Seysara (Page 3 of 4)

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.

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).

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.

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.

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, USAAlmirall

This Patient Information has been approved by the U.S. Food and Drug Administration.	Issued: 07/2019
PATIENT INFORMATION SEYSARA® (SAY’ sara) (sarecycline) tablets
What is SEYSARA? SEYSARA is a prescription medicine used to treat moderate to severe acne vulgaris in people 9 years and older. SEYSARA should not be used for the treatment or prevention of infections It is not known if SEYSARA is safe and effective for use for longer than 12 weeks. It is not known if SEYSARA is safe and effective in children under 9 years of age.
Do not take SEYSARA: if you are allergic to medicines in the tetracycline-class. Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure.
What should I tell my healthcare provider before taking SEYSARA? Before taking SEYSARA, tell your healthcare provider about all of your medical conditions, including if you: have diarrhea or watery stools have vision problems are pregnant or plan to become pregnant. SEYSARA may harm your unborn baby. Taking SEYSARA during the second and third trimesters of pregnancy may cause serious side effects on the growth of bone and teeth of your baby. Stop taking SEYSARA and call your healthcare provider right away if you become pregnant during your treatment with SEYSARA. are breastfeeding or plan to breastfeed. SEYSARA can pass into your breast milk and may harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take SEYSARA. You should not breastfeed during treatment with SEYSARA. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. SEYSARA and other medicines can affect each other causing serious side effects. Especially tell your healthcare provider if you take: a blood thinner a penicillin antibiotic medicine antacids that contain aluminum, calcium or magnesium or iron-containing products an acne medication taken by mouth that contains isotretinoin or acitretin
How should I take SEYSARA? Take SEYSARA exactly as your healthcare provider tells you. Skipping doses or not taking all doses of SEYSARA may: make the treatment not work as well. increase the chance that the bacteria will become resistant to SEYSARA. Take SEYSARA 1 time a day with or without food. Take SEYSARA with enough fluid to completely swallow the tablet and to lower your risk of getting irritation or ulcers in your esophagus. Your esophagus is the tube that connects your mouth to your stomach. If you take too much SEYSARA, stop taking SEYSARA and call your healthcare provider right away or go to the nearest hospital emergency room.
What should I avoid during treatment with SEYSARA? Avoid sunlight or artificial sunlight, such as a tanning booth or sunlamp. You could get severe sunburn. Use sunscreen and wear loose-fitting clothes that cover your skin while out in sunlight. Stop taking SEYSARA if you get sunburn. You should not drive or operate dangerous machinery until you know how SEYSARA affects you. Tetracyclines may cause you to feel dizzy or lightheaded, or have a spinning feeling (vertigo).
What are the possible side effects of SEYSARA? SEYSARA may cause serious side effects, including: Harm to an unborn baby. See “What should I tell my healthcare provider before taking SEYSARA?” Permanent teeth discoloration. SEYSARA may permanently turn a baby or child’s teeth yellow-gray-brown during tooth development. You should not use SEYSARA during tooth development. Tooth development happens in the second and third trimesters of pregnancy, and from birth to 8 years of age. Slow bone growth. SEYSARA may slow bone growth in infants and children. Slow bone growth is reversible after stopping treatment with SEYSARA. Diarrhea. Diarrhea can happen with most antibiotics, including SEYSARA. This diarrhea may be caused by an infection (Clostridium difficile) in your intestines. Call your healthcare provider right away if you get watery or bloody stools. Central nervous system effects. See “What should I avoid while taking SEYSARA?” Central nervous system effects such as light headedness, dizziness, and a spinning feeling (vertigo) may go away during your treatment with SEYSARA or if treatment is stopped. Call your healthcare provider if these symptoms do not go away. Increased pressure around the brain (intracranial hypertension). This condition may lead to vision changes and permanent vision loss. You may be more likely to get intracranial hypertension if you are a female of childbearing potential and are overweight or have a history of intracranial hypertension. Stop taking SEYSARA and tell your healthcare provider right away if you have blurred vision, vision loss, or headaches. Sensitivity to sunlight (photosensitivity). See “What should I avoid during treatment with SEYSARA?” The most common side effect of SEYSARA is nausea. SEYSARA may cause fertility problems in males. This may affect your ability to father a child. Talk to your healthcare provider if you have concerns about fertility. These are not all the possible side effects of SEYSARA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Almirall at 1-866-665-2782.
How should I store SEYSARA? Store SEYSARA at room temperature between 68°F to 77°F (20°C to 25°C). Keep SEYSARA away from moisture and excessive heat. Keep SEYSARA and all medicines out of the reach of children.
General information about the safe and effective use of SEYSARA. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use SEYSARA for a condition for which it was not prescribed. Do not give SEYSARA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about SEYSARA that is written for health professionals.
What are the ingredients in SEYSARA? Active ingredient: sarecycline hydrochloride Inactive ingredients: 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 titanium dioxide. © 2019 Almirall, LLC. All rights reserved. ALMIRALL ALMIRALL 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