Seysara

6 ADVERSE REACTIONS Most common adverse reaction (incidence ≥ 1%) is nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Almirall at 1-866-665-2782 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience 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. A total of 1064 subjects and 1069 subjects with moderate to severe acne vulgaris were treated with SEYSARA and placebo, respectively, for 12 weeks in 3 controlled clinical trials. The only adverse drug reaction that was reported in at least 1% of subjects was nausea, SEYSARA (3.1%) versus placebo (2.0%). The following additional adverse drug reactions occurred in less than 1% of female SEYSARA subjects: vulvovaginal mycotic infection (0.8%) and vulvovaginal candidiasis (0.6%).

4 CONTRAINDICATIONS SEYSARA is contraindicated in persons who have shown hypersensitivity to any of the tetracyclines. SEYSARA is contraindicated in persons who have shown hypersensitivity to any of the tetracyclines. ( 4 )

11 DESCRIPTION SEYSARA (sarecycline) tablets are a tetracycline class drug for oral administration. Sarecycline hydrochloride is chemically described as (4 S ,4a S ,5a R ,12a S )-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-7-[(methoxy-(methyl)-amino)- methyl]-1,11-dioxo-1,4,4a,5,5a,6,11, 12a-octahydrotetracene-2-carboxamide monohydrochloride with an empirical formula of C 24 H 29 N 3 O 8 .HCl and a molecular weight of 523.96. The structural formula is represented below: SEYSARA tablets contain 64.5 mg, 107.5 mg, and 161.2 mg of sarecycline hydrochloride equivalent to 60 mg, 100 mg, and 150 mg sarecycline respectively. Inactive ingredients in the tablet formulations are: microcrystalline cellulose, povidone, sodium starch glycolate, and sodium stearyl fumarate. The yellow film coating contains D&C yellow #10 aluminum lake, iron oxide yellow, methacrylic acid copolymer type C, polyethylene glycol, polyvinyl alcohol, sodium bicarbonate, talc, and titatnium dioxide. Chemical Structure

2 DOSAGE AND ADMINISTRATION The recommended dosage of SEYSARA is based on body weight described in Table 1 . If there is no improvement after 12 weeks, reassess treatment with SEYSARA. Table 1: Dosing Table for SEYSARA Body Weight (kg) Tablet Strength 33 to 54 kg 60 mg tablet 55 to 84 kg 100 mg tablet 85 to 136 kg 150 mg tablet Take SEYSARA once daily, with or without food. To reduce the risk of esophageal irritation and ulceration, administer SEYSARA with adequate amounts of fluid. The recommended dosage of SEYSARA is once daily with or without food ( 2 ): 60 mg for patients who weigh 33-54 kg, 100 mg for patients who weigh 55-84 kg, 150 mg for patients who weigh 85-136 kg.

1 INDICATIONS AND USAGE SEYSARA ® (sarecycline) tablet, is indicated for the treatment of inflammatory lesions of non-nodular moderate to severe acne vulgaris in patients 9 years of age and older. Limitations of Use Efficacy of SEYSARA beyond 12 weeks and safety beyond 12 months have not been established. SEYSARA has not been evaluated in the treatment of infections [see Clinical Studies ( 14 )] . To reduce the development of drug-resistant bacteria as well as to maintain the effectiveness of other antibacterial drugs, SEYSARA should be used only as indicated [see Warnings and Precautions ( 5.6 )] . SEYSARA ® is a tetracycline-class drug indicated for the treatment of inflammatory lesions of non-nodular moderate to severe acne vulgaris in patients 9 years of age and older. ( 1 ) Limitations of Use Efficacy of SEYSARA beyond 12 weeks and safety beyond 12 months have not been established. SEYSARA has not been evaluated in the treatment of infections. To reduce the development of drug-resistant bacteria as well as to maintain the effectiveness of other antibacterial drugs, SEYSARA should be used only as indicated [see Warnings and Precautions ( 5.6 )].

10 OVERDOSAGE In case of overdosage, discontinue medication, treat symptomatically, and institute supportive measures. Dialysis does not alter serum half-life and thus would not be of benefit in treating cases of overdose.

7 DRUG INTERACTIONS Oral retinoids: avoid coadministration. ( 5.4 , 7.1 ) Antacids and iron preparations: separate dosing of SEYSARA. ( 7.1 ) Penicillin: avoid coadministration. ( 7.2 ) Anticoagulants: decrease anticoagulant dosage as appropriate. ( 7.2 ) P-glycoprotein substrates: monitor for toxicities of drugs that may require dosage reduction. ( 7.2 ) 7.1 Effect of Other Drugs on SEYSARA Oral Retinoids Tetracyclines may cause increased intracranial pressure as do oral retinoids, including isotretinoin and acitretin [see Warnings and Precautions ( 5.4 )] . Avoid coadministration of SEYSARA with oral retinoids. Antacids and Iron Preparations Coadministration with antacids containing aluminum, calcium or magnesium, bismuth subsalicylate, and iron-containing preparations may impair absorption of SEYSARA, similar to other tetracyclines, which may decrease its efficacy. Separate dosing of SEYSARA from antacids containing aluminum, calcium or magnesium, bismuth subsalicylate, and iron-containing preparations. 7.2 Effect of SEYSARA on Other Drugs Penicillin Similar to other tetracyclines, SEYSARA may interfere with the bactericidal action of penicillin. Avoid coadministration of SEYSARA with penicillin. Anticoagulants Similar to other tetracyclines, SEYSARA may depress plasma prothrombin activity, which may increase the risk of bleeding in patients who are on anticoagulant therapy. Decrease anticoagulant dosage when coadministered with SEYSARA as appropriate. P-Glycoprotein (P-gp) Substrates Concomitant use of SEYSARA may increase concentrations of concomitantly administered P-gp substrates (e.g. digoxin). Monitor for toxicities of drugs that are P-gp substrates and may require dosage reduction when given concurrently with SEYSARA [see Clinical Pharmacology ( 12.3 )] . Oral Hormonal Contraceptives There is no clinically significant effect of SEYSARA on the efficacy of oral contraceptives containing ethinyl estradiol and norethindrone acetate [see Clinical Pharmacology ( 12.3 )] .

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Sarecycline is an aminomethylcycline within the tetracycline class of drugs. [see CLINICAL PHARMACOLOGY ( 12.4 )] . The mechanism of action of SEYSARA in treating the inflammatory lesions of non-nodular acne vulgaris is not known. 12.2 Pharmacodynamics The pharmacodynamics of SEYSARA for the treatment of acne vulgaris are unknown. Cardiac Electrophysiology At approximately 3 times the maximum recommended dose, SEYSARA did not prolong the QT interval to a clinically relevant extent. 12.3 Pharmacokinetics Increasing the SEYSARA dose from 60 to 150 mg once daily in healthy subjects resulted in a slightly less than proportional increase in sarcyeline steady-state C max and AUC tau . A mean accumulation ratio of sarecycline ranges from 1.5 to 1.6 fold with repeated dosing. Steady-state of sarecycline was reached by Day 7. Absorption The median time to peak plasma concentration (T max ) of sarecycline is 1.5 to 2.0 hours. Effect of Food Coadministration with a high-fat (approximately 50% of total caloric content of the meal), high-calorie (800 to 1000 Kcal) meal that included milk delayed T max by approximately 0.53 hour and decreased sarecycline C max by 31% and AUC by 27%. Distribution Protein binding of sarecycline is 62.5% to 74.7% in vitro. The mean apparent volume of distribution of sarecycline at steady-state ranges from 91.4 L to 97.0 L. Elimination The mean apparent oral clearance (CL/F) of sarecycline at steady state is approximately 3 L/h. The mean elimination half-life of sarecycline is 21 to 22 hours. Metabolism Metabolism of sarecycline by enzymes in human liver microsomes is minimal (< 15%) in vitro. Minor metabolites resulting from non-enzymic epimerization, O-/N-demethylation, hydroxylation, and desaturation have been found. Excretion After a single 100 mg oral dose of radiolabeled sarecycline, 42.6% of the dose was recovered in feces (14.9% as unchanged) and 44.1% in urine (24.7% as unchanged). Specific Populations No clinically significant differences in the pharmacokinetics of sarecycline were observed based on age (11 to 73 years), weight (42 to 133 kg), sex, renal impairment, or mild to moderate hepatic impairment (Child Pugh A to B). The effect of end-stage renal disease (ESRD) or severe hepatic impairment (Child-Pugh C) on sarecycline pharmacokinetics has not been assessed. Drug Interaction Studies Clinical Studies Coadministration of SEYSARA with a combination oral contraceptive, ethinyl estradiol (EE) 20 mcg plus norethindrone (NE) acetate 1 mg, increased EE C max by 14% and AUC tau by 11%, and increased NE C max by 18% and AUC tau by 23%. Coadministration of a single dose of SEYSARA 150 mg resulted in a 26% increase in C max of digoxin, a P-gp substrate. In Vitro Studies Sarecycline is not a substrate for P-gp, BCRP, OATP1B1, or OATP1B3. Sarecycline is a P-gp inhibitor. Sarecycline does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4/5 isozymes, and does not inhibit OATP1B1, OATP1B3, OCT2, OAT1, OAT3, or BCRP. Sarecycline does not induce CYP1A2, CYP2B6, or CYP3A4/5 isozymes. 12.4 Microbiology Mechanism of Action In P. acnes , sarecycline binds to the 30S ribosomal subunit and interacts with 16S ribosomal RNA. Furthermore, it protrudes its C7 moiety into the mRNA binding channel to interact with mRNA. Sarecycline blocks P. acnes protein synthesis and inhibits bacterial growth however, the clinical significance is unknown. Resistance P. acnes strains displayed a low propensity for the development of resistance to sarecycline, with spontaneous mutation frequencies being 10 -10 at 4 – 8 × MIC. Antimicrobial Activity Sarecycline is active in vitro against most isolates of Propionibacterium acnes .

12.1 Mechanism of Action Sarecycline is an aminomethylcycline within the tetracycline class of drugs. [see CLINICAL PHARMACOLOGY ( 12.4 )] . The mechanism of action of SEYSARA in treating the inflammatory lesions of non-nodular acne vulgaris is not known.

12.2 Pharmacodynamics The pharmacodynamics of SEYSARA for the treatment of acne vulgaris are unknown. Cardiac Electrophysiology At approximately 3 times the maximum recommended dose, SEYSARA did not prolong the QT interval to a clinically relevant extent.

12.3 Pharmacokinetics Increasing the SEYSARA dose from 60 to 150 mg once daily in healthy subjects resulted in a slightly less than proportional increase in sarcyeline steady-state C max and AUC tau . A mean accumulation ratio of sarecycline ranges from 1.5 to 1.6 fold with repeated dosing. Steady-state of sarecycline was reached by Day 7. Absorption The median time to peak plasma concentration (T max ) of sarecycline is 1.5 to 2.0 hours. Effect of Food Coadministration with a high-fat (approximately 50% of total caloric content of the meal), high-calorie (800 to 1000 Kcal) meal that included milk delayed T max by approximately 0.53 hour and decreased sarecycline C max by 31% and AUC by 27%. Distribution Protein binding of sarecycline is 62.5% to 74.7% in vitro. The mean apparent volume of distribution of sarecycline at steady-state ranges from 91.4 L to 97.0 L. Elimination The mean apparent oral clearance (CL/F) of sarecycline at steady state is approximately 3 L/h. The mean elimination half-life of sarecycline is 21 to 22 hours. Metabolism Metabolism of sarecycline by enzymes in human liver microsomes is minimal (< 15%) in vitro. Minor metabolites resulting from non-enzymic epimerization, O-/N-demethylation, hydroxylation, and desaturation have been found. Excretion After a single 100 mg oral dose of radiolabeled sarecycline, 42.6% of the dose was recovered in feces (14.9% as unchanged) and 44.1% in urine (24.7% as unchanged). Specific Populations No clinically significant differences in the pharmacokinetics of sarecycline were observed based on age (11 to 73 years), weight (42 to 133 kg), sex, renal impairment, or mild to moderate hepatic impairment (Child Pugh A to B). The effect of end-stage renal disease (ESRD) or severe hepatic impairment (Child-Pugh C) on sarecycline pharmacokinetics has not been assessed. Drug Interaction Studies Clinical Studies Coadministration of SEYSARA with a combination oral contraceptive, ethinyl estradiol (EE) 20 mcg plus norethindrone (NE) acetate 1 mg, increased EE C max by 14% and AUC tau by 11%, and increased NE C max by 18% and AUC tau by 23%. Coadministration of a single dose of SEYSARA 150 mg resulted in a 26% increase in C max of digoxin, a P-gp substrate. In Vitro Studies Sarecycline is not a substrate for P-gp, BCRP, OATP1B1, or OATP1B3. Sarecycline is a P-gp inhibitor. Sarecycline does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4/5 isozymes, and does not inhibit OATP1B1, OATP1B3, OCT2, OAT1, OAT3, or BCRP. Sarecycline does not induce CYP1A2, CYP2B6, or CYP3A4/5 isozymes.

20231109

11

3 DOSAGE FORMS AND STRENGTHS SEYSARA (sarecycline) tablets: 60 mg: capsule-shaped, yellow, film-coated tablets debossed with “S60” on one side and blank on the other side. 100 mg: capsule-shaped, yellow, film-coated tablets debossed with “S100” on one side and blank on the other side. 150 mg: capsule-shaped, yellow, film-coated tablets debossed with “S150” on one side and blank on the other side. Tablets: 60 mg, 100 mg, 150 mg ( 3 )

Seysara sarecycline hydrochloride SARECYCLINE HYDROCHLORIDE SARECYCLINE MICROCRYSTALLINE CELLULOSE POVIDONE, UNSPECIFIED SODIUM STARCH GLYCOLATE TYPE A POTATO SODIUM STEARYL FUMARATE D&C YELLOW NO. 10 FERRIC OXIDE YELLOW METHACRYLIC ACID - ETHYL ACRYLATE COPOLYMER (1:1) TYPE A POLYETHYLENE GLYCOL, UNSPECIFIED POLYVINYL ALCOHOL, UNSPECIFIED SODIUM BICARBONATE TALC TITANIUM DIOXIDE S60 Seysara sarecycline hydrochloride SARECYCLINE HYDROCHLORIDE SARECYCLINE MICROCRYSTALLINE CELLULOSE POVIDONE, UNSPECIFIED SODIUM STARCH GLYCOLATE TYPE A POTATO SODIUM STEARYL FUMARATE D&C YELLOW NO. 10 FERRIC OXIDE YELLOW METHACRYLIC ACID - ETHYL ACRYLATE COPOLYMER (1:1) TYPE A POLYETHYLENE GLYCOL, UNSPECIFIED POLYVINYL ALCOHOL, UNSPECIFIED SODIUM BICARBONATE TALC TITANIUM DIOXIDE S100 Seysara sarecycline hydrochloride SARECYCLINE HYDROCHLORIDE SARECYCLINE MICROCRYSTALLINE CELLULOSE POVIDONE, UNSPECIFIED SODIUM STARCH GLYCOLATE TYPE A POTATO SODIUM STEARYL FUMARATE D&C YELLOW NO. 10 FERRIC OXIDE YELLOW METHACRYLIC ACID - ETHYL ACRYLATE COPOLYMER (1:1) TYPE A POLYETHYLENE GLYCOL, UNSPECIFIED POLYVINYL ALCOHOL, UNSPECIFIED SODIUM BICARBONATE TALC TITANIUM DIOXIDE S150

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In a 2-year oral mouse carcinogenicity study and a 2-year oral rat carcinogenicity study, no drug-related neoplasms were observed in male mice at oral doses of sarecycline up to 100 mg/kg/day (approximately equal to the MRHD based on AUC comparison) or in female mice at doses up to 60 mg/kg/day (approximately equal to the MRHD based on AUC comparison), or in rats at doses up to 200/100 mg/kg/day (dose reduced from 200 to 100 mg/kg/day due to increased mortality; 8 times the MRHD based on AUC comparison). Sarecycline was not mutagenic or clastogenic in a series of in vitro and in vivo genotoxicity studies, including a bacteria reverse mutation (Ames) assay, an in vitro chromosomal aberration assay in CHO cells, the L5178Y/TK +/- Mouse Lymphoma Assay, and an in vivo micronucleus assay in rats. In a fertility and early embryonic development study in rats, sarecycline was administered to both male and female rats at oral doses up to 400 mg/kg/day prior to pairing and through the mating and postmating period. Female fertility was not affected at doses up to 400 mg/kg/day (8 times the MRHD based on AUC comparison). In sperm evaluation, decreased sperm motility, decreased sperm count and concentration, and an increase in percent abnormal sperm occurred at 400 mg/kg/day (8 times the MRHD based on AUC comparison). Male fertility was not affected at doses up to 150 mg/kg/day (4 times the MRHD based on AUC comparison).

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In a 2-year oral mouse carcinogenicity study and a 2-year oral rat carcinogenicity study, no drug-related neoplasms were observed in male mice at oral doses of sarecycline up to 100 mg/kg/day (approximately equal to the MRHD based on AUC comparison) or in female mice at doses up to 60 mg/kg/day (approximately equal to the MRHD based on AUC comparison), or in rats at doses up to 200/100 mg/kg/day (dose reduced from 200 to 100 mg/kg/day due to increased mortality; 8 times the MRHD based on AUC comparison). Sarecycline was not mutagenic or clastogenic in a series of in vitro and in vivo genotoxicity studies, including a bacteria reverse mutation (Ames) assay, an in vitro chromosomal aberration assay in CHO cells, the L5178Y/TK +/- Mouse Lymphoma Assay, and an in vivo micronucleus assay in rats. In a fertility and early embryonic development study in rats, sarecycline was administered to both male and female rats at oral doses up to 400 mg/kg/day prior to pairing and through the mating and postmating period. Female fertility was not affected at doses up to 400 mg/kg/day (8 times the MRHD based on AUC comparison). In sperm evaluation, decreased sperm motility, decreased sperm count and concentration, and an increase in percent abnormal sperm occurred at 400 mg/kg/day (8 times the MRHD based on AUC comparison). Male fertility was not affected at doses up to 150 mg/kg/day (4 times the MRHD based on AUC comparison).

NDA209521

Seysara

sarecycline hydrochloride

16110-247

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL - NDC: 16110-245-30 - 60 mg 30-count Bottle Label 60 mg 30-count Bottle Label

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Patient Information ). Patients taking SEYSARA should receive the following information and instructions: SEYSARA should not be used by pregnant women or women attempting to conceive a child [see Use in Specific Populations ( 8.1 )] . Advise a woman that breastfeeding is not recommended during SEYSARA therapy. Advise patients that C. difficile colitis can occur with antibiotic therapy. If patients develop watery or bloody stools, they should seek medical attention. Advise patients that intracranial hypertension can occur with tetracycline therapy. If patients experience headache or blurred vision, they should seek medical attention. Patients who experience central nervous system symptoms should be cautioned about driving vehicles or using hazardous machinery while on SEYSARA therapy. Patients should seek medical help for persistent central nervous system symptoms. Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. Advise patients to minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while using SEYSARA. If patients need to be outdoors while using SEYSARA, they should wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician. Treatment should be discontinued at the first evidence of skin erythema. Advise patients that because of the potential for drug-resistant bacteria to develop during the use of SEYSARA, take SEYSARA as directed. Skipping doses or not completing the full course of therapy may decrease the effectiveness of the current treatment course and increase the likelihood that bacteria will develop resistance and will not be treatable by other antibacterial drugs in the future. Advise patients to drink fluids liberally along with SEYSARA to reduce the risk of esophageal irritation and ulceration [see Dosage and Administration ( 2 )] . © 2019 Almirall, LLC. All rights reserved. SEYSARA ® is a registered trademark of Almirall, LLC. Almirall ® and its design are trademarks of Almirall, LLC. Distributed by: Almirall, LLC Malvern, PA 19355, USA Almirall

14 CLINICAL STUDIES The safety and efficacy of once daily SEYSARA was assessed in two 12-week multicenter, randomized, double-blind, placebo-controlled studies (Study 1 [NCT02320149] and Study 2 [NCT02322866]). Efficacy was assessed in a total of 2002 subjects 9 years of age and older. Overall, 57% were female, 78% were Caucasian, 15% were Black or African American and 51% were adults (18 to 45 years of age). Subjects were randomized to receive either SEYSARA or placebo once daily. The two co-primary efficacy endpoints were: Percentage of subjects with Investigator’s Global Assessment (IGA) success: a score of clear (0) or almost clear (1) and 2-point decrease from baseline on IGA score at Week 12. Absolute reduction from baseline in inflammatory lesion counts at Week 12. The results at Week 12 are presented in the following table. Table 2: Clinical Efficacy of SEYSARA at Week 12 Study 1 Study 2 SEYSARA (N=483) Placebo (N=485) SEYSARA (N=519) Placebo (N=515) Investigator’s Global Assessment IGA Success 21.9% 10.5% 22.6% 15.3% Inflammatory Lesions Mean absolute reduction 15.3 10.2 15.5 11.1 Mean percent reduction 52.2% 35.2% 50.8% 36.4% Mean absolute and percent reduction in inflammatory lesions was also greater with SEYSARA compared to placebo at Weeks 3, 6, and 9 for both studies.

8.5 Geriatric Use Clinical studies of SEYSARA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

8.4 Pediatric Use The safety and effectiveness of SEYSARA have been established in pediatric patients 9 years of age and older for the treatment of moderate to severe inflammatory lesions of non-nodular acne vulgaris [see Pharmacokinetics ( 12.3 ) and Clinical Studies ( 14 )] . Safety and effectiveness of SEYSARA in pediatric patients below the age of 9 years has not been established. Use of tetracycline-class antibiotics below the age of 8 is not recommended due to the potential for tooth discoloration [see Warnings and Precautions ( 5.1 )] .

8.1 Pregnancy Risk Summary SEYSARA, like tetracycline class drugs, may cause fetal harm, permanent discoloration of teeth, and reversible inhibition of bone growth when administered during pregnancy [see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.4 )] . The limited available human data are not sufficient to inform a drug-associated risk for birth defects or miscarriage. Tetracyclines are known to cross the placental barrier; therefore, SEYSARA may be transmitted from the mother to the developing fetus. In animal reproduction studies, sarecycline induced skeletal malformations in fetuses when orally administered to pregnant rats during the period of organogenesis at a dose 1.4 times the maximum recommended human dose (MRHD) of 150 mg/day (based on AUC comparison). When dosing with sarecycline continued through the period of lactation, decreases in offspring survival, offspring body weight, and implantation sites and viable embryos in offspring females occurred at a dose 3 times the MRHD (based on AUC comparison) [see Data ] . The potential risk to the fetus outweighs the potential benefit to the mother from SEYSARA use during pregnancy; therefore, pregnant patients should discontinue SEYSARA as soon as pregnancy is recognized. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risk of major birth defects and miscarriage for the indicated population is unknown. 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 Animal Data In an embryofetal developmental study in rats, sarecycline was administered to pregnant rats at oral doses up to 500 mg/kg/day during the period of organogenesis. Decreases in maternal body weight, fetal body weight and litter size and increases in the number of resorption and postimplantation loss occurred at 500 mg/kg/day (7 times the MRHD based on AUC comparison). Skeletal malformations (bent forelimb, hindlimb, and scapula) occurred at all dose levels (≥ 50 mg/kg/day, 1.4 times the MRHD based on AUC comparison). In an embryofetal developmental study in rabbits, sarecycline was administered to pregnant rabbits at oral doses up to 150 mg/kg/day during the period of organogenesis. Excessive maternal toxicity (mortality/moribundity/abortion) occurred at 150 mg/kg/day (5 times the MRHD based on AUC comparison) and this dose group was terminated early. Maternal moribundity also occurred at 100 mg/kg/day (0.6 times the MRHD based on AUC comparison). No significant embryofetal toxicity or malformations were observed at doses up to 100 mg/kg/day (0.6 times the MRHD based on AUC comparison). In a pre- and post-natal developmental study in rats, sarecycline was administered to maternal rats at oral doses up to 400 mg/kg/day during the period of organogenesis through lactation. Excessive litter toxicity (litter loss and stillbirth) occurred at 400 mg/kg/day (8 times the MRHD based on AUC comparison), which led to early termination of dams at parturition. Decreases in body weight and food consumption of dams during the lactation period occurred at 150 mg/kg/day (3 times the MRHD based on AUC comparison). Decreases in offspring survival and offspring body weight during the preweaning and growth period, and decreases in implantation sites and viable embryos in female offspring occurred at 150 mg/kg/day (3 times the MRHD based on AUC comparison). No significant maternal or developmental toxicity was observed at 50 mg/kg/day (1.4 times the MRHD based on AUC comparison).

5.1 Teratogenic Effects SEYSARA, like other tetracyclines, can cause fetal harm when administered to a pregnant woman. If SEYSARA is used during pregnancy or if the patient becomes pregnant while taking SEYSARA, the patient should be informed of the potential hazard to the fetus and treatment should be stopped immediately. The use of drugs of the tetracycline-class during tooth development (second and third trimesters of pregnancy, infancy, and childhood up to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown). This adverse reaction is more common during long-term use of these drugs, but has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in fibula growth rate has been observed in premature human infants given oral tetracycline in doses of 25 mg/kg every 6 hours. This reaction was shown to be reversible when the drug was discontinued. Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can cause retardation of skeletal development on the developing fetus. Evidence of embryotoxicity has been noted in animals treated with SEYSARA during pregnancy in association with maternal toxicity [see Use in Specific Populations ( 8.1 )] .

8 USE IN SPECIFIC POPULATIONS Sarecycline, like other tetracycline-class drugs, can cause fetal harm when administered to a pregnant woman. ( 5.1 , 8.1 ) The use of drugs of the tetracycline class during tooth development may cause permanent discoloration of teeth. ( 5.1 , 8.4 ) Lactation: Breastfeeding is not recommended. ( 8.2 ) 8.1 Pregnancy Risk Summary SEYSARA, like tetracycline class drugs, may cause fetal harm, permanent discoloration of teeth, and reversible inhibition of bone growth when administered during pregnancy [see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.4 )] . The limited available human data are not sufficient to inform a drug-associated risk for birth defects or miscarriage. Tetracyclines are known to cross the placental barrier; therefore, SEYSARA may be transmitted from the mother to the developing fetus. In animal reproduction studies, sarecycline induced skeletal malformations in fetuses when orally administered to pregnant rats during the period of organogenesis at a dose 1.4 times the maximum recommended human dose (MRHD) of 150 mg/day (based on AUC comparison). When dosing with sarecycline continued through the period of lactation, decreases in offspring survival, offspring body weight, and implantation sites and viable embryos in offspring females occurred at a dose 3 times the MRHD (based on AUC comparison) [see Data ] . The potential risk to the fetus outweighs the potential benefit to the mother from SEYSARA use during pregnancy; therefore, pregnant patients should discontinue SEYSARA as soon as pregnancy is recognized. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risk of major birth defects and miscarriage for the indicated population is unknown. 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 Animal Data In an embryofetal developmental study in rats, sarecycline was administered to pregnant rats at oral doses up to 500 mg/kg/day during the period of organogenesis. Decreases in maternal body weight, fetal body weight and litter size and increases in the number of resorption and postimplantation loss occurred at 500 mg/kg/day (7 times the MRHD based on AUC comparison). Skeletal malformations (bent forelimb, hindlimb, and scapula) occurred at all dose levels (≥ 50 mg/kg/day, 1.4 times the MRHD based on AUC comparison). In an embryofetal developmental study in rabbits, sarecycline was administered to pregnant rabbits at oral doses up to 150 mg/kg/day during the period of organogenesis. Excessive maternal toxicity (mortality/moribundity/abortion) occurred at 150 mg/kg/day (5 times the MRHD based on AUC comparison) and this dose group was terminated early. Maternal moribundity also occurred at 100 mg/kg/day (0.6 times the MRHD based on AUC comparison). No significant embryofetal toxicity or malformations were observed at doses up to 100 mg/kg/day (0.6 times the MRHD based on AUC comparison). In a pre- and post-natal developmental study in rats, sarecycline was administered to maternal rats at oral doses up to 400 mg/kg/day during the period of organogenesis through lactation. Excessive litter toxicity (litter loss and stillbirth) occurred at 400 mg/kg/day (8 times the MRHD based on AUC comparison), which led to early termination of dams at parturition. Decreases in body weight and food consumption of dams during the lactation period occurred at 150 mg/kg/day (3 times the MRHD based on AUC comparison). Decreases in offspring survival and offspring body weight during the preweaning and growth period, and decreases in implantation sites and viable embryos in female offspring occurred at 150 mg/kg/day (3 times the MRHD based on AUC comparison). No significant maternal or developmental toxicity was observed at 50 mg/kg/day (1.4 times the MRHD based on AUC comparison). 8.2 Lactation Risk Summary Tetracyclines are excreted in human milk. Because of the potential for serious adverse reactions on bone and tooth development in nursing infants from tetracycline-class antibiotics, advise a woman that breastfeeding is not recommended with SEYSARA therapy [see Warnings and Precautions ( 5.1 )] . 8.3 Females and Males of Reproductive Potential Infertility Avoid using SEYSARA in males who are attempting to conceive a child. In a fertility study in rats, sarecycline adversely affected spermatogenesis when orally administered to male rats at a dose 8 times the MRHD (based on AUC comparison) [see Nonclinical Toxicology ( 13.1 )] . 8.4 Pediatric Use The safety and effectiveness of SEYSARA have been established in pediatric patients 9 years of age and older for the treatment of moderate to severe inflammatory lesions of non-nodular acne vulgaris [see Pharmacokinetics ( 12.3 ) and Clinical Studies ( 14 )] . Safety and effectiveness of SEYSARA in pediatric patients below the age of 9 years has not been established. Use of tetracycline-class antibiotics below the age of 8 is not recommended due to the potential for tooth discoloration [see Warnings and Precautions ( 5.1 )] . 8.5 Geriatric Use Clinical studies of SEYSARA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied 1) SEYSARA (sarecycline) tablets, 60 mg are capsule-shaped, yellow, film-coated tablets debossed with “S60” on one side and blank on the other side. Bottles of 30 tablets with child-resistant closure: NDC: 16110-245-30 2) SEYSARA (sarecycline) tablets, 100 mg are capsule-shaped, yellow, film-coated tablets debossed with “S100” on one side and blank on the other side. Bottles of 30 tablets with child-resistant closure: NDC: 16110-246-30 3) SEYSARA (sarecycline) tablets, 150 mg are capsule-shaped, yellow, film-coated tablets debossed with “S150” on one side and blank on the other side. Bottles of 30 tablets with child-resistant closure: NDC: 16110-247-30 Storage Store at 20°C - 25°C (68°F - 77°F); excursions permitted to 15°C - 30°C (59°F - 86°F) [See USP Controlled Room Temperature]. Handling Protect from moisture and excessive heat.

Storage Store at 20°C - 25°C (68°F - 77°F); excursions permitted to 15°C - 30°C (59°F - 86°F) [See USP Controlled Room Temperature]. Handling Protect from moisture and excessive heat.