ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The most common adverse reactions (incidence >= 1%) are pain, dryness, exfoliation erythema, dermatitis, pruritus and irritation (all at the application site). (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Galderma Laboratories, L.P. at 1-866-735-4137 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical trials experience. The following adverse reactions are discussed in greater detail elsewhere in the labeling:Hypersensitivity [see Warnings and Precautions (5.1)] Skin Irritation [see Warnings and Precautions (5.2)] Because clinical trials are conducted under widely varying conditions, adverse reaction rates are observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In two multicenter, randomized, double-blind, vehicle-controlled trials (Trial and 2), 832 subjects years of age and older with facial acne vulgaris applied TWYNDO Cream (N=555) or vehicle (N=277) daily for 12 weeks. The majority of subjects were White (73%) and female (59%). Approximately 33% were Hispanic/Latino, and 46% were younger than 18 years of age. Adverse reactions reported in >= 1.0% of subjects treated with TWYNEO Cream (and for which the rate exceeded the rate for vehicle), as well as the corresponding rates reported in subjects treated with vehicle are presented in Table 1.Table 1:Adverse Reactions Reported by >= 1% of Subjects with Facial Acne Vulgaris Treated with TWYNEO Cream and More Frequently than Vehicle in Trials and 2TWYNEO Cream(N 555)n (%)Vehicle Cream(N 277)n (%)Application Site Pain59 (10.6)1 (0.4)Application Site Dryness27 (4.9)1 (0.4)Application Site Exfoliation23 (4.1)0Application Site Erythema22 (4.0)0Application Site Dermatitis7 (1.3)1 (0.4)Application Site Pruritus7 (1.3)0Application Site Irritation6 (1.1)1 (0.4) Application site pain defined as application site stinging, burning or pain.Local tolerability evaluations were conducted at each study visit in the clinical trial by assessment of erythema, scaling, pigmentation, dryness, itching, burning and stinging. Table presents the active assessment of the signs and symptoms of local facial tolerability at Week 12 in subjects treated with TWYNEO Cream.Table 2. Facial Cutaneous Tolerability Assessment at Week 12 in Subjects with Acne Vulgaris Treated with TWYNEO CreamTWYNDEO Cream(N=494)(%)Vehicle(N 264)(%)MildModerateSevereMildModerateSevereErythema 33.06.90.226.98.00Pigmentation27.36.30.426.54.50Dryness22.35.30.416.72.30Scaling16.42.6012.90.80Burning5.92.203.40.80Itching11.11.808.72.70Stinging5.30.201.91.10 The denominators for calculating the percentages were 494 of 555 subjects treated with TWYNEO Cream and 264 of 277 subjects treated with vehicle in these trials who had cutaneous signs and local tolerability results reported at Week 12.Local tolerability scores for erythema, scaling, dryness, itching, burning and stinging rose during the first two weeks of treatment and decreased thereafter.. Hypersensitivity [see Warnings and Precautions (5.1)] Skin Irritation [see Warnings and Precautions (5.2)] 6.2 Postmarketing Experience. The following adverse reactions have been identified during use of benzoyl peroxide. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. Immune System Disorders: Anaphylaxis, angioedema and uticaria.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity, mutagenicity, and impairment of fertility studies were not conducted with TWYNEO Cream.. Benzoyl peroxideThe role of benzoyl peroxide as tumor promoter has been well established in several animal species; however the significance of this finding in humans is unknown. No significant increase in tumor formation was observed in rats treated topically with 15 to 25% benzoyl peroxide carbopol gel (5 to times the concentration of benzoyl peroxide in TWYNEO Cream) for two years. Similar results were obtained in mice topically treated with 25% benzoyl peroxide carbopol gel for 56 weeks followed by intermittent treatment with 15% benzoyl peroxide gel for the rest of the two-year study period, and in mice treated topically with 5% benzoyl peroxide carbopol gel for two years.Bacterial mutagenicity assays (Ames test) conducted with benzoyl peroxid have provided mixed results. Mutagenic potential was observed in few studies but not in majority of investigations. Benzoyl peroxide has been found to cause DNA strand breaks in variety of mammalian cell types and to cause sister chromatid exchanges in Chinese hamster ovary cells.Fertility studies were not conducted with benzoyl peroxide.. TretinoinIn 91-week dermal study, 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. 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, respectively. These doses are 1.3 and 2.7 times the MRHD based on BSA comparison and assuming 100% absorption. The biological significance of these findings is not clear because they occurred at doses that exceeded the dermal maximally tolerated dose (MTD) 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 (0.07 times the MRHD based on BSA comparison and assuming 100% absorption). The genotoxic potential of tretinoin was evaluated in an in vitro bacterial reversion test and an in vivo rat micronucleus assay, both of which 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 2.7 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 (1.3 times MRHD based on BSA comparison and assuming 100% absorption) were observed.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Benzoyl peroxide is an oxidizing agent with bactericidal and keratolytic effects, but the precise mechanism of action is unknown. Tretinoin is metabolite of vitamin 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 (RAR RARss, RAR) which act to modify gene expression, subsequent protein synthesis, and epithelial cell growth an differentiation. It has not been established whether the clinical effects of tretinoin are mediated through activation of retinoic acid receptors, other mechanisms.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.. 12.2 Pharmacodynamics. Pharmacodynamics of TWYNEO Cream in the treatment of acne vulgaris are unknown.. 12.3 Pharmacokinetics. The systemic exposure of benzoyl peroxide was not assessed. Benzoyl peroxide is absorbed by skin where it is converted to benzoic acid and eliminated in the urine.Plasma concentrations of tretinoin and its major metabolites were evaluated in 35 subjects in an open-label, randomized, pharmacokinetic (PK) study. Subjects years of age and older with acne vulgaris applied mean dose of 1.9 TWYNEO Cream to the skin of the face, shoulders, upper back and upper chest once daily for 14 days. Steady-state PK characteristics were determined from samples drawn on Day 14. The mean baseline corrected Cmax and AUC0-24 of tretinoin and its metabolites after once daily application of TWYNEO Cream for 14 days are provided in Table 3. No detectable levels of the metabolites all-trans 4-keto retinoic acid and 9-cis retinoid acid were found in subjects treated with TWYNEO Cream.Table 3: Pharmacokinetics of Tretinoin and its Major Metabolites When Treated with TWYNEO Cream in Subjects Years of Age and Older With Acne Vulgaris for 14 DaysAge Group (years)nCompoundMean(+- SD)Cmax (ng/mL)Mean(+- SD)AUC0-24 (ng-h/mL) >= 18 years of age12tretinoin0.15 +- 0.170.63 +- 0.954-keto 13-cis RA0.27 +- 0.292.88 +- 3.6113-cis RA0.21 +- 0.191.99 +- 2.9012 to 1715tretinoin0.19 +- 0.181.56 +- 1.974-keto 13-cis RA 0.32 +- 0.282.39 +- 3.0513-cis RA 0.28 +- 0.35 1.79 +- 2.799 to 11tretinoin0.18 +- 0.222.06 +- 3.964-keto 13-cis RA 0.34 +- 0.362.89 +- 3.1713-cis RA0.13 +- 0.090.96 +- 1.36.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The safety and efficacy of TWYNEO Cream was evaluated in the treatment of acne vulgaris in two multicenter, randomized, double-blind, vehicle-controlled trials [Trial NCT03761784), Trial (NCT03761810)], which were identical in design. The trials were conducted in 858 subjects years of age and older, with facial acne vulgaris who were treated once daily for 12 weeks with either TWYNEO Cream or vehicle.Subjects were required to have score of moderate (3) or severe (4) on the Investigator Global Assessment (IGA), 20 to 100 inflammatory lesions (papules, pustules and nodules), 30 to 150 non-inflammatory lesions (open and closed comedones) and two or fewer facial nodules.Overall, 73% of subjects were White and 59% were female. Eighteen (18) (2%) subjects were to 11 years of age, 370 (43%) subjects were 12 to 17 years of age, and 470 (55%) subjects were 18 years of age or older. At baseline, subjects had mean inflammatory lesion count of 30.7 and mean non-inflammatory lesion count of 46.4. Additionally, 91% of subjects had an IGA score of (moderate).The co-primary efficacy endpoints were the absolute change from baseline in non-inflammatory lesion count, and absolute change in inflammatory lesion count at Week 12 and the proportion of subjects with treatment success at Week 12, defined as an IGA score of (clear) or (almost clear), and at least two-grade improvement (decrease) from baseline at Week 12. The efficacy results are provided in Table 4.Table 4: Efficacy Results in Subjects with Acne Vulgaris at Week 12 (Trials and 2)Trial 1Trial 2TWYNEO Cream(N 281)VehicleN 143)TWYNEO Cream(N 290)Vehicle(N 144)IGA Success33.9%14.3%26.8%15.1%Difference from Vehicle25.7%11.6%(95% CI)(17.1%, 34.2%)(3.6%, 19.7%)Inflammatory LesionsMean Absolute Change from Baseline-21.6-14.8-16.2-14.1Difference from Vehicle-6.8-2.1(95% CI) (-9.1, -4.6)(-3.9, -0.4)Mean Percent Change from Baseline 66.1%-43.5%-57.6%-50.8%Difference from Vehicle-22.6%-6.8%(95% CI)(-29.2%, -16.0%)(-13.1%, -0.5%) Non-Inflammatory LesionsMean Absolute Change from Baseline-29.7-19.8-24.2-17.4Difference from Vehicle-9.9-6.8(95% CI)(-13.0, -6.8)(-9.9, -3.7)Mean Percent Change from Baseline-61.6%-40.9%-54.4%-41.5%Difference from Vehicle-20.7%-13.0%(95% CI)(-27.2%, -14.2%)(-19.6%, -6.4%)Investigator Global Assessment (IGA) success was defined as an IGA score of (clear) or1 (almost clear) with at least at two-grade reduction from baseline. Means presented in table are Least Square (LS) Means.

DESCRIPTION SECTION.

11 DESCRIPTION. TWYNEO (tretinoin and benzoyl peroxide) Cream is yellow cream for topical use. Each gram of TWYNEO Cream contains mg (0.1%) of tretinoin and 30 mg (3%) of benzoyl peroxide. Tretinoin is retinoid and benzoyl peroxide is an oxidizing agent.The chemical name for 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. Tretinoin has the following structural formula:Molecular Formula: C20H28O2 Molecular Weight: 300.44 The chemical name for benzoyl peroxide is benzoyl benzenecarboperoxoate. Benzoyl peroxide has the following structural formula:Molecular Formula: C14H10O4 Molecular Weight: 242.23The formulation of TWYNEO Cream uses silica (silicon dioxide) core shell structures to separately micro-encapsulate tretinoin crystals and benzoyl peroxide crystals inclusion inclusion of the two active ingredients in the cream. TWYNEO Cream contains the following inactive ingredients: anhydrous citric acid, butylated hydroxytoluene,carbomer homopolymer type C, cetrimonium chloride, cetyl alcohol, cyclomethicone, edetate disodium, glycerin, hydrochloric acid, imidurea, (S)lactic acid, macrogol stearate, mono and di-glycerides, polyquaternium-7, purified water, silicon dioxide, sodium hydroxide, squalane, tetraethyl ortho silicate and white wax.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information). Hypersensitivity Inform patients that serious hypersensitivity reactions have occurred with the use of benzoyl peroxide products. If patient experiences serious hypersensitivity reaction, instruct patient to discontinue TWYNEO Cream immediately and seek medical help [see Warnings and Precautions (5.1)]. Skin Irritation Inform patients that TWYNEO Cream may cause irritation such as erythema, dryness, stinging or burning. Advise the patient to use moisturizer for irritation. [see Warnings and Precautions (5.2)]. Photosensitivity Advise patients to minimize unprotected exposure to sunlight and sunlamps; recommend the use of sunscreen products and protective apparel (e.g., hat) over treated areas when sun exposure cannot be avoided. [see Warnings and Precautions (5.3)]. Administration Instructions Advise patients to apply TWYNEO Cream exactly as directed in thin layer, avoiding the eyes, lips, paranasal creases and mucous membranes and to wash hands immediately after application. Inform patients that TWYNEO Cream may bleach hair or colored fabric [see Dosage and Administration 2 )]. Discard Instructions Instruct patients to store TWYNEO Cream at room temperature and to discard 12 weeks after date of dispensing or 30 days after first opening, whichever is sooner. [see How Supplied/Storage and Handling (16)].

LABORATORY TESTS SECTION.

6.1 Clinical trials experience. The following adverse reactions are discussed in greater detail elsewhere in the labeling:Hypersensitivity [see Warnings and Precautions (5.1)] Skin Irritation [see Warnings and Precautions (5.2)] Because clinical trials are conducted under widely varying conditions, adverse reaction rates are observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In two multicenter, randomized, double-blind, vehicle-controlled trials (Trial and 2), 832 subjects years of age and older with facial acne vulgaris applied TWYNDO Cream (N=555) or vehicle (N=277) daily for 12 weeks. The majority of subjects were White (73%) and female (59%). Approximately 33% were Hispanic/Latino, and 46% were younger than 18 years of age. Adverse reactions reported in >= 1.0% of subjects treated with TWYNEO Cream (and for which the rate exceeded the rate for vehicle), as well as the corresponding rates reported in subjects treated with vehicle are presented in Table 1.Table 1:Adverse Reactions Reported by >= 1% of Subjects with Facial Acne Vulgaris Treated with TWYNEO Cream and More Frequently than Vehicle in Trials and 2TWYNEO Cream(N 555)n (%)Vehicle Cream(N 277)n (%)Application Site Pain59 (10.6)1 (0.4)Application Site Dryness27 (4.9)1 (0.4)Application Site Exfoliation23 (4.1)0Application Site Erythema22 (4.0)0Application Site Dermatitis7 (1.3)1 (0.4)Application Site Pruritus7 (1.3)0Application Site Irritation6 (1.1)1 (0.4) Application site pain defined as application site stinging, burning or pain.Local tolerability evaluations were conducted at each study visit in the clinical trial by assessment of erythema, scaling, pigmentation, dryness, itching, burning and stinging. Table presents the active assessment of the signs and symptoms of local facial tolerability at Week 12 in subjects treated with TWYNEO Cream.Table 2. Facial Cutaneous Tolerability Assessment at Week 12 in Subjects with Acne Vulgaris Treated with TWYNEO CreamTWYNDEO Cream(N=494)(%)Vehicle(N 264)(%)MildModerateSevereMildModerateSevereErythema 33.06.90.226.98.00Pigmentation27.36.30.426.54.50Dryness22.35.30.416.72.30Scaling16.42.6012.90.80Burning5.92.203.40.80Itching11.11.808.72.70Stinging5.30.201.91.10 The denominators for calculating the percentages were 494 of 555 subjects treated with TWYNEO Cream and 264 of 277 subjects treated with vehicle in these trials who had cutaneous signs and local tolerability results reported at Week 12.Local tolerability scores for erythema, scaling, dryness, itching, burning and stinging rose during the first two weeks of treatment and decreased thereafter.. Hypersensitivity [see Warnings and Precautions (5.1)] Skin Irritation [see Warnings and Precautions (5.2)].

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity, mutagenicity, and impairment of fertility studies were not conducted with TWYNEO Cream.. Benzoyl peroxideThe role of benzoyl peroxide as tumor promoter has been well established in several animal species; however the significance of this finding in humans is unknown. No significant increase in tumor formation was observed in rats treated topically with 15 to 25% benzoyl peroxide carbopol gel (5 to times the concentration of benzoyl peroxide in TWYNEO Cream) for two years. Similar results were obtained in mice topically treated with 25% benzoyl peroxide carbopol gel for 56 weeks followed by intermittent treatment with 15% benzoyl peroxide gel for the rest of the two-year study period, and in mice treated topically with 5% benzoyl peroxide carbopol gel for two years.Bacterial mutagenicity assays (Ames test) conducted with benzoyl peroxid have provided mixed results. Mutagenic potential was observed in few studies but not in majority of investigations. Benzoyl peroxide has been found to cause DNA strand breaks in variety of mammalian cell types and to cause sister chromatid exchanges in Chinese hamster ovary cells.Fertility studies were not conducted with benzoyl peroxide.. TretinoinIn 91-week dermal study, 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. 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, respectively. These doses are 1.3 and 2.7 times the MRHD based on BSA comparison and assuming 100% absorption. The biological significance of these findings is not clear because they occurred at doses that exceeded the dermal maximally tolerated dose (MTD) 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 (0.07 times the MRHD based on BSA comparison and assuming 100% absorption). The genotoxic potential of tretinoin was evaluated in an in vitro bacterial reversion test and an in vivo rat micronucleus assay, both of which 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 2.7 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 (1.3 times MRHD based on BSA comparison and assuming 100% absorption) were observed.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The systemic exposure of benzoyl peroxide was not assessed. Benzoyl peroxide is absorbed by skin where it is converted to benzoic acid and eliminated in the urine.Plasma concentrations of tretinoin and its major metabolites were evaluated in 35 subjects in an open-label, randomized, pharmacokinetic (PK) study. Subjects years of age and older with acne vulgaris applied mean dose of 1.9 TWYNEO Cream to the skin of the face, shoulders, upper back and upper chest once daily for 14 days. Steady-state PK characteristics were determined from samples drawn on Day 14. The mean baseline corrected Cmax and AUC0-24 of tretinoin and its metabolites after once daily application of TWYNEO Cream for 14 days are provided in Table 3. No detectable levels of the metabolites all-trans 4-keto retinoic acid and 9-cis retinoid acid were found in subjects treated with TWYNEO Cream.Table 3: Pharmacokinetics of Tretinoin and its Major Metabolites When Treated with TWYNEO Cream in Subjects Years of Age and Older With Acne Vulgaris for 14 DaysAge Group (years)nCompoundMean(+- SD)Cmax (ng/mL)Mean(+- SD)AUC0-24 (ng-h/mL) >= 18 years of age12tretinoin0.15 +- 0.170.63 +- 0.954-keto 13-cis RA0.27 +- 0.292.88 +- 3.6113-cis RA0.21 +- 0.191.99 +- 2.9012 to 1715tretinoin0.19 +- 0.181.56 +- 1.974-keto 13-cis RA 0.32 +- 0.282.39 +- 3.0513-cis RA 0.28 +- 0.35 1.79 +- 2.799 to 11tretinoin0.18 +- 0.222.06 +- 3.964-keto 13-cis RA 0.34 +- 0.362.89 +- 3.1713-cis RA0.13 +- 0.090.96 +- 1.36.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryAvailable data from published observational studies of topical tretinoin in pregnant women have not established drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Studies conducted with benzoyl peroxide have not demonstrated systemic absorption and maternal use is not expected to result in fetal exposure to benzoyl peroxide. There are no data on TWYNEO Cream use in pregnant women.There are reports of major birth defects reported with maternal use of topical tretinoin similar to those seen in infants exposed to oral retinoids, but those case reports do not establish pattern or association with tretinoin-related embryopathy (see Data).Animal reproductive studies have not been conducted with TWYNEO Cream or benzoyl peroxide. Topical administration of tretinoin to pregnant rats during organogenesis was associated with malformations (craniofacial abnormalities [hydrocephaly], asymmetrical thyroids, variations in ossification, and increased supernumerary ribs) at doses greater than mg tretinoin/kg/day, approximately times the maximum recommended human dose (MRHC) 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 background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 to 4% of miscarriage is 15 to 20% of clinically recognized pregnancies.. DataHuman DataWhile 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 DataFor purposes of comparison of the animal exposure to human exposure, the MRHD is defined as 1.5 of TWYNEO Cream (containing 0.1% tretinoin) applied daily to 60-kg person (0.03 mg tretinoin/kg body weight).Topical tretinoin embryofetal development studies have generated equivocal results. There is evidence of malformations (shortened or kinked tail) after topical tretinoin administration in Wistar rats at doses greater than mg/kg/day (approximately times the MHRD based on BSA comparison and assuming 100% absorption). Anomalies (humerus: short 13%, bent 6%, or parietal incompletely ossified 14%) have also been reported when 10 mg/kg/day 9approximately 50 times the MRHD based on BSA comparison and assuming 100% absorption) was topically applied to pregnant rats during organogenesis. Increased incidence of domed head and hydrocephaly, typical of retinoid-induced fetal malformations were noted in New Zealand White rabbits administered topical doses greater than 0.2 mg/kg/day (2.2 times the MRHD based on BSA comparison and assuming 100% absorption).Oral tretinoin induced malformations in rats, mice, hamsters, and nonhuman primates when administered during the period of organogenesis. Fetal malformations were observed when tretinoin was orally administered to pregnant Wistar rats during organogenesis. It was teratogenic and fetotoxic in Wistar rats when given orally or topically in doses greater than mg/kg/day (approximately times the MRHD based on BSA comparison and assuming 100% absorption). In 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 and assuming 100% absorption). No fetal malformations were observed at an oral dose of mg/kg/day (approximately 50 times the MRHD base on BSA comparison and assuming 100% absorption). Increased skeletal variations were observed at all doses, and dose-related increase in embryo lethality and abortion was 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 dose of 2.5 mg/kg/day (13 times the MRHD based on BSA comparison and assuming 100% absorption). Topical tretinoin has been shown to be fetotoxic in rabbits when administered at dose of 0.5 mg/kg/day (5 times the MRHD based on BSA comparison and assuming 100% absorption).

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryAvailable data from published observational studies of topical tretinoin in pregnant women have not established drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Studies conducted with benzoyl peroxide have not demonstrated systemic absorption and maternal use is not expected to result in fetal exposure to benzoyl peroxide. There are no data on TWYNEO Cream use in pregnant women.There are reports of major birth defects reported with maternal use of topical tretinoin similar to those seen in infants exposed to oral retinoids, but those case reports do not establish pattern or association with tretinoin-related embryopathy (see Data).Animal reproductive studies have not been conducted with TWYNEO Cream or benzoyl peroxide. Topical administration of tretinoin to pregnant rats during organogenesis was associated with malformations (craniofacial abnormalities [hydrocephaly], asymmetrical thyroids, variations in ossification, and increased supernumerary ribs) at doses greater than mg tretinoin/kg/day, approximately times the maximum recommended human dose (MRHC) 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 background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 to 4% of miscarriage is 15 to 20% of clinically recognized pregnancies.. DataHuman DataWhile 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 DataFor purposes of comparison of the animal exposure to human exposure, the MRHD is defined as 1.5 of TWYNEO Cream (containing 0.1% tretinoin) applied daily to 60-kg person (0.03 mg tretinoin/kg body weight).Topical tretinoin embryofetal development studies have generated equivocal results. There is evidence of malformations (shortened or kinked tail) after topical tretinoin administration in Wistar rats at doses greater than mg/kg/day (approximately times the MHRD based on BSA comparison and assuming 100% absorption). Anomalies (humerus: short 13%, bent 6%, or parietal incompletely ossified 14%) have also been reported when 10 mg/kg/day 9approximately 50 times the MRHD based on BSA comparison and assuming 100% absorption) was topically applied to pregnant rats during organogenesis. Increased incidence of domed head and hydrocephaly, typical of retinoid-induced fetal malformations were noted in New Zealand White rabbits administered topical doses greater than 0.2 mg/kg/day (2.2 times the MRHD based on BSA comparison and assuming 100% absorption).Oral tretinoin induced malformations in rats, mice, hamsters, and nonhuman primates when administered during the period of organogenesis. Fetal malformations were observed when tretinoin was orally administered to pregnant Wistar rats during organogenesis. It was teratogenic and fetotoxic in Wistar rats when given orally or topically in doses greater than mg/kg/day (approximately times the MRHD based on BSA comparison and assuming 100% absorption). In 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 and assuming 100% absorption). No fetal malformations were observed at an oral dose of mg/kg/day (approximately 50 times the MRHD base on BSA comparison and assuming 100% absorption). Increased skeletal variations were observed at all doses, and dose-related increase in embryo lethality and abortion was 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 dose of 2.5 mg/kg/day (13 times the MRHD based on BSA comparison and assuming 100% absorption). Topical tretinoin has been shown to be fetotoxic in rabbits when administered at dose of 0.5 mg/kg/day (5 times the MRHD based on BSA comparison and assuming 100% absorption).. 8.2 Lactation. Risk SummaryThere are no data on the presence of benzoyl peroxide and 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 mothers clinical need for TWYNEO Cream and any potential adverse effects on the breastfed child from TWYNEO or from the underlying maternal condition.. 8.4 Pediatric Use. The safety and effectiveness of TWYNEO Cream for the topical treatment of acne vulgaris have been established in pediatric patients years of age and older based on evidence from two multicenter, randomized, double-blind, parallel-group, vehicle-controlled, 12-week clinical trials and an open-label pharmacokinetic study. total of 283 pediatric subjects years of age and older received TWYNEO Cream in the clinical studies [see Clinical Pharmacology (12.3) and Clinical Studies (14)]. The safety and effectiveness of TWYNEO Cream in pediatric patients below years of age have not been established.. 8.5 Geriatric Use. Clinical trials of TWYNEO Cream did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently than younger subjects.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hypersensitivity: Severe hypersensitivity reactions, including anaphylaxis and angiodema, have been reported with use of benzoyl peroxide products. (4, 5.1)Skin Irritation: Pain, dryness, exfoliation, erythema, and irritation may occur with use of TWYNEO Cream. Avoid application of TWYNEO Cream to cuts abrasions, eczematous or sunburned skin. (5.2)Photosensitivity: Minimize unprotected exposure to sunlight and sunlamps. Use sunscreen and protective clothing when sun exposure cannot be avoided. (5.3). Hypersensitivity: Severe hypersensitivity reactions, including anaphylaxis and angiodema, have been reported with use of benzoyl peroxide products. (4, 5.1). Skin Irritation: Pain, dryness, exfoliation, erythema, and irritation may occur with use of TWYNEO Cream. Avoid application of TWYNEO Cream to cuts abrasions, eczematous or sunburned skin. (5.2). Photosensitivity: Minimize unprotected exposure to sunlight and sunlamps. Use sunscreen and protective clothing when sun exposure cannot be avoided. (5.3). 5.1 Hypersensitivity. Hyper sensitive reactions, including anaphylaxis, angioedema, and urticaria, have been reported with the use of benzoyl peroxide products. If serious hypersensitivity reaction occurs, discontinue TWYNEO Cream immediately and initiate appropriate therapy.. 5.2 Skin Irritation. Patients using TWYNEO Cream may experience application site dryness, pain, exfoliation, erythema, dermatitis, pruritus, and irritation [see Adverse Reactions (6.1)]. Depending upon the severity of these adverse reactions, instruct patients to use moisturizer, reduce the frequency of the application of TWYNEO Cream, or discontinue use. Avoid application of TWYNEO Cream to cuts, abrasions, eczematous, or sunburned skin.. 5.3 Photosensitivity. TWYNEO Cream may increase sensitivity to ultraviolet light. Minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while using TWYNEO Cream. Instruct patients to implement sun protection measures (e.g., sunscreen and loose-fitting clothes) when sun exposure cannot be avoided. Discontinue TWYNEO Cream at the first evidence of sunburn.