Ulipristal Acetate

Ella is a progesterone agonist/antagonist emergency contraceptive indicated for prevention of pregnancy following unprotected intercourse or a known or suspected contraceptive failure [see Dosage and Administration (2.1) ] . Ella is not intended for routine use as a contraceptive. Ella is a progesterone agonist/antagonist emergency contraceptive indicated for prevention of pregnancy following unprotected intercourse or a known or suspected contraceptive failure. Ella is not intended for routine use as a contraceptive. ( 1 )

• Take one tablet orally as soon as possible, within 120 hours (5 days) after unprotected intercourse or a known or suspected contraceptive failure. Take with or without food. Take at any time during the menstrual cycle. ( 2.1 )
• After ella use, initiate or resume hormonal contraception no sooner than 5 days after the intake of ella and use a reliable barrier method until the next menstrual period. ( 2.2 )
• If vomiting occurs within 3 hours of taking ella , consider repeating the dose. ( 2.3 )

2.1 Recommended Dosage and Administration

• Take one tablet of ella orally as soon as possible within 120 hours (5 days) after unprotected intercourse or a known or suspected contraceptive failure.
• Take ella with or without food.
• Take ella at any time during the menstrual cycle.

2.2 Recommendations Regarding Use with Hormonal Contraception After ella use, initiate or resume hormonal contraception no sooner than 5 days after the intake of ella and use a reliable barrier method until the next menstrual period. For known or suspected failure of hormonal contraception refer to the hormonal contraceptive’s prescribing information for instructions on what to do [see Warnings and Precautions (5.5) , Drug Interactions (7.1) and Clinical Pharmacology (12.2 )] .

2.3 Recommendation in Case of Gastrointestinal Disturbances If vomiting occurs within 3 hours of taking ella , consider repeating the dose.

The ella tablet is supplied as a white to off-white, round, curved tablet containing 30 mg of ulipristal acetate and is marked " ella " on both sides. 30 mg tablet ( 3 )

Ella is contraindicated for use in the case of known or suspected pregnancy [see Use in Specific Populations (8.1) ].

• Known or suspected pregnancy ( 4 )

5 WARNINGS AND PRECAUTIONS

• Existing Pregnancy: ella is not indicated for termination of an existing pregnancy. ( 5.1)
• Ectopic pregnancy: Evaluate women who become pregnant or complain of lower abdominal pain after taking ella for ectopic pregnancy. ( 5.2 )
• Fertility Following Use : Rapid return of fertility is likely. Subsequent acts of intercourse should be protected by a reliable barrier method of contraception until the next menstrual period. ( 5.5 )
• Effect on Menstrual Cycle: ella may alter the next expected menses. If menses is delayed beyond 1 week, rule out pregnancy. ( 5.6 )
• Ella does not protect against STI/HIV. ( 5.7 )

5.1 Existing Pregnancy Ella is not indicated for termination of an existing pregnancy.

5.2 Ectopic Pregnancy A history of ectopic pregnancy is not a contraindication to use of this emergency contraceptive method. Healthcare providers, however, should consider the possibility of ectopic pregnancy in women who become pregnant or complain of lower abdominal pain after taking ella . A follow-up physical or pelvic examination is recommended if there is any doubt concerning the general health or pregnancy status of any woman after taking ella .

5.3 Repeated Use Ella is for occasional use as an emergency contraceptive. It should not replace a regular method of contraception. Repeated use of ella within the same menstrual cycle is not recommended, as safety and efficacy of repeat use within the same cycle has not been evaluated.

5.4 CYP3A4 Inducers A CYP3A4 inducer, rifampin, decreases the plasma concentration of ella significantly. Ella should not be administered with CYP3A4 inducers [see Drug interactions (7.1) and Clinical Pharmacology (12.3) ] .

5.5 Fertility Following Use A rapid return of fertility is likely following treatment with ella for emergency contraception. After use of ella , a reliable barrier method of contraception should be used with subsequent acts of intercourse until the next menstrual period. After using ella , if a woman wishes to initiate hormonal contraception as a regular method, she can do so, no sooner than 5 days after the intake of ella and she should use a reliable barrier method until the next menstrual period [ see Dosage and Administration (2.2) , Drug Interactions (7.1 and 7.3 ) and Clinical Pharmacology (12.2) ]. Progestin-containing contraceptives may impair the ability of ella to delay ovulation. Advise women to follow the instructions on the initiation or resumption of hormonal contraceptives after ella intake [see Dosage and Administration(2.2) ].

5.6 Effect on Menstrual Cycle After ella intake, menses sometimes occur earlier or later than expected by a few days. In clinical trials, cycle length was increased by a mean of 2.5 days but returned to normal in the subsequent cycle. Seven percent of subjects reported menses occurring more than 7 days earlier than expected, and 19% reported a delay of more than 7 days. If there is a delay in the onset of expected menses beyond 1 week, rule out pregnancy. Nine percent of women studied reported intermenstrual bleeding after use of ella .

5.7 Sexually Transmitted Infections/HIV Ella does not protect against HIV infection (the virus that causes AIDS) or other sexually transmitted infections (STIs).

Several in vivo drug interaction studies have shown that ella is predominantly metabolized by CYP3A4.

• Drugs or herbal products that induce CYP3A4 decrease the effectiveness of ella . ( 7.1 )
• Initiation of progestin-containing contraceptives may impair the ability of ella to delay ovulation. ( 7.1 )

7.1 Changes in Emergency Contraceptive Effectiveness Associated with Co-Administration of Other Products CYP3A inducers Drugs or herbal products that induce CYP3A4 decrease the plasma concentrations of ella , and may decrease its effectiveness [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3) ] . Avoid co-administration of ella and drugs or herbal products such as:

• barbiturates
• bosentan
• carbamazepine
• felbamate
• griseofulvin
• oxcarbazepine
• phenytoin
• rifampin
• St. John's Wort
• topiramate Hormonal contraceptives Progestin-containing contraceptives may impair the ability of ella to delay ovulation. After using ella , if a woman wishes to initiate or resume hormonal contraception, she can do so, no sooner than 5 days after the intake of ella and she should use a reliable barrier method until the next menstrual period. If a woman used ella due to a known or suspected failure of her hormonal contraception refer to the hormonal contraceptive’s prescribing information for instructions on what to do [see Dosage and Administration (2.2) , Warnings and Precautions (5.5) and Clinical Pharmacology (12.2) ] .

7.2 Increase in Plasma Concentrations of ella Associated with Co-Administered Drugs CYP3A4 inhibitors such as itraconazole or ketoconazole increase plasma concentrations of ella [see Pharmacokinetics (12.3) ] .

7.3 Effects of ella on Co-Administered Drugs Hormonal contraceptives: ella may impact the effect of the progestin component of hormonal contraceptives. Therefore, if a woman wishes to use hormonal contraception after using ella , she should use a reliable barrier method for subsequent acts of intercourse until her next menstrual period [see Dosage and Administration (2.2) , Warnings and Precautions (5.5) and Clinical Pharmacology (12.2) ] .

The most common adverse reactions (≥ 5%) in the clinical trials were headache (18%), abdominal pain (12%), nausea (12%), dysmenorrhea (9%), fatigue (6%) and dizziness (5%). ( 6 )To report SUSPECTED ADVERSE REACTIONS, contact HRA Pharma America Inc., at 844-994-0329 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 clinical practice. Ella was studied in an open-label multicenter trial (Open-Label Study) and in a comparative, randomized, single-blind, multicenter trial (Single-Blind Comparative Study). In these studies, a total of 2,637 (1,533 + 1,104) women in the 30 mg ulipristal acetate groups were included in the safety analysis. The mean age of women who received ulipristal acetate was 24.5 years and the mean body mass index (BMI) was 25.3. The racial demographics of those enrolled were 67% Caucasian, 20% Black or African American, 2% Asian, and 12% other. The most common adverse reactions (≥ 10%) in the clinical trials for women receiving ella were headache (18% overall), nausea (12% overall) and abdominal and upper abdominal pain (12% overall). Table 1 lists those adverse reactions that were reported in ≥ 5% of subjects in the clinical studies ( 14 ). Table 1: Adverse Reactions in ≥ 5% of Women (%) Receiving a Single Dose of ella (30 mg Ulipristal Acetate) Most Common Adverse Reactions Open-Label Study Single-Blind Comparative Study N = 1,533 N = 1,104 Headache 18 19 Nausea 12 13 Abdominal and upper abdominal pain 15 8 Dysmenorrhea 7 13 Fatigue 6 6 Dizziness 5 5 6.2 Postmarketing Experience Adolescents: the safety profile observed in adolescents aged 17 and younger in studies and post-marketing is similar to the safety profile in adults [see Pediatric Use (8.4) ] . The following adverse reactions have been identified during post-approval use of ella : Skin and Subcutaneous Tissue Disorders: Acne Hypersensitivity reactions, including rash, urticaria, pruritis, and angioedema Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Experience with ulipristal acetate overdose is limited. In a clinical study, single doses equivalent to up to 4 times ella were administered to a limited number of subjects without any adverse reactions.

Risk Summary Ella is contraindicated for use during an existing or suspected pregnancy. No signal of concern regarding pregnancy complications was found in postmarketing studies [see Data ]. Isolated cases of major malformations in ella- exposed pregnancies were identified; however, the data are not sufficient to determine a risk for birth defects with inadvertent use of ella during pregnancy. Miscarriage was reported in 14% of the known pregnancy outcomes; a rate that is similar to the U.S. background rate for miscarriage. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. In animal reproduction studies, no malformations were observed during repeated administration of ulipristal acetate to pregnant rats, rabbits and monkeys at daily drug exposures ⅓, ½, and 3 times respectively, the human exposure at a dose of 30 mg [ see Data ] . Data Human Data Ella pregnancy exposure data was collected in the U.S. and Europe from 1999 to 2015 and analyzed post-marketing using data from interventional clinical trials, observational studies and pharmacovigilance reports. Known pregnancy outcomes were available for 462/784 pregnancies in which women received ella at doses of 30 mg or greater during the conception cycle or during pregnancy. Data of pregnancies with known outcome were analyzed prospectively for 272 cases and retrospectively for 190 cases. Pregnancy outcomes included 302 elective abortions (2 for fetal anomalies including 1 with trisomy 21), 63 spontaneous abortions, and 13 ectopic pregnancies. No maternal or fetal deaths were reported. 84 pregnancies continued until birth, with congenital anomalies reported in 5 infants, including 4 major malformations (2/4 with genetic syndromes). Although these data do not allow estimation of the prevalence rate of congenital anomalies associated with inadvertent use of ella in pregnancy or determination of a causal relationship between reported anomalies and ella , they show that ella -exposed pregnancies were not associated with a pattern of increased risk of adverse outcomes. Animal Data Ulipristal acetate was administered repeatedly to pregnant rats and rabbits during the period of organogenesis. Embryofetal loss was noted in all pregnant rats and in half of the pregnant rabbits following 12 and 13 days of dosing, at daily drug exposures 1/3 and 1/2 the human exposure, respectively, based on body surface area (mg/m 2 ). There were no malformations of the surviving fetuses in these studies. Adverse effects were not observed in the offspring of pregnant rats administered ulipristal acetate during the period of organogenesis through lactation at drug exposures 1/24 the human exposure based on AUC. Administration of ulipristal acetate to pregnant monkeys for 4 days during the first trimester caused pregnancy termination in 2/5 animals at daily drug exposures 3 times the human exposure based on body surface area.

There is no relevant use of ulipristal acetate for children of prepubertal age in the indication emergency contraception . Adolescents: Safety and efficacy of ella have been established in women of reproductive age. The clinical trials of ella enrolled 41 females under age 18, and a post-marketing observational study evaluating effectiveness and safety of ella in adolescents enrolled 279 females under age 18, including 76 under age 16 years. In these studies, the safety and efficacy profile observed in adolescents aged 17 and younger was similar to that in adults. Use of ella before menarche is not indicated.

This product is not intended for use in postmenopausal women.

The ella (ulipristal acetate) tablet for oral use contains 30 mg of a single active steroid ingredient, ulipristal acetate [17α-acetoxy-11β-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione], a synthetic progesterone agonist/antagonist. The inactive ingredients are lactose monohydrate, povidone K-30, croscarmellose sodium and magnesium stearate. Ulipristal acetate is a white to yellow crystalline powder which has a molecular weight of 475.6. The structural formula is: C 30 H 37 NO 4 Ulipristal acetate structural formula

When taken immediately before ovulation is to occur, ella postpones follicular rupture. The likely primary mechanism of action of ulipristal acetate for emergency contraception is therefore inhibition or delay of ovulation; however, alterations to the endometrium that may affect implantation may also contribute to efficacy.

Ulipristal acetate is a selective progesterone receptor modulator with antagonistic and partial agonistic effects (a progesterone agonist/antagonist) at the progesterone receptor. It binds the human progesterone receptor and prevents progesterone from occupying its receptor. The pharmacodynamics of ulipristal acetate depend on the timing of administration in the menstrual cycle. Administration in the mid-follicular phase causes inhibition of folliculogenesis and reduction of estradiol concentration. Pharmacodynamic data showed that administration of ella to 34 women in the late follicular phase postponed follicular rupture for at least 5 days in all (100%) of 8 subjects who took ella before the luteinizing hormone (LH) surge and 11 (79%) of 14 subjects who took ella immediately before ovulation (when LH has already started to rise). However, treatment was not effective in postponing follicular rupture when administered on the day of LH peak. Dosing in the early luteal phase does not significantly delay endometrial maturation but decreases endometrial thickness by 0.6 ± 2.2 mm (mean ± SD). Hormonal Contraceptives after ella intake: In women initiating hormonal contraception (quickstart scenario) : When a combined oral contraceptive pill (COC) containing ethinyl estradiol 30 µg + levonorgestrel 150 µg was started the day after ella intake during the follicular phase, ella did not interfere with the COC’s ability to suppress ovarian activity, as assessed by measurement of follicle size via transvaginal ultrasound, combined with serum progesterone and estradiol levels: ovarian activity was suppressed in 61.5% (24/39) of subjects receiving ella plus COC and 62.2% (23/37) of subjects receiving a placebo plus the COC. The incidence of ovulation was similar between the group that received ella plus the COC [33.3% (13/39)] and the group that received a placebo plus the COC [32.4% (12/37)]. [see Dosage and Administration (2.2) , Warnings and Precautions (5.5) and Drug Interactions (7.3) ] . The initiation of a desogestrel 75 µg progestin-only pill (POP) the day after ella intake during the follicular phase was associated with a higher incidence of ovulation in the six days following ella intake compared to an ella -only treatment group, and a relatively slower onset (3 to 4 days) of thickened cervical mucus compared to a group given desogestrel without prior ella intake (2 days), suggesting an effect of prior use of ella on the ability of desogestrel to inhibit mucus permeability. [See Dosage and Administration (2.2) , Warnings and Precautions (5.5) and Drug Interactions (7.1 ; 7.3 )] . When a COC containing ethinyl estradiol 30 µg + levonorgestrel 150 µg was started 2 days after ella intake, ella 's ability to delay ovulation, as assessed by transvaginal ultrasound, was reduced: follicular rupture occurred in 9/33 subjects (27%) in less than 5 days, compared to 1/33 subjects after ella alone (3%). [See Dosage and Administration (2.2) , Warnings and Precautions (5.5) and Drug Interactions (7.1) ] . In women resuming combined hormonal contraception (missed pills scenario): The effects on ovarian activity of delaying versus immediately resuming COCs after ella intake were investigated in 49 women who had been using COCs containing ethinyl estradiol 30 µg + levonorgestrel 150 µg once daily for 21 days followed by 7 days of placebo pills for at least one cycle. All subjects missed three consecutive pills (Days 5-7) during the first week of pills in the subsequent cycle and took ella on the following day (Day 8). These subjects were randomized to resume their COCs either on the same day as ella intake versus five days later. No ovulations with potential risk of pregnancy occurred in either group in the five days following ella intake. However, in the group that waited five days to resume taking COCs, 4/23 (17.4%) women did ovulate later in the cycle (Days 18-26) whereas no ovulations (0/26) occurred in the group that resumed COC intake on the same day as ella intake. Whether similar results can be expected with other COC products containing different progestins or missed active pills during different weeks in a treatment cycle is unknown.

Absorption Following a single dose administration of ella in 20 women under fasting conditions, maximum plasma concentrations of ulipristal acetate and the active metabolite, monodemethyl-ulipristal acetate, were 176 and 69 ng/ml and were reached at 0.9 and 1 hour, respectively. Figure 1: Mean (± SD) Plasma Concentration-time Profile of Ulipristal Acetate and Monodemethyl-ulipristal Acetate Following Single Dose Administration of 30 mg Ulipristal Acetate Table 2: Pharmacokinetic Parameter Values Following Administration of ella (ulipristal acetate) Tablet 30 mg to 20 Healthy Female Volunteers under Fasting Conditions Mean (± SD) C max (ng/ml) AUC 0-t (ng

• hr/ml) AUC 0-∞ (ng
• hr/ml) t max (hr)* t 1/2 (hr) Ulipristal acetate 176 (89) 548 (259) 556 (260) 0.9 (0.5-2.0) 32 (6.3) Monodemethyl- ulipristal acetate 69 (26) 240 (59) 246 (59) 0.9 (0.8-2.0) 27 (6.9) C max = maximum concentration AUC 0-t = area under the drug concentration curve from time 0 to time of last determinable concentration AUC 0-∞ = area under the drug concentration curve from time 0 to infinity t max = time to maximum concentration t 1/2 = elimination half-life * Median (range) Effect of food: Administration of ella together with a high-fat breakfast resulted in approximately 40 - 45% lower mean C max , a delayed t max (from a median of 0.75 hours to 3 hours) and 20 - 25% higher mean AUC 0-∞ of ulipristal acetate and monodemethyl-ulipristal acetate compared with administration in the fasting state. These differences are not expected to impair the efficacy or safety of ella to a clinically significant extent; therefore, ella can be taken with or without food. Distribution Ulipristal acetate is highly bound (> 94%) to plasma proteins, including high density lipoprotein, alpha-l-acid glycoprotein, and albumin. Metabolism Ulipristal acetate is metabolized to mono-demethylated and di-demethylated metabolites. In vitro data indicate that this is predominantly mediated by CYP3A4. The mono-demethylated metabolite is pharmacologically active. Excretion The terminal half-life of ulipristal acetate in plasma following a single 30 mg dose is estimated to be 32.4 ± 6.3 hours. Drug interactions CYP3A4 inducers: When a single 30 mg dose of ulipristal acetate was administered following administration of the strong CYP3A4 inducer, rifampin 600 mg once daily for 9 days, C max and AUC of ulipristal acetate decreased by 90% and 93% respectively. The C max and AUC of monodemethyl-ulipristal acetate decreased by 84% and 90% respectively [see Drug Interactions (7.1) ] . CYP3A4 inhibitors: When a single 10 mg dose of ulipristal acetate was administered following administration of the strong CYP3A4 inhibitor, ketoconazole 400 mg once daily for 7 days, C max and AUC of ulipristal acetate increased by 2- and 5.9- fold, respectively. While the AUC of monodemethyl-ulipristal acetate increased by 2.4-fold, C max of monodemethyl-ulipristal acetate decreased by 47%. There was no in vivo drug-drug interaction study between ulipristal acetate 30 mg and CYP3A4 inhibitors [see Drug Interactions (7.1) ] . In vitro studies demonstrated that ella does not induce or inhibit the activity of cytochrome P450 enzymes. P-glycoprotein (P-gp) transporter: In vitro data indicate that ulipristal may be an inhibitor of P-gp at clinically relevant concentrations. When a single 60 mg dose of fexofenadine, a substrate of P-gp glycoprotein, was administered 1.5 hours after the administration of a single 10 mg dose of ulipristal acetate, there was no increase in C max or AUC of fexofenadine. Breast Cancer Resistance Protein (BCRP) transporter: In vitro data indicate that ulipristal acetate may be an inhibitor of BCRP at the intestinal level. The effects of ella on P-gp and BCRP transporters are unlikely to have any clinical consequences when considering ella 's single dose treatment regimen, although there was no in vivo drug interaction study between ulipristal acetate 30 mg ( ella ) and substrates of P-pg and BCRP transporters. Figure 1

, Mutagenesis, Impairment of Fertility Carcinogenicity: Carcinogenicity potential was evaluated in rats and mice. Sprague Dawley rats were exposed to ulipristal acetate daily for 99-100 weeks at doses of 1, 3, or 10 mg/kg/day, representing exposures up to 31 times higher than exposures at the maximum recommended human dose (MRHD). There were no drug-related neoplasms in male rats. In female rats, potential treatment-related neoplastic findings were limited to adrenal cortical adenomas in the intermediate dose group (3 mg/kg/day). Despite the increase, this incidence of adrenal cortical adenomas in females may not be relevant to clinical use. Tg.rasH2 transgenic mice were exposed to ulipristal acetate for 26 weeks at doses of 5, 45, or 130 mg/kg/day, representing exposures 100 times higher than exposures at the MRHD. There was no drug-related increase in neoplasm incidence in male or female mice. Genotoxicity: Ulipristal acetate was not genotoxic in the Ames assay, in vitro mammalian assays utilizing mouse lymphoma cells and human peripheral blood lymphocytes , and in an in vivo micronucleus assay in mice. Impairment of Fertility: Single oral doses of ulipristal acetate prevented ovulation in 50% of rats at 2 times the human exposure based on body surface area (mg/m 2 ). Single doses of ulipristal acetate given on post-coital days 4 or 5 prevented pregnancy in 80-100% of rats and in 50% of rabbits when given on post-coital days 5 or 6 at drug exposures 4 and 12 times the human exposure based on body surface area. Lower doses administered for 4 days to rats and rabbits were also effective at preventing ovulation and pregnancy .

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-Approved patient Labeling (Patient Information). Administration Instructions

• Instruct patients to take ella as soon as possible and not more than 120 hours after unprotected intercourse or a known or suspected contraceptive failure.
• Advise patients to contact their healthcare provider immediately in case of vomiting within 3 hours of taking the tablet, to discuss whether to take another tablet.
• Advise patients that after using ella , a reliable barrier method of contraception should be used for all subsequent acts of intercourse until the next menstrual period.
• Advise patients that after using ella , additional levonorgestrel emergency contraceptive pills should not be used within 5 days of ella intake.
• Advise patients that after using ella , hormonal contraception should be initiated or resumed no sooner than 5 days after the intake of ella and to use a reliable contraceptive barrier method until the next menstrual period.
• Advise patients with known or suspected failure of a hormonal contraceptive to refer to the hormonal contraceptive’s prescribing information for instructions on what to do. Ectopic Pregnancy Advise patients to seek medical attention if they experience severe lower abdominal pain 3 to 5 weeks after taking ella , in order to be evaluated for an ectopic pregnancy [see Warnings and Precautions (5.2) ] . Effect on Menstrual Cycle Advise women that after ella intake, menses may occur earlier or later than expected, by a few days. Advise patients to contact their healthcare provider and consider the possibility of pregnancy if their period is delayed after taking ella by more than 1 week beyond the date it was expected [see Warnings and Precautions (5.6) ] . Sexually Transmistted Infections/HIV Inform women that ella does not protect against HIV infection (the virus that causes AIDS) and other sexually transmitted diseases/infections [see Warnings and Precautions (5.7) ]. Drug Interactions Advise women to inform their healthcare provider if they take herbal supplements such as St. John’s wort [see Drug Interactions (7.1) ].