable effect level was 2 mg/kg/day (19 times the MRHD based on BSA comparison).

In two vehicle-controlled trials, Retin-A Micro (tretinoin) Gel microsphere, 0.1%, applied once daily was significantly more effective than vehicle in reducing the acne lesion counts. The mean reductions in lesion counts from baseline after treatment for 12 weeks are shown in the following table:

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 1: Mean Percent Reduction in Lesion Counts Retin-A Micro (tretinoin) Gel microsphere, 0.1%</span> </caption> <col width="24%"/> <col width="19%"/> <col width="19%"/> <col width="19%"/> <col width="19%"/> <thead> <tr class="First"> <th align="left" class="Toprule" valign="top"></th><th align="left" class="Toprule" colspan="2" valign="top"><span class="Bold">Retin-A Micro</span> <br/> <span class="Bold">(tretinoin) Gel</span> <br/> <span class="Bold">microsphere, 0.1%</span></th><th align="left" class="Toprule" colspan="2" valign="top"><span class="Bold">Vehicle Gel</span></th> </tr> <tr class="Last"> <th align="left" class="Botrule" valign="top"></th><th align="left" class="Botrule" valign="top"><span class="Bold">Study #1</span> <br/> <span class="Bold">72 pts</span></th><th align="left" class="Botrule" valign="top"><span class="Bold">Study #2</span> <br/> <span class="Bold">71 pts</span></th><th align="left" class="Botrule" valign="top"><span class="Bold">Study #1</span> <br/> <span class="Bold">72 pts</span></th><th align="left" class="Botrule" valign="top"><span class="Bold">Study #2</span> <br/> <span class="Bold">67 pts</span></th> </tr> </thead> <tbody> <tr class="First"> <td class="Toprule" valign="top"> <p class="First">Non-inflammatory lesion counts</p> </td><td class="Toprule" valign="top"> <p class="First">49%</p> </td><td class="Toprule" valign="top"> <p class="First">32%</p> </td><td class="Toprule" valign="top"> <p class="First">22%</p> </td><td class="Toprule" valign="top"> <p class="First">3%</p> </td> </tr> <tr> <td valign="top"> <p class="First">Inflammatory lesion counts</p> </td><td valign="top"> <p class="First">37%</p> </td><td valign="top"> <p class="First">29%</p> </td><td valign="top"> <p class="First">18%</p> </td><td valign="top"> <p class="First">24%</p> </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First">Total lesion counts</p> </td><td class="Botrule" valign="top"> <p class="First">45%</p> </td><td class="Botrule" valign="top"> <p class="First">32%</p> </td><td class="Botrule" valign="top"> <p class="First">23%</p> </td><td class="Botrule" valign="top"> <p class="First">16%</p> </td> </tr> </tbody> </table></div>

Retin-A Micro (tretinoin) Gel microsphere, 0.1%, was also significantly superior to the vehicle in the investigator's global evaluation of the clinical response. In Study #1, thirty-five percent (35%) of subjects using Retin-A Micro (tretinoin) Gel microsphere, 0.1%, achieved an excellent result, as compared to eleven percent (11%) of subjects on the vehicle control. In Study #2, twenty-eight percent (28%) of patients using Retin-A Micro (tretinoin) Gel microsphere, 0.1%, achieved an excellent result, as compared to nine percent (9%) of the subjects on the vehicle control.

In two vehicle-controlled clinical trials, Retin-A Micro (tretinoin) Gel microsphere, 0.04%, applied once daily, was more effective (p<0.05) than vehicle in reducing the acne lesion counts. The mean reductions in lesion counts from baseline after treatment for 12 weeks are shown in the following table:

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 2: Mean Percent Reduction in Lesion Counts Retin-A Micro (tretinoin) Gel microsphere, 0.04%</span> </caption> <col width="24%"/> <col width="19%"/> <col width="19%"/> <col width="19%"/> <col width="19%"/> <thead> <tr class="First"> <th align="left" class="Botrule Lrule Rrule Toprule" valign="top"></th><th align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">Retin-A Micro (tretinoin)</span> <br/> <span class="Bold">Gel microsphere, 0.04%</span></th><th align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">Vehicle Gel</span></th> </tr> <tr class="Last"> <th align="left" class="Botrule Lrule Rrule Toprule" valign="top"></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Study #3</span> <br/> <span class="Bold">108 pts</span></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Study #4</span> <br/> <span class="Bold">111 pts</span></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Study #3</span> <br/> <span class="Bold">110 pts</span></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Study #4</span> <br/> <span class="Bold">103 pts</span></th> </tr> </thead> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Non-inflammatory lesion counts</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">37%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">29%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">-2%*</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">14%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Inflammatory lesion <br/> counts </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">44%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">41%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">13%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">30%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Total lesion counts</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">40%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">35%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">8%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">20%</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" colspan="5" valign="top"> <p class="First">* - That is, a mean percent increase of 2%</p> </td> </tr> </tbody> </table></div>

Retin-A Micro (tretinoin) Gel microsphere, 0.04%, was also superior (p<0.05) to the vehicle in the investigator's global evaluation of the clinical response. In Study #3, fourteen percent (14%) of subjects using Retin-A Micro (tretinoin) Gel microsphere, 0.04%, achieved an excellent result compared to five percent (5%) of subjects on vehicle control. In Study #4, nineteen percent (19%) of subjects using Retin-A Micro (tretinoin) Gel microsphere, 0.04%, achieved an excellent result compared to nine percent (9%) of subjects on vehicle control.

Retin-A Micro Gel is opaque and white to very pale yellow in color.

Retin-A Micro Gel, 0.1%, is supplied in 20 gram tube (NDC 0187-5140-20), 45 gram tube (NDC 0187-5140-45) and 50 gram pump (NDC 0187-5140-50).

Retin-A Micro Gel, 0.08%, is supplied in 50 gram pump (NDC 0187-5148-50).

Retin-A Micro Gel, 0.06%, is supplied in 50 gram pump (NDC 0187-5146-50).

Retin-A Micro Gel, 0.04%, is supplied in 20 gram tube (NDC 0187-5144-20), 45 gram tube (NDC 0187-5144-45) and 50 gram pump (NDC 0187-5144-50).

Store at 20° to 25°C (68° to 77°F); excursions permitted from 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Store pump upright.

Keep out of reach of children.

Advise the patient to read the FDA-approved patient labeling (Patient Information).

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The patient should be instructed to:

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Cleanse the treatment area thoroughly, before treatment, with a mild, non-medicated cleanser. Do not use more than the recommended amount and do not apply Retin-A Micro more than once daily as this will not produce faster or better results, but may increase irritation.

{ "type": "p", "children": [], "text": "Cleanse the treatment area thoroughly, before treatment, with a mild, non-medicated cleanser. Do not use more than the recommended amount and do not apply Retin-A Micro more than once daily as this will not produce faster or better results, but may increase irritation." }

Minimize exposure to sunlight, including sunlamps. Recommend the use of sunscreen products and protective apparel (e.g., hat) when exposure cannot be avoided.

{ "type": "p", "children": [], "text": "Minimize exposure to sunlight, including sunlamps. Recommend the use of sunscreen products and protective apparel (e.g., hat) when exposure cannot be avoided." }

Distributed by: Bausch Health US, LLC Bridgewater, NJ 08807 USA

{ "type": "p", "children": [], "text": "\nDistributed by:\n Bausch Health US, LLC \n Bridgewater, NJ 08807 USA\n\n " }

Manufactured by: Bausch Health Companies Inc. Laval, Quebec H7L 4A8, Canada

{ "type": "p", "children": [], "text": "\nManufactured by:\n Bausch Health Companies Inc. \n Laval, Quebec H7L 4A8, Canada\n\n " }

Retin-A Micro is a trademark of Bausch Health Companies Inc. or its affiliates.

{ "type": "p", "children": [], "text": "Retin-A Micro is a trademark of Bausch Health Companies Inc. or its affiliates." }

Microsponge is a registered trademark of AMCOL International Corporation. All other product/brand names and/or logos are trademarks of the respective owners.

{ "type": "p", "children": [], "text": "Microsponge is a registered trademark of AMCOL International Corporation. \n All other product/brand names and/or logos are trademarks of the respective owners.\n " }

© 2025 Bausch Health Companies Inc. or its affiliates

{ "type": "p", "children": [], "text": "© 2025 Bausch Health Companies Inc. or its affiliates" }

9454708

{ "type": "p", "children": [], "text": "9454708" }

NDC0187-5148-50

{ "type": "p", "children": [], "text": "\nNDC0187-5148-50\n\n " }

RETIN-A MICRO ® (tretinoin) Gel microsphere 0.08%

{ "type": "p", "children": [], "text": "\nRETIN-A MICRO\n \n ®\n\n(tretinoin) Gel microsphere\n\n0.08%\n" }

PUMP

{ "type": "p", "children": [], "text": "\nPUMP\n" }

For Topical Use Only Rx Only

{ "type": "p", "children": [], "text": "\nFor Topical Use Only\n\nRx Only\n" }

Ortho Dermatologics

{ "type": "p", "children": [], "text": "\nOrtho Dermatologics\n" }

NET WT. 50 g

{ "type": "p", "children": [], "text": "NET WT. 50 g" }

9440607 20000365H

{ "type": "p", "children": [], "text": "9440607 \n 20000365H\n " }

NDC0187-5146-50

{ "type": "p", "children": [], "text": "\nNDC0187-5146-50\n\n " }

RETIN-A MICRO ® (tretinoin) Gel microsphere 0.06%

{ "type": "p", "children": [], "text": "\nRETIN-A MICRO\n \n ®\n\n(tretinoin) Gel microsphere\n\n0.06%\n" }

PUMP

{ "type": "p", "children": [], "text": "\nPUMP\n" }

For Topical Use Only Rx only

{ "type": "p", "children": [], "text": "\nFor Topical Use Only\n\nRx only\n" }

Ortho Dermatologics

{ "type": "p", "children": [], "text": "\nOrtho Dermatologics\n" }

NET WT. 50 g

{ "type": "p", "children": [], "text": "NET WT. 50 g" }

9581503 20001795D

{ "type": "p", "children": [], "text": "9581503 \n 20001795D\n " }

NDC0187-5144-50

{ "type": "p", "children": [], "text": "\nNDC0187-5144-50\n\n " }

RETIN-A MICRO ® (tretinoin gel) microsphere 0.04%

{ "type": "p", "children": [], "text": "\nRETIN-A MICRO\n \n ®\n\n(tretinoin gel) microsphere\n\n0.04%\n" }

PUMP

{ "type": "p", "children": [], "text": "\nPUMP\n" }

For Topical Use Only Rx Only

{ "type": "p", "children": [], "text": "\nFor Topical Use Only\n\nRx Only\n" }

Ortho Dermatologics

{ "type": "p", "children": [], "text": "\nOrtho Dermatologics\n" }

Net Wt. 50g

{ "type": "p", "children": [], "text": "\nNet Wt. 50g\n\n " }

9450906 50104776F

{ "type": "p", "children": [], "text": "9450906 \n 50104776F\n " }

NDC0187-5140-50

{ "type": "p", "children": [], "text": "\nNDC0187-5140-50\n\n " }

RETIN-A MICRO ® (tretinoin gel) microsphere 0.1%

{ "type": "p", "children": [], "text": "\nRETIN-A MICRO\n \n ®\n\n(tretinoin gel) microsphere\n\n0.1%\n" }

PUMP

{ "type": "p", "children": [], "text": "\nPUMP\n" }

For Topical Use Only Rx Only

{ "type": "p", "children": [], "text": "\nFor Topical Use Only\n\nRx Only\n" }

Ortho Dermatologics

{ "type": "p", "children": [], "text": "\nOrtho Dermatologics\n" }

Net Wt. 50g

{ "type": "p", "children": [], "text": "\nNet Wt. 50g\n\n " }

9450706 50104801E

{ "type": "p", "children": [], "text": "9450706 \n 50104801E\n " }

ALTRENO® (tretinoin) lotion, 0.05% is indicated for the topical treatment of acne vulgaris in patients 9 years of age and older.

{ "type": "p", "children": [], "text": "ALTRENO® (tretinoin) lotion, 0.05% is indicated for the topical treatment of acne vulgaris in patients 9 years of age and older. " }

Apply a thin layer of ALTRENO to the affected areas once daily. Avoid the eyes, mouth, paranasal creases, and mucous membranes.

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ALTRENO is for topical use only. Not for ophthalmic, oral, or intravaginal use.

{ "type": "p", "children": [], "text": "ALTRENO is for topical use only. Not for ophthalmic, oral, or intravaginal use." }

Lotion, 0.05%

{ "type": "p", "children": [], "text": "Lotion, 0.05%" }

Each gram of ALTRENO contains 0.5 mg (0.05%) tretinoin in an opaque, pale yellow topical lotion.

{ "type": "p", "children": [], "text": "Each gram of ALTRENO contains 0.5 mg (0.05%) tretinoin in an opaque, pale yellow topical lotion." }

None.

{ "type": "p", "children": [], "text": "None." }

Patients using ALTRENO may experience application site dryness, pain, erythema, irritation, and exfoliation. Depending upon the severity of these adverse reactions, instruct patients to use a moisturizer, reduce the frequency of the application of ALTRENO, or discontinue use. Avoid application of ALTRENO to eczematous or sunburned skin.

Minimize unprotected exposure to ultraviolet light including sunlight and sunlamps during the use of ALTRENO. Warn patients who normally experience high levels of sun exposure and those with inherent sensitivity to sun to exercise caution. Use sunscreen products and protective clothing over treated areas when sun exposure cannot be avoided.

ALTRENO contains soluble fish proteins. Use with caution in patients with known sensitivity or allergy to fish. Advise patients to contact their healthcare provider if they develop pruritus or urticaria.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

In 2 randomized, double-blind, vehicle-controlled trials, subjects age 9 years and older applied ALTRENO or vehicle once daily for 12 weeks. The majority of subjects were White (74%) and female (55%). Approximately 47% were Hispanic/Latino and 45% were younger than 18 years of age. Adverse reactions reported by ≥1% of subjects treated with ALTRENO and more frequently than vehicle are summarized in Table 1.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 1: Adverse Reactions Reported by ≥1% of Subjects Treated with ALTRENO and More Frequently than Vehicle</span> </caption> <col width="37%"/> <col width="33%"/> <col width="30%"/> <thead> <tr class="First"> <th align="center" class="Botrule Lrule Rrule Toprule" colspan="3" valign="bottom"><span class="Bold">Adverse Reactions </span> <br/> <span class="Bold">n (%)</span></th> </tr> <tr class="Last"> <th align="left" class="Botrule Lrule Rrule" valign="bottom"></th><th align="center" class="Botrule Lrule Rrule" valign="bottom"><span class="Bold">ALTRENO </span> <br/> <span class="Bold">N=767</span></th><th align="center" class="Botrule Lrule Rrule" valign="bottom"><span class="Bold">Vehicle </span> <br/> <span class="Bold">N=783</span></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>Application site pain defined as application site stinging, burning or pain.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">Application site dryness</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">29 (4)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First">1 (&lt;1)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="bottom"> <p class="First">Application site pain<a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> <p class="First">25 (3)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> <p class="First">3 (&lt;1)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="bottom"> <p class="First">Application site erythema</p> </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> <p class="First">12 (2)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> <p class="First">1 (&lt;1)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="bottom"> <p class="First">Application site irritation</p> </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> <p class="First">7 (1)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> <p class="First">1 (&lt;1)</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="bottom"> <p class="First">Application site exfoliation</p> </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> <p class="First">6 (1)</p> </td><td class="Botrule Lrule Rrule" valign="bottom"> <dl> <dt> </dt> <dd>3 (&lt;1)</dd> </dl> </td> </tr> </tbody> </table></div>

Skin irritation was evaluated by active assessment of erythema, scaling, hypopigmentation, hyperpigmentation, itching, burning and stinging. The percentage of subjects who were assessed to have these signs and symptoms at any post baseline visit are summarized in Table 2.

<div class="scrollingtable"><table cellpadding="0pt" width="100%"> <caption> <span>Table 2: Application Site Tolerability Reactions at Any Post Baseline Visit</span> </caption> <col width="35%"/> <col width="32%"/> <col width="32%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">ALTRENO</span> </p> <p> <span class="Bold">N=760</span> </p> <p> <span class="Bold">Mild/Mod/Severe</span> </p> </td><td align="center" class="Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Vehicle</span> </p> <p> <span class="Bold">N=782</span> </p> <p> <span class="Bold">Mild/Mod/Severe</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Erythema</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">51%</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">44%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Scaling</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">49%</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">30%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Hypopigmentation</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">12%</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">10%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Hyperpigmentation</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">35%</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">35%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Itching</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">35%</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">28%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Burning</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">30%</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">14%</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Stinging</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">21%</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">8%</p> </td> </tr> </tbody> </table></div>

Risk Summary

Available data from published observational studies of topical tretinoin in pregnant women have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are no data on ALTRENO use in pregnant women.

The systemic levels following topical administration are lower than with administration of oral tretinoin; however, absorption of this product may result in fetal exposure. There are reports of major birth defects similar to those seen in infants exposed to oral retinoids, but these case reports do not establish a pattern or association with tretinoin-related embryopathy (see Data).

Animal reproduction studies have not been conducted with ALTRENO. Topical administration of tretinoin in a different formulation to pregnant rats during organogenesis was associated with malformations (craniofacial abnormalities [hydrocephaly], asymmetrical thyroids, variations in ossification, and increased supernumerary ribs) at doses up to 0.5 mg tretinoin/kg/day, approximately 2 times the maximum recommended human dose (MRHD) based on body surface area (BSA) comparison and assuming 100% absorption. Oral administration of tretinoin to pregnant cynomolgus monkeys during organogenesis was associated with malformations at 10 mg/kg/day (approximately 100 times the MRHD based on BSA comparison and assuming 100% absorption) (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of major birth defects, loss, and other adverse outcomes. The background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies.

Data

Human Data

While available studies cannot definitively establish the absence of risk, published data from multiple prospective controlled observational studies on the use of topical tretinoin products during pregnancy have not identified an association with topical tretinoin and major birth defects or miscarriage. The available studies have methodologic limitations, including small sample size and in some cases, lack of physical exam by an expert in birth defects. There are published case reports of infants exposed to topical tretinoin during the first trimester that describe major birth defects similar to those seen in infants exposed to oral retinoids; however, no pattern of malformations has been identified and no causal association has been established in these cases. The significance of these spontaneous reports in terms of risk to the fetus is not known.

Animal Data

Tretinoin in a 0.05% gel formulation was topically administered to pregnant rats during organogenesis at doses of 0.1, 0.3 and 1 g/kg/day (0.05, 0.15, 0.5 mg tretinoin/kg/day). Possible tretinoin malformations (craniofacial abnormalities [hydrocephaly], asymmetrical thyroids, variations in ossification, and increased supernumerary ribs) were observed at maternal doses of 0.5 mg tretinoin/kg/day (approximately 2 times the MRHD based on BSA comparison and assuming 100% absorption). These findings were not observed in control animals. Other maternal and reproductive parameters in tretinoin-treated animals were not different from control. For purposes of comparison of the animal exposure to human exposure, the MRHD is defined as 4 g of ALTRENO applied daily to a 60 kg person.

Other topical tretinoin embryofetal development studies have generated equivocal results. There is evidence for malformations (shortened or kinked tail) after topical administration of tretinoin to pregnant Wistar rats during organogenesis at doses greater than 1 mg/kg/day (approximately 5 times the MRHD based on BSA comparison and assuming 100% absorption). Anomalies (humerus: short 13%, bent 6%, os parietal incompletely ossified 14%) have also been reported when 10 mg/kg/day (approximately 50 times the MRHD based on BSA comparison and assuming 100% absorption) was topically applied to pregnant rats during organogenesis. Supernumerary ribs have been a consistent finding in rat fetuses when pregnant rats were treated topically or orally with retinoids.

Oral administration of tretinoin during organogenesis has been shown to induce malformations in rats, mice, rabbits, hamsters, and nonhuman primates. Fetal malformations were observed when tretinoin was orally administered to pregnant Wistar rats during organogenesis at doses greater than 1 mg/kg/day (approximately 5 times the MRHD based on BSA comparison). In the cynomolgus monkey, fetal malformations were reported when an oral dose of 10 mg/kg/day was administered to pregnant monkeys during organogenesis (approximately 100 times the MRHD based on BSA comparison). No fetal malformations were observed at an oral dose of 5 mg/kg/day (approximately 50 times the MRHD based on BSA comparison). Increased skeletal variations were observed at all doses in this study and dose-related increases in embryo lethality and abortion were reported in this study. Similar results have also been reported in pigtail macaques.

Oral tretinoin has been shown to be fetotoxic in rats when administered at doses 10 times the MRHD based on BSA comparison. Topical tretinoin has been shown to be fetotoxic in rabbits when administered at doses 4 times the MRHD based on BSA comparison.

Risk Summary

There are no data on the presence of tretinoin or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. It is not known whether topical administration of tretinoin could result in sufficient systemic absorption to produce detectable concentrations in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ALTRENO and any potential adverse effects on the breastfed child from ALTRENO.

Safety and effectiveness of ALTRENO for the topical treatment of acne vulgaris have been established in pediatric patients age 9 years to less than 17 years based on evidence from two multicenter, randomized, double-blind, parallel-group, vehicle-controlled, 12-week trials and an open-label pharmacokinetic study. A total of 318 pediatric subjects aged 9 to less than 17 years received ALTRENO in the clinical studies [see Clinical Pharmacology (12.3) and Clinical Studies (14)].

The safety and effectiveness of ALTRENO in pediatric patients below the age of 9 years have not been established.

Clinical trials of ALTRENO did not include any subjects age 65 years and older to determine whether they respond differently from younger subjects.

ALTRENO (tretinoin) lotion is an opaque, pale yellow lotion containing 0.05% tretinoin by weight for topical administration.

{ "type": "p", "children": [], "text": "ALTRENO (tretinoin) lotion is an opaque, pale yellow lotion containing 0.05% tretinoin by weight for topical administration. " }

Chemically, tretinoin is all-trans-retinoic acid, also known as (all-E)-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoic acid. It is a member of the retinoid class of compounds and a metabolite of vitamin A. Tretinoin has the following chemical structure:

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Molecular Formula: C20H28O2 Molecular Weight: 300.44

{ "type": "p", "children": [], "text": "Molecular Formula: C20H28O2 Molecular Weight: 300.44" }

Each gram of ALTRENO contains 0.5 mg (0.05%) of tretinoin in an opaque, pale yellow lotion base consisting of benzyl alcohol, butylated hydroxytoluene, carbomer copolymer type B (Pemulen TR-1), carbomer homopolymer type A (Carbopol 981), glycerin, methylparaben, mineral oil, octoxynol-9, purified water, sodium hyaluronate, soluble collagen and trolamine.

{ "type": "p", "children": [], "text": "Each gram of ALTRENO contains 0.5 mg (0.05%) of tretinoin in an opaque, pale yellow lotion base consisting of benzyl alcohol, butylated hydroxytoluene, carbomer copolymer type B (Pemulen TR-1), carbomer homopolymer type A (Carbopol 981), glycerin, methylparaben, mineral oil, octoxynol-9, purified water, sodium hyaluronate, soluble collagen and trolamine." }

Tretinoin is a metabolite of vitamin A that binds with high affinity to specific retinoic acid receptors located in both the cytosol and nucleus.

Tretinoin activates three members of the retinoic acid (RAR) nuclear receptors (RARα, RARβ, and RARγ) which act to modify gene expression, subsequent protein synthesis, and epithelial cell growth and differentiation. It has not been established whether the clinical effects of tretinoin are mediated through activation of retinoic acid receptors, other mechanisms, or both.

Although the exact mode of action of tretinoin in acne treatment is unknown, current evidence suggests that topical tretinoin decreases cohesiveness of follicular epithelial cells with decreased microcomedo formation. Additionally, tretinoin stimulates mitotic activity and increased turnover of follicular epithelial cells causing extrusion of the comedones.

The pharmacodynamics of ALTRENO in the treatment of acne vulgaris are unknown.

Plasma concentrations of tretinoin and its major metabolites (isotretinoin and 4-oxo-isotretinoin) were evaluated in 20 subjects in an open-label, randomized, pharmacokinetic study. Subjects aged 10 years to less than 17 years old with acne vulgaris applied approximately 3.5 g of ALTRENO to the skin of the entire face (excluding eyes and lips), neck, upper chest, upper back and shoulders once daily for 14 days. Single-dose pharmacokinetic (PK) characteristics were determined from samples drawn on Days 1 and 2 of dosing and steady-state PK characteristics were determined from samples drawn on Days 14 and 15 under maximal use conditions. The mean baseline corrected Cmax and AUC0-t of tretinoin and its metabolites after once daily application of ALTRENO for 14 days are shown below:

<div class="scrollingtable"><table width="75.22%"> <col width="30%"/> <col width="29%"/> <col width="29%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Compound</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Mean (±SD) C<span class="Sub">max</span></span> <br/> <span class="Bold"> (ng/mL)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Mean (±SD) AUC<span class="Sub">0-t </span>(ng*h/mL)</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">Tretinoin</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">0.33 (0.33)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">6.46 (5.15)</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">Isotretinoin</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">0.49 (0.66)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">9.30 (9.95)</p> </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">4-oxo-isotretinoin</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">0.57 (0.82)</p> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">14.51 (18.28)</p> </td> </tr> </tbody> </table></div>

The mean concentrations of tretinoin and its metabolites (isotretinoin and 4‑oxo‑isotretinoin) remain relatively stable and unchanged over the 24‑hour period after both the Day 1 dose and the Day 14 dose. Systemic concentrations of tretinoin appear to be at or near steady state by Day 14. Mean accumulation ratios of the baseline corrected AUC between Day 14 and Day 1 were 1.5, 4.5 and 7.3 for tretinoin, isotretinoin, and 4-oxo-isotretinoin, respectively.

A 2-year dermal mouse carcinogenicity study was conducted with topical administration of 0.005%, 0.025% and 0.05% of a tretinoin gel formulation. Although no drug-related tumors were observed in surviving animals, the irritating nature of the drug product precluded daily dosing, confounding data interpretation and reducing the biological significance of these results.

Studies in hairless albino mice with a different formulation suggest that concurrent exposure to tretinoin may enhance the tumorigenic potential of carcinogenic doses of UVB and UVA light from a solar simulator. This effect was confirmed in a later study in pigmented mice, and dark pigmentation did not overcome the enhancement of photocarcinogenesis by 0.05% tretinoin. Although the significance of these studies to humans is not clear, patients should minimize exposure to sunlight or artificial ultraviolet irradiation sources.

The genotoxic potential of tretinoin was evaluated in an in vitro bacterial reversion test, an in vitro chromosomal aberration assay in human lymphocytes and an in vivo rat micronucleus assay. All tests were negative.

In dermal fertility studies of another tretinoin formulation in rats, slight (not statistically significant) decreases in sperm count and motility were seen at 0.5 mg/kg/day (approximately 2 times the MRHD based on BSA comparison and assuming 100% absorption), and slight (not statistically significant) increases in the number and percent of nonviable embryos in females treated with 0.25 mg/kg/day and above (approximately the MRHD based on BSA comparison and assuming 100% absorption) were observed.

The safety and efficacy of once daily use of ALTRENO for the treatment of acne vulgaris were assessed in two multicenter, randomized, double-blind clinical trials enrolling 1640 subjects age 9 years and older with acne vulgaris. Enrolled subjects had a score of moderate (3) or severe (4) on the Evaluator’s Global Severity Score (EGSS), 20 to 40 inflammatory lesions (papules, pustules, and nodules), 20 to 100 non-inflammatory lesions (open and closed comedones) and two or fewer facial nodules. The coprimary efficacy endpoints of success on the EGSS, absolute change in noninflammatory lesion count, and absolute change in inflammatory lesion count were assessed at Week 12. Success on the EGSS was defined as at least a 2-grade improvement from Baseline and an EGSS score of clear (0) or almost clear (1). Table 3 lists the efficacy results for trials 1 (NCT02491060) and 2 (NCT02535871).

{ "type": "p", "children": [], "text": "The safety and efficacy of once daily use of ALTRENO for the treatment of acne vulgaris were assessed in two multicenter, randomized, double-blind clinical trials enrolling 1640 subjects age 9 years and older with acne vulgaris. Enrolled subjects had a score of moderate (3) or severe (4) on the Evaluator’s Global Severity Score (EGSS), 20 to 40 inflammatory lesions (papules, pustules, and nodules), 20 to 100 non-inflammatory lesions (open and closed comedones) and two or fewer facial nodules. The coprimary efficacy endpoints of success on the EGSS, absolute change in noninflammatory lesion count, and absolute change in inflammatory lesion count were assessed at Week 12. Success on the EGSS was defined as at least a 2-grade improvement from Baseline and an EGSS score of clear (0) or almost clear (1). Table 3 lists the efficacy results for trials 1 (NCT02491060) and 2 (NCT02535871)." }

<div class="scrollingtable"><table width="80%"> <caption> <span>Table 3: Efficacy Results at Week 12</span> </caption> <col width="37%"/> <col width="28%"/> <col width="28%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Toprule" valign="top"> <p class="First"> <span class="Bold">Trial 1</span> </p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First"> <span class="Bold">ALTRENO </span> <br/> <span class="Bold">N=406</span> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Vehicle</span> <br/> <span class="Bold">N=414</span> </p> </td> </tr> <tr> <td class="Lrule" valign="top"> <p class="First"> <span class="Bold">EGSS</span> </p> </td><td valign="top"></td><td class="Rrule" valign="top"></td> </tr> <tr> <td class="Lrule" valign="top"> <p class="First">Clear or Almost Clear and</p> </td><td align="center" valign="top"> <p class="First">16.5%</p> </td><td align="center" class="Rrule" valign="top"> <p class="First">6.9%</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First">2-Grade Reduction from Baseline</p> </td><td class="Botrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Lrule" valign="top"> <p class="First"> <span class="Bold">Non-Inflammatory Facial Lesions</span> </p> </td><td valign="top"></td><td class="Rrule" valign="top"></td> </tr> <tr> <td class="Lrule" valign="top"> <p class="First">  Mean Absolute Reduction</p> </td><td align="center" valign="top"> <p class="First">17.8</p> </td><td align="center" class="Rrule" valign="top"> <p class="First">10.6</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First">  Mean Percent Reduction</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">47.5%</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">27.3%</p> </td> </tr> <tr> <td class="Lrule" valign="top"> <p class="First"> <span class="Bold">Inflammatory Facial Lesions</span> </p> </td><td valign="top"></td><td class="Rrule" valign="top"></td> </tr> <tr> <td class="Lrule" valign="top"> <p class="First">  Mean Absolute Reduction</p> </td><td align="center" valign="top"> <p class="First">13.1</p> </td><td align="center" class="Rrule" valign="top"> <p class="First">10.2</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First">  Mean Percent Reduction</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">50.9%</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">40.4%</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First"> <span class="Bold">Trial 2</span> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First"> <span class="Bold">ALTRENO </span> <br/> <span class="Bold">N=413</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Vehicle</span> <br/> <span class="Bold">N=407</span> </p> </td> </tr> <tr> <td class="Lrule" valign="top"> <p class="First"> <span class="Bold">EGSS</span> </p> </td><td valign="top"></td><td class="Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First">Clear or Almost Clear and </p> <p>2-Grade Reduction from Baseline</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">19.8%</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">12.5%</p> </td> </tr> <tr> <td class="Lrule" valign="top"> <p class="First"> <span class="Bold">Non-Inflammatory Facial Lesions</span> </p> </td><td valign="top"></td><td class="Rrule" valign="top"></td> </tr> <tr> <td class="Lrule" valign="top"> <p class="First">  Mean Absolute Reduction</p> </td><td align="center" valign="top"> <p class="First">21.9</p> </td><td align="center" class="Rrule" valign="top"> <p class="First">13.9</p> </td> </tr> <tr> <td class="Botrule Lrule" valign="top"> <p class="First">  Mean Percent Reduction</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">45.6%</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">31.9%</p> </td> </tr> <tr> <td class="Lrule" valign="top"> <p class="First"> <span class="Bold">Inflammatory Facial Lesions</span> </p> </td><td valign="top"></td><td class="Rrule" valign="top"></td> </tr> <tr> <td class="Lrule" valign="top"> <p class="First">  Mean Absolute Reduction</p> </td><td align="center" valign="top"> <p class="First">13.9</p> </td><td align="center" class="Rrule" valign="top"> <p class="First">10.7</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule" valign="top"> <p class="First">  Mean Percent Reduction</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">53.4%</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">41.5%</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"80%\">\n<caption>\n<span>Table 3: Efficacy Results at Week 12</span>\n</caption>\n<col width=\"37%\"/>\n<col width=\"28%\"/>\n<col width=\"28%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Lrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Trial 1</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">ALTRENO </span>\n<br/>\n<span class=\"Bold\">N=406</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Vehicle</span>\n<br/>\n<span class=\"Bold\">N=414</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">EGSS</span>\n</p>\n</td><td valign=\"top\"></td><td class=\"Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\">\n<p class=\"First\">Clear or Almost Clear and</p>\n</td><td align=\"center\" valign=\"top\">\n<p class=\"First\">16.5%</p>\n</td><td align=\"center\" class=\"Rrule\" valign=\"top\">\n<p class=\"First\">6.9%</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule\" valign=\"top\">\n<p class=\"First\">2-Grade Reduction from Baseline</p>\n</td><td class=\"Botrule\" valign=\"top\"></td><td class=\"Botrule Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Non-Inflammatory Facial Lesions</span>\n</p>\n</td><td valign=\"top\"></td><td class=\"Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\">\n<p class=\"First\">  Mean Absolute Reduction</p>\n</td><td align=\"center\" valign=\"top\">\n<p class=\"First\">17.8</p>\n</td><td align=\"center\" class=\"Rrule\" valign=\"top\">\n<p class=\"First\">10.6</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule\" valign=\"top\">\n<p class=\"First\">  Mean Percent Reduction</p>\n</td><td align=\"center\" class=\"Botrule\" valign=\"top\">\n<p class=\"First\">47.5%</p>\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">27.3%</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Inflammatory Facial Lesions</span>\n</p>\n</td><td valign=\"top\"></td><td class=\"Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\">\n<p class=\"First\">  Mean Absolute Reduction</p>\n</td><td align=\"center\" valign=\"top\">\n<p class=\"First\">13.1</p>\n</td><td align=\"center\" class=\"Rrule\" valign=\"top\">\n<p class=\"First\">10.2</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule\" valign=\"top\">\n<p class=\"First\">  Mean Percent Reduction</p>\n</td><td align=\"center\" class=\"Botrule\" valign=\"top\">\n<p class=\"First\">50.9%</p>\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">40.4%</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Trial 2</span>\n</p>\n</td><td align=\"center\" class=\"Botrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">ALTRENO </span>\n<br/>\n<span class=\"Bold\">N=413</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Vehicle</span>\n<br/>\n<span class=\"Bold\">N=407</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">EGSS</span>\n</p>\n</td><td valign=\"top\"></td><td class=\"Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule\" valign=\"top\">\n<p class=\"First\">Clear or Almost Clear and </p>\n<p>2-Grade Reduction from Baseline</p>\n</td><td align=\"center\" class=\"Botrule\" valign=\"top\">\n<p class=\"First\">19.8%</p>\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">12.5%</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Non-Inflammatory Facial Lesions</span>\n</p>\n</td><td valign=\"top\"></td><td class=\"Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\">\n<p class=\"First\">  Mean Absolute Reduction</p>\n</td><td align=\"center\" valign=\"top\">\n<p class=\"First\">21.9</p>\n</td><td align=\"center\" class=\"Rrule\" valign=\"top\">\n<p class=\"First\">13.9</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule\" valign=\"top\">\n<p class=\"First\">  Mean Percent Reduction</p>\n</td><td align=\"center\" class=\"Botrule\" valign=\"top\">\n<p class=\"First\">45.6%</p>\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">31.9%</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Inflammatory Facial Lesions</span>\n</p>\n</td><td valign=\"top\"></td><td class=\"Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\">\n<p class=\"First\">  Mean Absolute Reduction</p>\n</td><td align=\"center\" valign=\"top\">\n<p class=\"First\">13.9</p>\n</td><td align=\"center\" class=\"Rrule\" valign=\"top\">\n<p class=\"First\">10.7</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule\" valign=\"top\">\n<p class=\"First\">  Mean Percent Reduction</p>\n</td><td align=\"center\" class=\"Botrule\" valign=\"top\">\n<p class=\"First\">53.4%</p>\n</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">41.5%</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

ALTRENO (tretinoin) lotion, 0.05% is an opaque, pale yellow topical lotion and available as:

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Storage and Handling Conditions

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Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Protect from freezing.

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Store pump upright.

{ "type": "p", "children": [], "text": "Store pump upright." }

Advise the patient to read the FDA-approved patient labeling (Patient Information).

{ "type": "p", "children": [], "text": "Advise the patient to read the FDA-approved patient labeling (Patient Information)." }

{ "type": "", "children": [], "text": "" }

Distributed by: Bausch Health US, LLCBridgewater, NJ 08807 USA

{ "type": "p", "children": [], "text": "\nDistributed by:\nBausch Health US, LLCBridgewater, NJ 08807 USA" }

Manufactured by: Bausch Health Companies Inc.Laval, Quebec H7L 4A8, Canada

{ "type": "p", "children": [], "text": "\nManufactured by:\nBausch Health Companies Inc.Laval, Quebec H7L 4A8, Canada " }

{ "type": "", "children": [], "text": "" }

PATIENT INFORMATIONALTRENO® (al-TREN-oh)(tretinoin) lotion, 0.05%for topical use

{ "type": "p", "children": [], "text": "PATIENT INFORMATIONALTRENO® (al-TREN-oh)(tretinoin) lotion, 0.05%for topical use " }

Important information: ALTRENO is for use on skin only. Do not use ALTRENO in your eyes, mouth, the corners of your nose, or vagina.

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What is ALTRENO?

{ "type": "p", "children": [], "text": "\nWhat is ALTRENO?\n" }

ALTRENO is a prescription medicine used on the skin (topical) to treat people with acne. Acne is a condition in which the skin has blackheads, whiteheads, and other pimples.

{ "type": "p", "children": [], "text": "ALTRENO is a prescription medicine used on the skin (topical) to treat people with acne. Acne is a condition in which the skin has blackheads, whiteheads, and other pimples." }

It is not known if ALTRENO is safe and effective in children under 9 years of age.

{ "type": "p", "children": [], "text": "It is not known if ALTRENO is safe and effective in children under 9 years of age." }

Before using ALTRENO, tell your healthcare provider about all your medical conditions, including if you:

{ "type": "p", "children": [], "text": "\nBefore using ALTRENO, tell your healthcare provider about all your medical conditions, including if you:" }

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Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.

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How should I use ALTRENO?

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Applying ALTRENO:

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Tube: Squeeze the lotion from the tube onto a fingertip. Apply a thin layer to cover the affected areas, as prescribed by your doctor. Spread ALTRENO evenly over the affected areas.

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Pump: Fully depress the pump to dispense ALTRENO onto a fingertip. Apply a thin layer to cover the affected areas, as prescribed by your doctor. Spread ALTRENO evenly over the affected areas.

{ "type": "p", "children": [], "text": "\nPump: Fully depress the pump to dispense ALTRENO onto a fingertip. Apply a thin layer to cover the affected areas, as prescribed by your doctor. Spread ALTRENO evenly over the affected areas." }

{ "type": "", "children": [], "text": "" }

What should I avoid while using ALTRENO?

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What are the possible side effects of ALTRENO?

{ "type": "p", "children": [], "text": "\nWhat are the possible side effects of ALTRENO?\n" }

ALTRENO may cause serious side effects, including:

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Skin irritation. ALTRENO may cause irritation including skin dryness, pain, redness, excessive flaking or peeling. If you develop these symptoms, your healthcare provider may tell you to use a moisturizer, decrease the number of times you apply ALTRENO, or completely stop treatment with ALTRENO. Avoid applying ALTRENO to skin that is affected by eczema or sunburned skin.

{ "type": "p", "children": [], "text": "\nSkin irritation. ALTRENO may cause irritation including skin dryness, pain, redness, excessive flaking or peeling. If you develop these symptoms, your healthcare provider may tell you to use a moisturizer, decrease the number of times you apply ALTRENO, or completely stop treatment with ALTRENO. Avoid applying ALTRENO to skin that is affected by eczema or sunburned skin." }

These are not all the possible side effects of ALTRENO.

{ "type": "p", "children": [], "text": "These are not all the possible side effects of ALTRENO." }

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

{ "type": "p", "children": [], "text": "Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088." }

How should I store ALTRENO?

{ "type": "p", "children": [], "text": "\nHow should I store ALTRENO?\n" }

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Keep ALTRENO and all medicines out of the reach of children.

{ "type": "p", "children": [], "text": "\nKeep ALTRENO and all medicines out of the reach of children.\n" }

General information about the safe and effective use of ALTRENO

{ "type": "p", "children": [], "text": "\nGeneral information about the safe and effective use of ALTRENO\n" }

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ALTRENO for a condition for which it was not prescribed. Do not give ALTRENO to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about ALTRENO that is written for health professionals.

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What are the ingredients in ALTRENO?

{ "type": "p", "children": [], "text": "\nWhat are the ingredients in ALTRENO?\n" }

Active ingredient: tretinoin

{ "type": "p", "children": [], "text": "\nActive ingredient: tretinoin " }

Inactive ingredients: benzyl alcohol, butylated hydroxytoluene, carbomer copolymer type B (Pemulen TR-1), carbomer homopolymer type A (Carbopol 981), glycerin, methylparaben, mineral oil, octoxynol-9, purified water, sodium hyaluronate, soluble collagen and trolamine.

{ "type": "p", "children": [], "text": "\nInactive ingredients: benzyl alcohol, butylated hydroxytoluene, carbomer copolymer type B (Pemulen TR-1), carbomer homopolymer type A (Carbopol 981), glycerin, methylparaben, mineral oil, octoxynol-9, purified water, sodium hyaluronate, soluble collagen and trolamine." }

Distributed by: Bausch Health US, LLC, Bridgewater, NJ 08807 USA

{ "type": "p", "children": [], "text": "\nDistributed by:\nBausch Health US, LLC, Bridgewater, NJ 08807 USA" }

Manufactured by: Bausch Health Companies Inc., Laval, Quebec H7L 4A8, Canada

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For more information, call 1-800-321-4576.

{ "type": "p", "children": [], "text": "For more information, call 1-800-321-4576." }

ALTRENO is a trademark of Bausch Health Companies Inc. or its affiliates.

{ "type": "p", "children": [], "text": "ALTRENO is a trademark of Bausch Health Companies Inc. or its affiliates." }

© 2020 Bausch Health Companies Inc. or its affiliates

{ "type": "p", "children": [], "text": "© 2020 Bausch Health Companies Inc. or its affiliates" }

This Patient Information has been approved by the U.S. Food and Drug Administration.

{ "type": "p", "children": [], "text": "This Patient Information has been approved by the U.S. Food and Drug Administration." }

9650303

{ "type": "p", "children": [], "text": "9650303" }

Revised: 03/2020

{ "type": "p", "children": [], "text": "Revised: 03/2020" }

NDC 0187-0005-20

{ "type": "p", "children": [], "text": "\nNDC 0187-0005-20" }

For Topical Use Only Not for Eye Use

{ "type": "p", "children": [], "text": "\nFor Topical Use Only\n\nNot for Eye Use\n" }

ALTRENO® (tretinoin) Lotion, 0.05%

{ "type": "p", "children": [], "text": "\nALTRENO®\n(tretinoin) Lotion, 0.05% " }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

Net Wt. 20 g

{ "type": "p", "children": [], "text": "\nNet Wt. 20 g\n" }

Ortho Dermatologics

{ "type": "p", "children": [], "text": "\nOrtho Dermatologics\n" }

Tretinoin capsules are indicated for the induction of remission in adults and pediatric patients 1 year of age and older with acute promyelocytic leukemia (APL) characterized by the presence of the t(15;17) translocation or PML/RARα gene expression, and who are refractory to or who have relapsed from anthracycline chemotherapy or for whom anthracycline-based chemotherapy is contraindicated.

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Verify pregnancy status in females of reproductive potential prior to initiating tretinoin capsules. Females of reproductive potential must have a negative pregnancy test before initiating tretinoin capsules [see Use in Specific Populations (8.3)].

The recommended dosage of tretinoin capsules is 22.5 mg/m2 orally twice daily until complete remission is documented. Discontinue tretinoin capsules 30 days after achievement of complete remission or after 90 days of treatment, whichever occurs first.

Discontinue tretinoin capsules if the t(15;17) translocation or PML/RARα fusion has not been identified [see Warnings and Precautions (5.3)].

Take tretinoin capsules with a meal.

Swallow tretinoin capsules whole with water. Do not chew, dissolve, or open capsule.

Do not take a missed dose of tretinoin capsules unless it is more than 10 hours until the next scheduled dose.

If vomiting occurs after tretinoin capsules administration, do not take an additional dose, but continue with the next scheduled dose.

Capsules: 10 mg, two-tone (lengthwise) with reddish-brown opaque and yellow gelatin shell, imprinted with “TR” with black ink on the yellow side.

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Tretinoin capsules are contraindicated in patients with a known hypersensitivity to tretinoin capsules, any of its components, or other retinoids. Reactions have included rash, pruritus, face edema, and dyspnea [see Adverse Reactions (6.1)].

{ "type": "p", "children": [], "text": "Tretinoin capsules are contraindicated in patients with a known hypersensitivity to tretinoin capsules, any of its components, or other retinoids. Reactions have included rash, pruritus, face edema, and dyspnea [see Adverse Reactions (6.1)].\n" }

Tretinoin capsules can cause embryo-fetal loss and malformations when administered to a pregnant woman. Tretinoin capsules are a retinoid and there is an increased risk of major congenital malformations, spontaneous abortions and premature births following exposure to retinoids during pregnancy in humans. Tretinoin has teratogenic and embryotoxic effects in mice, rats, hamsters, rabbits and pigtail monkeys at doses less than the human dose on a mg/m2 basis.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use 2 effective methods of contraception during treatment with tretinoin capsules and for 1 month following the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with tretinoin capsules and for 1 week following the last dose [see Use in Specific Populations (8.1, 8.3)].

Differentiation Syndrome, which may be life-threatening or fatal, occurred in about 26% of patients with APL who received tretinoin capsules [see Adverse Reactions (6.1)]. Symptoms include fever, dyspnea, acute respiratory distress, weight gain, radiographic pulmonary infiltrates, pleural and pericardial effusions, edema, and hepatic, renal, and multi-organ failure. This syndrome has been accompanied by impaired myocardial contractility and episodic hypotension and it has been observed with or without concomitant leukocytosis. This syndrome generally occurs during the first month of treatment, as early as following the first dose. Endotracheal intubation and mechanical ventilation were required in some cases due to progressive hypoxemia and several patients have died with multi-organ failure.

At the first signs or symptoms of this syndrome, immediately administer dexamethasone 10 mg intravenously every 12 hours until signs and symptoms have abated for at least 3 days and initiate hemodynamic monitoring until resolution of signs and symptoms. Consider withholding tretinoin capsules for moderate and severe differentiation syndrome until resolution [see Adverse Reactions (6.1)].

Tretinoin capsules may be initiated based on the morphological diagnosis of acute promyelocytic leukemia (APL). Confirm the diagnosis of APL by detection of the t(15;17) translocation using cytogenetic studies or PML/RARα fusion using molecular diagnostic techniques. Tretinoin capsules are not recommended for use in patients without these genetic markers [see Indications and Usage (1)].

Rapidly evolving leukocytosis, which can be life-threatening, occurred in about 40% of patients with APL who received tretinoin capsules [see Adverse Reactions (6.1)]. Patients who present with a baseline white blood cell count (WBC) > 5 × 109/L have an increased risk. Patients who receive chemotherapy with tretinoin capsules may be at a reduced risk. Rapidly evolving leukocytosis is associated with a higher risk of life-threatening complications.

Consider administering cytoreductive chemotherapy (including an anthracycline if not contraindicated or hydroxyurea) with tretinoin capsules in the setting of leukocytosis, as clinically indicated.

Retinoids, including tretinoin capsules, have been associated with intracranial hypertension, especially in pediatric patients. Early signs and symptoms include papilledema, headache, nausea, vomiting, and visual disturbances. Evaluate patients with these symptoms for intracranial hypertension, and, if present, institute appropriate care in concert with neurological assessment. Consider interruption, dose reduction, or discontinuation of tretinoin capsules as appropriate.

The concomitant use of other products (e.g., tetracyclines) that can cause intracranial hypertension may increase the risk. Avoid concomitant use of tretinoin capsules with other products that can cause intracranial hypertension [see Drug Interactions (7.2)].

Hypercholesterolemia and/or hypertriglyceridemia has occurred in up to 60% of patients who received tretinoin capsules. These changes may be reversible upon completion of treatment. The clinical consequences of increased triglycerides and cholesterol are unknown, but venous thrombosis and myocardial infarction have been reported in patients who ordinarily are at low risk for such complications.

Monitor fasting triglycerides and cholesterol at baseline and periodically during treatment.

Elevated liver function test results occurred in 50% to 60% of patients during treatment with tretinoin capsules. Most of these abnormalities resolved without interruption of tretinoin capsules or after completion of treatment.

Monitor liver function test at baseline and during treatment as clinically indicated. Consider withholding tretinoin capsules if liver function test results increase to greater than 5 times the upper limit of normal values until resolution.

Venous and arterial thromboembolic events, including cerebrovascular accident, myocardial infarction and renal infarct have been reported with tretinoin capsules [see Adverse Reactions (6.2)]. These events may occur during the first month of treatment. Patients taking anti-fibrinolytic agents may have an increased risk.

Avoid concomitant use of tretinoin capsules and anti-fibrinolytic agents, such as tranexamic acid, aminocaproic acid or aprotinin [see Drug Interactions (7.4)].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Acute Promyelocytic Leukemia

The safety of tretinoin capsules was evaluated in patients with APL who received tretinoin capsules at a dose of 22.5 mg/m2 orally twice daily [see Clinical Studies (14)].

The most common adverse reactions (≥30%) were headache, fever, skin/mucous membrane dryness, bone pain, malaise, shivering, upper respiratory tract disorders, dyspnea, hemorrhage, infections, nausea/vomiting, rash, peripheral edema, leukocytosis, pain, gastrointestinal hemorrhage, chest discomfort, abdominal pain.

Table 1 summarizes the adverse reactions for patients with APL.

Table 1. Adverse Reactions (≥ 10%) Occurring in Patients with APL Who Received Tretinoin Capsules

<div class="scrollingtable"><table width="100%"> <col width="50%"/> <col width="50%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"> <p class="First"> <span class="Bold">Adverse Reaction</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Tretinoin Capsules</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">  </p> <p> <span class="Bold">            All Grades</span> </p> <p> <span class="Bold">(%)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Nervous system disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Headache</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 86</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Dizziness</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 20</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Paresthesias</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 17</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Anxiety</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 17</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Insomnia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 14</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Depression</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 14</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Confusion</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 11</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">General disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Fever</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 83</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Skin/mucous membrane dryness</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 77</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Malaise</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 66</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Shivering</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 63</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Peripheral edema</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 52</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Pain</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 37</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Chest discomfort</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 32</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Edema</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 29</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Mucositis</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 26</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Weight increase</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 23</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Anorexia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 17</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Weight decrease</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 17</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Musculoskeletal and connective tissue disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Bone pain</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 77</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Myalgia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 14</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Respiratory, thoracic and mediastinal disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Upper respiratory tract disorders</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 63</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Dyspnea</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 60</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Respiratory insufficiency</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 26</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Pleural effusion</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 20</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Rales</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 14</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Expiratory wheezing</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 14</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Pneumonia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 14</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Vascular disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Hemorrhage</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 60</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Gastrointestinal hemorrhage</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 34</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Flushing</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 23</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Hypotension</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 14</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Hypertension</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 11</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Phlebitis</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 11</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Infections and infestations</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Infections</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 58</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Gastrointestinal disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Nausea/vomiting</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 57</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Abdominal pain</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 31</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Other gastrointestinal disorders</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 26</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Diarrhea</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 23</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Constipation</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 17</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Dyspepsia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 14</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Abdominal distention</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 11</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Skin and subcutaneous tissue disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Rash</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 54</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Pruritus</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 20</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Increased sweating</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 20</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Alopecia</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 14</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Skin changes</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 14</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Blood and lymphatic system disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Leukocytosis</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 49</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Differentiation syndrome<span class="Sup">1</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 26</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Disseminated intravascular coagulation</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 26</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Ear and labyrinth disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Earache or feeling of fullness in the ears</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 23</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Cardiac disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Arrhythmias</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 23</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Eye disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Visual disturbances</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 17</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Ocular disorders</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 17</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Renal and urinary disorders</span> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Renal insufficiency</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 11</p> </td> </tr> </tbody> </table></div>

1Differentiation syndrome can be associated with other commonly reported events such as fever, leukocytosis, dyspnea, pneumonia, pleural effusion, pericardial effusion, hypotension, edema, weight gain, and renal failure.

Adverse reactions that occurred in <10% of patients who received tretinoin capsules include:

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Erythema nodosum, basophilia and hyperhistaminemia, Sweet’s Syndrome, organomegaly, hypercalcemia, pancreatitis, myositis, thrombosis (both venous and arterial), thrombocytosis, genital ulceration and vasculitis, predominantly involving the skin.

Strong or moderate CYP3A Inhibitors

Avoid concomitant use of tretinoin capsules with strong CYP3A inhibitors if possible and monitor more frequently if concomitant use is unavoidable. Monitor patients taking moderate CYP3A inhibitors concomitantly with tretinoin capsules more frequently for adverse reactions.

Tretinoin is a CYP3A substrate. Concomitant use with a strong CYP3A4 inhibitor increases tretinoin plasma concentrations, which may increase the risk of adverse reactions [see Clinical Pharmacology (12.3)].

Strong CYP3A Inducers

Concomitant use of tretinoin capsules with strong CYP3A4 inducers may decrease tretinoin plasma concentrations, which may reduce its efficacy. Avoid concomitant use with strong CYP3A inducers if possible.

Intracranial hypertension has been reported in patients who received tretinoin capsules and concomitant use of other products that can cause intracranial hypertension, such as tetracyclines, may increase the risk. Avoid concomitant use of tretinoin capsules with other products agents that can cause intracranial hypertension [see Warnings and Precautions (5.5)].

The concomitant use of vitamin A with tretinoin capsules may lead to vitamin A related adverse reactions. Avoid concomitant use of tretinoin capsules with vitamin A.

Fatal thrombotic complications have been reported in patients who have received tretinoin capsules and concomitant use of anti-fibrinolytic agents may increase the risk. Avoid concomitant use of tretinoin capsules with anti-fibrinolytic agents [see Warnings and Precautions (5.8)].

Risk Summary

Based on findings in animals and its mechanism of action [see Clinical Pharmacology (12.1)], tretinoin capsules can cause embryo-fetal loss and malformations when administered to a pregnant woman. Tretinoin capsules are a retinoid and there is an increased risk of major congenital malformations, spontaneous abortions and premature births following exposure to retinoids during pregnancy in humans. Tretinoin was teratogenic and embryotoxic in mice, rats, hamsters, rabbits and pigtail monkeys at doses less than the human dose on a mg/m2 basis (see Data). Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Human Data

Tretinoin capsules are a retinoid and increased spontaneous abortions and major fetal abnormalities related to the use of retinoids have been documented in humans. Reported malformations include abnormalities of the central nervous system, musculoskeletal system, external ear, eye, thymus and great vessels; and facial dysmorphia, cleft palate, and parathyroid hormone deficiency. Some of these abnormalities were fatal. 

IQ scores less than 85, with or without obvious CNS abnormalities, have been reported in pediatrics exposed to retinoids in utero.

Animal Data

Tretinoin causes fetal resorptions and a decrease in live fetuses in all animals studied. Gross external, soft tissue and skeletal alterations occurred at doses higher than 0.7 mg/kg/day in mice, 2 mg/kg/day in rats, 7 mg/kg/day in hamsters, and at a dose of 10 mg/kg/day, the only dose tested, in pigtail monkeys (about 1/20, 1/4, and 1/2 and 4 times the human dose, respectively, on a mg/m2 basis).

There are no data on the presence of tretinoin in human milk, the effects on the breastfeed child or the effects on milk production. Because of the potential for serious adverse reactions from tretinoin capsules in breastfed infants, advise women not to breastfed during treatment with tretinoin capsules and for 1 week after the last dose.

Tretinoin capsules can cause embryo-fetal loss and malformations when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating tretinoin capsules. Females of reproductive potential must have a negative pregnancy test within 1 week prior to initiating tretinoin capsules with a sensitivity of at least 50 mIU/mL.

Contraception

Females

Advise females of reproductive potential to abstain continuously from sexual intercourse or to use two effective methods of contraception. Counsel patients to use two effective methods of contraception during treatment with tretinoin capsules and for 1 month after the last dose. Two methods of effective contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Refer females of reproductive potential to a qualified provider of contraceptive methods, if needed.

Males

Advise males with female partners of reproductive potential to use effective contraception during and after treatment with tretinoin capsules and for 1 week after the last dose.

Infertility

Males

Based on testicular toxicities observed in dogs, tretinoin capsules may impair male fertility [see Nonclinical Toxicology (13.1)]. The reversibility of effect on fertility is unknown.

Safety and effectiveness of tretinoin capsules have been established in pediatric patients 1 year of age and older and the information on this use is discussed throughout the labeling. The maximum tolerated dose is lower in pediatric patients compared to adults. Some pediatric patients experience severe headache and intracranial hypertension, which required management with an analgesic and a lumbar puncture. Dose reduction may be considered for pediatric patients experiencing serious and/or intolerable adverse reactions.

Safety and effectiveness in pediatric patients less than 1 year of age have not been established.

Across clinical studies of tretinoin capsules, 21% were 60 years and older. No overall differences in safety or effectiveness were observed between these patients and younger patients.

In case of overdose with tretinoin capsules, reversible signs of hypervitaminosis A (headache, nausea, vomiting, mucocutaneous symptoms) can appear. Overdosage with other retinoids has been associated with transient headache, facial flushing, cheilosis, abdominal pain, dizziness and ataxia. These symptoms have quickly resolved without apparent residual effects.

{ "type": "p", "children": [], "text": "In case of overdose with tretinoin capsules, reversible signs of hypervitaminosis A (headache, nausea, vomiting, mucocutaneous symptoms) can appear. Overdosage with other retinoids has been associated with transient headache, facial flushing, cheilosis, abdominal pain, dizziness and ataxia. These symptoms have quickly resolved without apparent residual effects." }

There is no specific treatment in the case of an overdose; however, it is important that the patient be treated in a special hematological unit.

{ "type": "p", "children": [], "text": "There is no specific treatment in the case of an overdose; however, it is important that the patient be treated in a special hematological unit." }

Tretinoin is a retinoid. The chemical name is all-trans retinoic acid. The molecular formula is C20H28O2 and the molecular weight is 300.44 g/mol. The structural formula is:

{ "type": "p", "children": [], "text": "Tretinoin is a retinoid. The chemical name is all-trans retinoic acid. The molecular formula is C20H28O2 and the molecular weight is 300.44 g/mol. The structural formula is:" }

It is a yellow to light orange, crystalline powder with melting point at about 182°C (with decomposition). Tretinoin is practically insoluble in water, sparingly soluble in methylene chloride, and slightly soluble in ethanol (96%).

{ "type": "p", "children": [], "text": "It is a yellow to light orange, crystalline powder with melting point at about 182°C (with decomposition). Tretinoin is practically insoluble in water, sparingly soluble in methylene chloride, and slightly soluble in ethanol (96%)." }

Tretinoin capsules are available as capsules containing 10 mg tretinoin for oral use. Each capsule also contains butylated hydroxyanisole, edetate disodium, soybean oil, hydrogenated vegetable oils, medium chain triglycerides, soya lecithin, and yellow beeswax. The gelatin capsule shell contains gelatin, glycerin, yellow iron oxide, red iron oxide and titanium dioxide. Capsules are printed with edible black ink, which consist of propylene glycol, iron oxide black, polyvinyl acetate phthalate and polyethylene glycol 400.

{ "type": "p", "children": [], "text": "Tretinoin capsules are available as capsules containing 10 mg tretinoin for oral use. Each capsule also contains butylated hydroxyanisole, edetate disodium, soybean oil, hydrogenated vegetable oils, medium chain triglycerides, soya lecithin, and yellow beeswax. The gelatin capsule shell contains gelatin, glycerin, yellow iron oxide, red iron oxide and titanium dioxide. Capsules are printed with edible black ink, which consist of propylene glycol, iron oxide black, polyvinyl acetate phthalate and polyethylene glycol 400. " }

Tretinoin induces cytodifferentiation and decreased proliferation of APL cells in culture and in vivo. In APL patients, tretinoin treatment produces an initial maturation of the primitive promyelocytes derived from the leukemic clone, followed by a repopulation of the bone marrow and peripheral blood by normal, polyclonal hematopoietic cells in patients achieving complete remission (CR). The exact mechanism of action of tretinoin in APL is unknown.

The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of tretinoin capsules have not been characterized.

Following the administration of tretinoin capsules 22.5 mg/m2 orally twice daily, the mean ± SD peak tretinoin concentrations after the first dose was 394 ± 89 and after 1 week of continuous treatment was 138 ± 139 ng/mL, while area under the curve (AUC) after the first dose was 537 ± 191 ng·h/mL and after 1 week of continuous treatment was 249 ± 185 ng·h/mL.

Absorption

Time to reach peak concentration was between 1 and 2 hours. The absolute bioavailability of tretinoin capsules was approximately 50%.

Effect of Food

The effect of food on the absorption of tretinoin capsules has not been characterized. Food increases the absorption of retinoids, as a class.

Distribution

The apparent volume of distribution of tretinoin has not been determined.

Protein binding is greater than 95%, predominately to albumin. Plasma protein binding remains constant over the concentration range of 10 to 500 ng/mL.

Elimination

The terminal elimination half-life of tretinoin following initial dosing is 0.5 to 2 hours in patients with APL.

Metabolism

Tretinoin induced its own metabolism with plasma concentrations after 1 week of continuous therapy decreased to one-third of their day 1 values. Tretinoin is metabolized by cytochrome P450 enzymes, CYP3A4, 2C8, and 2E and undergoes glucuronidation by UGT2B7. Metabolites include 9-cis retinoic acid, 13-cis retinoic acid, 4-oxo trans retinoic acid, 4-oxo cis retinoic acid, and 4-oxo trans retinoic acid glucuronide. The metabolites 4-oxo retinoic acid and 4-oxo trans retinoic acid glucuronide have one-third of the pharmacological activity of the parent compound.

Excretion

Following administration of radiolabeled tretinoin 2.75 mg and 50 mg (0.53 to 9.6 times the approved recommended dosage based on 1.7 m2), approximately 63% of radioactivity was recovered in the urine within 72 hours and 31% appeared in the feces within 6 days.

Specific Populations

The effect of age, sex, race, renal impairment, and hepatic impairment on the pharmacokinetics of tretinoin is unknown.

Drug Interaction Studies

Clinical Studies and Post Marketing Experience

Strong CYP3A inhibitors: Tretinoin AUC increased by 72% following concomitant use with ketoconazole (strong CYP3A inhibitor). Increased tretinoin toxicity has also been reported post-marketing with strong CYP3A inhibitors including certain antimycotics.

Moderate CYP3A Inhibitors: Increased tretinoin toxicity following concomitant use of tretinoin capsules with certain antimycotics that are moderate CYP3A4 inhibitors has been reported post-marketing.

In Vitro Studies

Effect of Tretinoin on Transporters: Tretinoin does not inhibit P-gp and BCRP in vitro.

No 2-year carcinogenicity studies in rodents have been conducted with tretinoin. In a carcinogenicity study, female B5D2F1 mice pretreated with a carcinogen diethylnitrosamine (DEN, intraperitoneal 50 mg/kg and 100 mg/kg) received dietary supplement of all-trans-retinoic acid (tretinoin) for 12 months. Tretinoin at a dose of 30 mg/kg/day in the diet (about 2 times the human dose on a mg/m2 basis) was shown to increase the rate of DEN-induced mouse hepatocellular carcinomas. Tretinoin in combination with 50 mg/kg of DEN also increased the incidence of hemangiomas and hemangiosarcomas.

Tretinoin was negative when tested in the Ames and Chinese hamster V79 cell HGPRT assays for mutagenicity. A 2-fold increase in the sister chromatid exchange (SCE) has been demonstrated in human diploid fibroblasts, but other chromosome aberration assays, including an in vitro assay in human peripheral lymphocytes and an in vivo mouse micronucleus assay, did not show a clastogenic or aneuploidogenic effect.

Adverse effects on fertility and reproductive performance were not observed in studies conducted in rats at doses up to 5 mg/kg/day (about 2/3 the human dose on a mg/m2 basis). In a 6-week toxicology study in dogs, testicular degeneration, with increased numbers of immature spermatozoa, were observed at 10 mg/kg/day (about 4 times the equivalent human dose in mg/m2).

The efficacy of tretinoin capsules has been evaluated in 114 previously treated patients and in 67 previously untreated (“de novo”) patients with APL in one open-label, uncontrolled single investigator clinical study (Memorial Sloan-Kettering Cancer Center [MSKCC]) and in two cohorts of compassionate cases treated by multiple investigators under the auspices of the National Cancer Institute (NCI). Patients received tretinoin capsules 22.5 mg/m2 orally twice daily for up to 90 days following the first dose or 30 days following achievement of complete remission. Efficacy results are shown Table 2.

{ "type": "p", "children": [], "text": "The efficacy of tretinoin capsules has been evaluated in 114 previously treated patients and in 67 previously untreated (“de novo”) patients with APL in one open-label, uncontrolled single investigator clinical study (Memorial Sloan-Kettering Cancer Center [MSKCC]) and in two cohorts of compassionate cases treated by multiple investigators under the auspices of the National Cancer Institute (NCI). Patients received tretinoin capsules 22.5 mg/m2 orally twice daily for up to 90 days following the first dose or 30 days following achievement of complete remission. Efficacy results are shown Table 2." }

Table 2. Efficacy Results in a Controlled Clinical Trial (MSKCC) and Compassionate Use

{ "type": "p", "children": [], "text": "\nTable 2. Efficacy Results in a Controlled Clinical Trial (MSKCC) and Compassionate Use\n" }

<div class="scrollingtable"><table width="100%"> <col width="14%"/> <col width="14%"/> <col width="14%"/> <col width="14%"/> <col width="14%"/> <col width="14%"/> <col width="14%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"> <p class="First"> <br/>   </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">MSKCC</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">NCI Cohort 1</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">NCI Cohort 2</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Relapsed</span> </p> <p> <span class="Bold">N = 20</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">De Novo</span> </p> <p> <span class="Bold">n = 15</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Relapsed*</span> </p> <p> <span class="Bold">N = 48</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">De Novo</span> </p> <p> <span class="Bold">n = 14</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Relapsed</span> </p> <p> <span class="Bold">n = 46</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">De Novo<span class="Sup">†</span></span> </p> <p> <span class="Bold">n = 38</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Complete<br/> Remission</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 16 (80%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 11 (73%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 24 (50%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 5 (36%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 24 (52%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 26 (68%)</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Median<br/> Survival</p> <p>(months)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 10.8</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> NR</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 5.8</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 0.5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 8.8</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> NR</p> </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> Median<br/> Follow-up</p> <p>(months)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 9.9</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 42.9</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 5.6</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 1.2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 8.0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> 13.1</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col width=\"14%\"/>\n<col width=\"14%\"/>\n<col width=\"14%\"/>\n<col width=\"14%\"/>\n<col width=\"14%\"/>\n<col width=\"14%\"/>\n<col width=\"14%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\" rowspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<br/>   </p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\"> <span class=\"Bold\">MSKCC</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\"> <span class=\"Bold\">NCI Cohort 1</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\"> <span class=\"Bold\">NCI Cohort 2</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> <span class=\"Bold\">Relapsed</span>\n</p>\n<p>\n<span class=\"Bold\">N = 20</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> <span class=\"Bold\">De Novo</span>\n</p>\n<p>\n<span class=\"Bold\">n = 15</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> <span class=\"Bold\">Relapsed*</span>\n</p>\n<p>\n<span class=\"Bold\">N = 48</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> <span class=\"Bold\">De Novo</span>\n</p>\n<p>\n<span class=\"Bold\">n = 14</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> <span class=\"Bold\">Relapsed</span>\n</p>\n<p>\n<span class=\"Bold\">n = 46</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> <span class=\"Bold\">De Novo<span class=\"Sup\">†</span></span>\n</p>\n<p>\n<span class=\"Bold\">n = 38</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> Complete<br/> Remission</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> 16 (80%)</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> 11 (73%)</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> 24 (50%)</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> 5 (36%)</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> 24 (52%)</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> 26 (68%)</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Median<br/> Survival</p>\n<p>(months)</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> 10.8</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> NR</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> 5.8</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> 0.5</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> 8.8</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> NR</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> Median<br/> Follow-up</p>\n<p>(months)</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> 9.9</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> 42.9</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> 5.6</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> 1.2</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> 8.0</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> 13.1</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

NR = Not Reached

{ "type": "p", "children": [], "text": "NR = Not Reached " }

NA = Not Available

{ "type": "p", "children": [], "text": "NA = Not Available" }

*Including 9 chemorefractory patients

{ "type": "p", "children": [], "text": "\n*Including 9 chemorefractory patients" }

†Including 8 patients who received chemotherapy but failed to enter remission

{ "type": "p", "children": [], "text": "\n†Including 8 patients who received chemotherapy but failed to enter remission" }

The median time to complete remission was between 40 and 50 days (range: 2 to 120 days). Most patients received cytotoxic chemotherapy during the remission phase.

{ "type": "p", "children": [], "text": "The median time to complete remission was between 40 and 50 days (range: 2 to 120 days). Most patients received cytotoxic chemotherapy during the remission phase." }

Ten of 15 pediatric cases achieved complete remission (8 of 10 males and 2 of 5 females).

{ "type": "p", "children": [], "text": "Ten of 15 pediatric cases achieved complete remission (8 of 10 males and 2 of 5 females)." }

Tretinoin capsules are supplied as 10 mg capsules, two-tone (lengthwise) with reddish-brown opaque and yellow gelatin shell, imprinted with “TR” with black ink on the yellow side. Supplied

{ "type": "p", "children": [], "text": "Tretinoin capsules are supplied as 10 mg capsules, two-tone (lengthwise) with reddish-brown opaque and yellow gelatin shell, imprinted with “TR” with black ink on the yellow side. Supplied" }

Bottles of 100 capsules, NDC 0904-6867-60

{ "type": "p", "children": [], "text": "Bottles of 100 capsules, NDC 0904-6867-60" }

Carton of 30 capsules (10 capsules each blister pack x 3), NDC 0904-6867-04

{ "type": "p", "children": [], "text": "Carton of 30 capsules (10 capsules each blister pack x 3), NDC 0904-6867-04" }

Store at 20ºC to 25ºC (68ºF to 77ºF); [see USP Controlled Room Temperature].

{ "type": "p", "children": [], "text": "Store at 20ºC to 25ºC (68ºF to 77ºF); [see USP Controlled Room Temperature]." }

Keep bottle tightly closed. Protect from light.

{ "type": "p", "children": [], "text": "Keep bottle tightly closed. Protect from light." }

Embryo-Fetal Toxicity

{ "type": "p", "children": [], "text": "\nEmbryo-Fetal Toxicity\n" }

Advise female patients of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1, 8.3)].

{ "type": "p", "children": [], "text": "Advise female patients of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1, 8.3)]." }

Advise females of reproductive potential to use 2 methods of effective contraception during treatment with tretinoin capsules and for 1 month after the last dose [see Use in Specific Populations (8.3)].

{ "type": "p", "children": [], "text": "Advise females of reproductive potential to use 2 methods of effective contraception during treatment with tretinoin capsules and for 1 month after the last dose [see Use in Specific Populations (8.3)]." }

Advise males with female partners of reproductive potential to use effective contraception during treatment with tretinoin capsules and for 1 week after the last dose [see Use in Specific Populations (8.3)].

{ "type": "p", "children": [], "text": "Advise males with female partners of reproductive potential to use effective contraception during treatment with tretinoin capsules and for 1 week after the last dose [see Use in Specific Populations (8.3)]." }

Differentiation Syndrome

{ "type": "p", "children": [], "text": "\nDifferentiation Syndrome\n" }

Advise patients that tretinoin capsules can cause differentiation syndrome. Ask patients to immediately report any symptoms suggestive of differentiation syndrome, such as fever, cough or difficulty breathing, decreased urinary output, low blood pressure, rapid weight gain, or swelling of their arms or legs, to their healthcare provider for further evaluation [see Warnings and Precautions (5.2)].

{ "type": "p", "children": [], "text": "Advise patients that tretinoin capsules can cause differentiation syndrome. Ask patients to immediately report any symptoms suggestive of differentiation syndrome, such as fever, cough or difficulty breathing, decreased urinary output, low blood pressure, rapid weight gain, or swelling of their arms or legs, to their healthcare provider for further evaluation [see Warnings and Precautions (5.2)]." }

Patients Without t(15;17) Translocation or PML/RARα Fusion

{ "type": "p", "children": [], "text": "\nPatients Without t(15;17) Translocation or PML/RARα Fusion\n" }

Advise patients that tretinoin capsules are not recommended for use in patients without t(15;17) translocation or PML/RARα fusion [see Warnings and Precautions (5.3)].

{ "type": "p", "children": [], "text": "Advise patients that tretinoin capsules are not recommended for use in patients without t(15;17) translocation or PML/RARα fusion [see Warnings and Precautions (5.3)]." }

Leukocytosis

{ "type": "p", "children": [], "text": "\nLeukocytosis\n" }

Inform patients that rapidly evolving leukocytosis, which can be life-threatening, can occur during treatment with tretinoin capsules [see Warnings and Precautions (5.4)].

{ "type": "p", "children": [], "text": "Inform patients that rapidly evolving leukocytosis, which can be life-threatening, can occur during treatment with tretinoin capsules [see Warnings and Precautions (5.4)]." }

Intracranial Hypertension

{ "type": "p", "children": [], "text": "\nIntracranial Hypertension\n" }

Advise patients that tretinoin capsules can cause intracranial hypertension, especially in pediatric patients. Ask patients to immediately report any symptoms suggestive of intracranial hypertension, such as headache, nausea, vomiting, and visual disturbances [see Warnings and Precautions (5.5)].

{ "type": "p", "children": [], "text": "Advise patients that tretinoin capsules can cause intracranial hypertension, especially in pediatric patients. Ask patients to immediately report any symptoms suggestive of intracranial hypertension, such as headache, nausea, vomiting, and visual disturbances [see Warnings and Precautions (5.5)]." }

Lipid Abnormalities

{ "type": "p", "children": [], "text": "\nLipid Abnormalities\n" }

Inform patients that hypercholesterolemia and/or hypertriglyceridemia can occur during treatment with tretinoin capsules. Advise patients on the need for monitoring fasting triglycerides and cholesterol [see Warnings and Precautions (5.6)].

{ "type": "p", "children": [], "text": "Inform patients that hypercholesterolemia and/or hypertriglyceridemia can occur during treatment with tretinoin capsules. Advise patients on the need for monitoring fasting triglycerides and cholesterol [see Warnings and Precautions (5.6)]." }

Hepatotoxicity

{ "type": "p", "children": [], "text": "\nHepatotoxicity\n" }

Advise patients that tretinoin capsules can cause elevated liver function tests. Advise patients on the need for monitoring of liver function tests [see Warnings and Precautions (5.7)].

{ "type": "p", "children": [], "text": "Advise patients that tretinoin capsules can cause elevated liver function tests. Advise patients on the need for monitoring of liver function tests [see Warnings and Precautions (5.7)]." }

Thromboembolic Events

{ "type": "p", "children": [], "text": "\nThromboembolic Events\n" }

Inform patients that venous and arterial thromboembolic events, including cerebrovascular accident, myocardial infarction and renal infarct can occur during treatment with tretinoin capsules [see Warnings and Precautions (5.8)].

{ "type": "p", "children": [], "text": " Inform patients that venous and arterial thromboembolic events, including cerebrovascular accident, myocardial infarction and renal infarct can occur during treatment with tretinoin capsules [see Warnings and Precautions (5.8)]." }

Lactation

{ "type": "p", "children": [], "text": "\nLactation\n" }

Advise women not to breastfeed during treatment with tretinoin capsules and for 1 week after the last dose [see Use in Specific Populations (8.2)].

{ "type": "p", "children": [], "text": "Advise women not to breastfeed during treatment with tretinoin capsules and for 1 week after the last dose [see Use in Specific Populations (8.2)].\n" }

Administration Instructions

{ "type": "p", "children": [], "text": "\nAdministration Instructions\n" }

Advise patients to swallow tretinoin capsules whole with water. Advise patients not to chew, dissolve, or open capsules. Advise patients not to take a missed dose of tretinoin capsules unless it is more than 10 hours until the next scheduled dose. Advise patients that if vomiting occurs after tretinoin capsules administration, that they should not take an additional dose, but continue with the next scheduled dose [see Dosage and Administration (2.2)].

{ "type": "p", "children": [], "text": "Advise patients to swallow tretinoin capsules whole with water. Advise patients not to chew, dissolve, or open capsules. Advise patients not to take a missed dose of tretinoin capsules unless it is more than 10 hours until the next scheduled dose. Advise patients that if vomiting occurs after tretinoin capsules administration, that they should not take an additional dose, but continue with the next scheduled dose [see Dosage and Administration (2.2)]." }

Effects on Ability to Drive and Use Machines

{ "type": "p", "children": [], "text": "\nEffects on Ability to Drive and Use Machines\n" }

Advise patients that the ability to drive or operate machinery might be impaired when treated with tretinoin capsules, particularly if patients are experiencing dizziness or severe headache.

{ "type": "p", "children": [], "text": "Advise patients that the ability to drive or operate machinery might be impaired when treated with tretinoin capsules, particularly if patients are experiencing dizziness or severe headache." }

Manufactured for: Endo USA Malvern, PA 19355

{ "type": "p", "children": [], "text": "Manufactured for: Endo USA Malvern, PA 19355" }

Packaged and Distributed by:

{ "type": "p", "children": [], "text": "\nPackaged and Distributed by:\n" }

MAJOR® PHARMACEUTICALS

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Indianapolis, IN 46268 USA

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Refer to package label for Distributor's NDC Number

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Made in France

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© 2024 Endo, Inc. or one of its affiliates.

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Revised: 03/2025

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MAJOR®

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NDC 0904-6867-04

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Unit Dose

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Tretinoin

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Capsules

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10 mg

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Contains the active ingredient found in Vesanoid*

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Pharmacist: Dispense with Patient

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Information Leaflet

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PATIENT: READ INFORMATION LEAFLET CAREFULLY

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CAUSES BIRTH DIFECTS. DO NOT GET PREGNANT.

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30 CAPSULES (3 x 10)

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Rx only

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