ulipristal acetate 30 MG Oral Tablet [Ella]
Generic Name: ULIPRISTAL ACETATE
Brand Name: Ella
- Substance Name(s):
- ULIPRISTAL ACETATE
DRUG INTERACTIONS
7 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 ) 7.1 Changes in Emergency Contraceptive Effectiveness Associated with Co-Administration of Other Products 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 Pharmacokinetics ( 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 [see Warnings and Precautions ( 5.5 ) and Pharmacodynamics ( 12.2 )] .
Avoid co-administration of ella and hormonal contraceptives.
If a woman wishes to start or resume hormonal contraception after the intake of ella , she should do so no sooner than 5 days afterwards, and she should use a reliable barrier method until the next menstrual period.
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 Warnings and Precautions ( 5.5 ) and Clincial Pharmacology( 12.2 )] .
OVERDOSAGE
10 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.
DESCRIPTION
11 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
CLINICAL STUDIES
14 Two multicenter clinical studies evaluated the efficacy and safety of ella .
An open-label study provided the primary data to support the efficacy and safety of ulipristal acetate for emergency contraception when taken 48 to 120 hours after unprotected intercourse.
A single-blind comparative study provided the primary data to support the efficacy and safety of ulipristal acetate for emergency contraception when taken 0 to 72 hours after unprotected intercourse and provided supportive data for ulipristal acetate for emergency contraception when taken > 72 to 120 hours after unprotected intercourse.
Women in both studies were required to have a negative pregnancy test prior to receiving emergency contraception.
The primary efficacy analyses were performed on subjects less than 36 years of age who had a known pregnancy status after taking study medication.
Table 3: Summary of Clinical Trial Results for Women Who Received a Single Dose of ella (30 mg Ulipristal Acetate) Open-Label Study 48 to 120 Hours * Single-Blind Comparative Study 0 to 72 Hours * N = 1,242 N = 844 Expected Pregnancy Rate ** 5.5 5.6 Observed Pregnancy Rate ** (95% confidence interval) 2.2 (1.5, 3.2) 1.9 (1.1, 3.1) * Time after unprotected intercourse when ella was taken ** Number of pregnancies per 100 women at risk for pregnancy 14.1 Open-Label Study This study was a multicenter open-label trial conducted at 40 family planning clinics in the United States.
Healthy women with a mean age of 24 years who requested emergency contraception 48 to 120 hours after unprotected intercourse received a dose of 30 mg ulipristal acetate ( ella ).
The median BMI for the study subjects was 25.3 and ranged from 16.1 to 61.3 kg/m 2 .
Twenty-seven pregnancies occurred in 1,242 women aged 18 to 35 years evaluated for efficacy.
The number of pregnancies expected without emergency contraception was calculated based on the timing of intercourse with regard to each woman’s menstrual cycle.
ella statistically significantly reduced the pregnancy rate, from an expected rate of 5.5% to an observed rate of 2.2%, when taken 48 to 120 hours after unprotected intercourse.
14.2 Single-Blind Comparative Study This study was a multicenter, single-blind, randomized comparison of the efficacy and safety of 30 mg ulipristal acetate ( ella ) to levonorgestrel (another form of emergency contraception).
Subjects were enrolled at 35 sites in the U.S., the United Kingdom and Ireland, with the majority (66%) having been enrolled in the U.S.
Healthy women with a mean age of 25 years who requested emergency contraception within 120 hours of unprotected intercourse were enrolled and randomly allocated to receive ella or levonorgestrel 1.5 mg.
The median BMI for the study subjects was 25.3 and ranged from 14.9 to 70.0 kg/m 2 .
In the ella group, 16 pregnancies occurred in 844 women aged 16 to 35 years when emergency contraception was taken 0 to 72 hours after unprotected intercourse.
The number of pregnancies expected without emergency contraception was calculated based on the timing of intercourse with regard to each woman’s menstrual cycle; ella statistically significantly reduced the pregnancy rate, from an expected 5.6% to an observed 1.9%, when taken within 72 hours after unprotected intercourse.
There were no pregnancies observed in the women who were administered ella more than 72 hours after unprotected intercourse (10% of women who received ella ).
14.3 Pooled Analysis Data from the two studies were pooled to provide a total efficacy population of women treated with ulipristal acetate up to 120 hours after UPI.
Time Trend analysis for the five 24-hour intervals from 0 to 120 hours between unprotected intercourse and treatment was conducted.
There were no significant differences in the observed pregnancy rates across the five time intervals.
Subgroup analysis of the pooled data by BMI showed that for women with BMI > 30 kg/m 2 (16% of all subjects), the observed pregnancy rate was 3.1% (95% CI: 1.7, 5.7), which was not significantly reduced compared to the expected pregnancy rate of 4.5% in the absence of emergency contraception taken within 120 hours after unprotected intercourse.
In the comparative study, a similar effect was seen for the comparator emergency contraception drug, levonorgestrel 1.5 mg.
For levonorgestrel, when used by women with BMI > 30 kg/m 2 , the observed pregnancy rate was 7.4% (95% CI: 3.9, 13.4), compared to the expected pregnancy rate of 4.4% in the absence of emergency contraception taken within 72 hours after unprotected intercourse.
HOW SUPPLIED
16 /STORAGE AND HANDLING ella (ulipristal acetate) tablet, 30 mg is supplied in a PVC-PE-PVDC or PVC-PVDC-aluminum blister.
The tablet is a white to off-white, round, curved tablet marked with ” ella ” on both sides.
NDC 50102-911-01 (1 tablet unit of use package) Store at 20-25°C (68-77°F).
[See USP controlled room temperature.] Keep the blister in the outer carton in order to protect from light.
Keep out of reach of children .
RECENT MAJOR CHANGES
Contraindication ( 4 ) 05/2018 Warnings and Precautions, Existing Pregnancy ( 5.1 ) 05/2018 Use in Specific Populations ( 8.1 ), ( 8.2 ) ( 8.3 ) 05/2018
GERIATRIC USE
8.5 Geriatric Use This product is not intended for use in postmenopausal women.
DOSAGE FORMS AND STRENGTHS
3 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 )
MECHANISM OF ACTION
12.1 Mechanism of Action 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.
INDICATIONS AND USAGE
1 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.
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 )
PEDIATRIC USE
8.4 Pediatric Use 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.
PREGNANCY
8.1 Pregnancy 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 wome 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.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS ella is not indicated for termination of an existing pregnancy( 5.1) Subsequent acts of intercourse should be protected by a reliable barrier method until next menstrual period.
If a woman wishes to use hormonal contraception, she should do so no sooner than 5 days after intake of ella .
( 5.5 ) Ectopic pregnancy: Women who become pregnant or complain of lower abdominal pain after taking ella should be evaluated for ectopic pregnancy.
( 5.2 ) Effect on menstrual cycle: ella may alter the next expected menses.
If menses is delayed beyond 1 week, pregnancy should be ruled out.
( 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 that occur in that same menstrual cycle.
Because ella and the progestin component of hormonal contraceptives both bind to the progesterone receptor, using them together could reduce their contraceptive effect.
After using ella , if a woman wishes to use hormonal contraception, she should 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 Drug Interactions ( 7.1 and 7.3 ) and Clinical Pharmacology ( 12.2 ) ].
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 (AIDS) or other sexually transmitted infections (STIs).
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION [See FDA- Approved Patient Labeling] Information for Patients 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 that they should not take ella if they know or suspect they are pregnant and that ella is not indicated for termination of an existing pregnancy.
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 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.
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.
Advise patients not to use ella as routine contraception, or to use it repeatedly in the same menstrual cycle.
Advise patients that using ella and hormonal contraceptives together can affect the effectiveness of each.
Advise patients to use a reliable barrier method for all subsequent acts of intercourse until the next menstrual period.
If a woman wishes to use hormonal contraception, she should do so no sooner than 5 days after intake of ella , and she should use a reliable barrier method until the next menstrual period.
Advise patients not to use ella if they are taking a CYP3A4 inducer.
Inform patients that ella does not protect against HIV infection (AIDS) and other sexually transmitted diseases/infections.
DOSAGE AND ADMINISTRATION
2 Instruct patients to take one tablet orally as soon as possible within 120 hours (5 days) after unprotected intercourse or a known or suspected contraceptive failure.
The tablet can be taken with or without food.
If vomiting occurs within 3 hours of ella intake, consideration should be given to repeating the dose.
ella can be taken at any time during the menstrual cycle.
One tablet taken orally as soon as possible, within 120 hours (5 days) after unprotected intercourse or a known or suspected contraceptive failure.
( 2 ) The tablet can be taken with or without food.
( 2 )