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Sarecycline Tablets

TABLE OF CONTENTS

1. DESCRIPTION 8. USE IN SPECIFIC POPULATIONS
2. INDICATIONS AND USAGE 9. OVERDOSAGE
3. DOSAGE AND ADMINISTRATION 10. MECHANISM OF ACTION
4. CONTRAINDICATIONS 11. PHARMACODYNAMICS
5. WARNINGS AND PRECAUTIONS 12. PHARMACOKINETICS
6. ADVERSE REACTIONS 13. HOW SUPPLIED/STORAGE AND HANDLING
7. DRUG INTERACTIONS

 

1. DESCRIPTION

Sarecycline tablets are a tetracycline class drug for oral administration. Sarecycline hydrochloride is chemically described as (4S,4aS,5aR,12aS)-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. The structural formula is represented below:

Empirical formula: C24H29N3O8.HCl - Molecular weight: 523.96 g/mol

Sarecycline 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 aluminium lake, iron oxide yellow, methacrylic acid copolymer type C, polyethylene glycol, polyvinyl alcohol, sodium bicarbonate, talc, and titatnium dioxide.

2. INDICATIONS AND USAGE

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 sarecycline beyond 12 weeks and safety beyond 12 months have not been established. Sarecycline has not been evaluated in the treatment of infections [see Clinical Studies].

To reduce the development of drug-resistant bacteria as well as to maintain the effectiveness of other antibacterial drugs, sarecycline should be used only as indicated [see Warnings and Precautions (5.6)].

3. DOSAGE AND ADMINISTRATION

The recommended dosage of sarecycline is based on body weight described in Table 1. If there is no improvement after 12 weeks, reassess treatment with sarecycline.

Table 1: Dosing Table for Sarecycline

Take sarecycline once daily, with or without food. To reduce the risk of esophageal irritation and ulceration, administer sarecycline with adequate amounts of fluid.

4. CONTRAINDICATIONS

Sarecycline is contraindicated in persons who have shown hypersensitivity to any of the tetracyclines.

5. WARNINGS AND PRECAUTIONS

5.1 Teratogenic Effects

A. Sarecycline, like other tetracyclines, can cause fetal harm when administered to a pregnant woman. If sarecycline is used during pregnancy or if the patient becomes pregnant while taking sarecycline, the patient should be informed of the potential hazard to the fetus and treatment should be stopped immediately.

B. 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.

C. 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 sarecycline during pregnancy in association with maternal toxicity [see Use in Specific Populations (8.1)].

5.2 Clostridium difficile Associated Diarrhea (Antibiotic Associated Colitis)

Clostridium difficile associated diarrhea (CDAD) has been reported with nearly all antibacterial agents, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to potential overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile should be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

5.3 Central Nervous System Effects

Central nervous system side effects including light-headedness, dizziness or vertigo have been reported with tetracycline use. Patients who experience these symptoms should be cautioned about driving vehicles or using hazardous machinery. These symptoms may disappear during therapy and may disappear when the drug is discontinued.

5.4 Intracranial Hypertension

Intracranial hypertension in adults and adolescents has been associated with the use of tetracyclines. Clinical manifestations include headache, blurred vision and papilledema. Although signs and symptoms of intracranial hypertension resolve after discontinuation of treatment, the possibility for sequelae such as visual loss that may be permanent or severe exists. Women of childbearing age who are overweight have a greater risk for developing intracranial hypertension. Patients should be questioned for visual disturbances prior to initiation of treatment with tetracyclines. Concomitant use of isotretinoin and sarecycline should be avoided because isotretinoin, a systemic retinoid, is also known to cause intracranial hypertension [see Drug Interactions (7.1)]. If visual disturbance occurs during treatment, patients should be checked for papilledema.

5.5 Photosensitivity

Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. Patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while using sarecycline. If patients need to be outdoors while using sarecycline, they should wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician.

5.6 Development of Drug Resistant Bacteria

Bacterial resistance to tetracyclines may develop in patients using sarecycline. Because of the potential for drug-resistant bacteria to develop during the use of sarecycline, it should only be used as indicated.

5.7 Superinfection/Potential for Microbial Overgrowth

As with other antibiotic preparations, use of sarecycline may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, sarecycline should be discontinued and appropriate therapy instituted.

6. ADVERSE REACTIONS

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 sarecycline 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, sarecycline (3.1%) versus placebo (2.0%).

The following additional adverse drug reactions occurred in less than 1% of female sarecycline subjects: vulvovaginal mycotic infection (0.8%) and vulvovaginal candidiasis (0.6%).

7. DRUG INTERACTIONS

7.1 Effect of Other Drugs on Sarecycline

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 sarecycline 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 sarecycline, similar to other tetracyclines, which may decrease its efficacy. Separate dosing of sarecycline from antacids containing aluminum, calcium or magnesium, bismuth subsalicylate, and iron-containing preparations.

7.2 Effect of Sarecycline on Other Drugs

Penicillin

Similar to other tetracycline, sarecycline may interfere with the bactericidal action of penicillin. Avoid coadministration of sarecycline with penicillin.

Anticoagulants

Similar to other tetracyclines, sarecycline 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 sarecycline as appropriate.

P-Glycoprotein (P-gp) Substrates

Concomitant use of sarecycline 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 sarecycline [see Clinical Pharmacology].

Oral Hormonal Contraceptives

There is no clinically significant effect of sarecycline on the efficacy of oral contraceptives containing ethinyl estradiol and norethindrone acetate [see Clinical Pharmacology].

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Sarecycline, 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 drugassociated risk for birth defects or miscarriage. Tetracyclines are known to cross the placental barrier; therefore, sarecycline 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 sarecycline use during pregnancy; therefore, pregnant patients should discontinue sarecycline as soon as pregnancy is recognized.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated 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 sarecycline therapy [see Warnings and Precautions (5.1)].

8.3 Females and Males of Reproductive Potential

Infertility

Avoid using sarecycline 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].

8.4 Pediatric Use

The safety and effectiveness of sarecycline 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].

Safety and effectiveness of sarecycline 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 sarecycline did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

9. 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.

10. MECHANISM OF ACTION

The mechanism of action of sarecycline in treating acne vulgaris is not known.

11. PHARMACODYNAMICS

The pharmacodynamics of sarecycline for the treatment of acne vulgaris are unknown.

Cardiac Electrophysiology

At approximately 3 times the maximum recommended dose, sarecycline did not prolong the QT interval to a clinically relevant extent.

12. PHARMACOKINETICS

Increasing the sarecycline dose from 60 to 150 mg once daily in healthy subjects resulted in a slightly less than proportional increase in sarcyeline steady-state Cmax and AUCtau. 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 (Tmax) 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 Tmax by approximately 0.53 hour and decreased sarecycline Cmax 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 sarecycline with a combination oral contraceptive, ethinyl estradiol (EE) 20 mcg plus norethindrone (NE) acetate 1 mg, increased EE Cmax by 14% and AUCtau by 11%, and increased NE Cmax by 18% and AUCtau by 23%.

Coadministration of a single dose of sarecycline 150 mg resulted in a 26% increase in Cmax 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.

13. HOW SUPPLIED/STORAGE AND HANDLING

How Supplied:

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: 0023-6245-30

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: 0023-6246-30

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: 0023-6247-30

Storage and Handling:

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

Protect from moisture and excessive heat.

Rx only

Rev 10/18