Included as part of the "PRECAUTIONS" Section
ella is not indicated for termination of an existing 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.
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.
A CYP3A4 inducer, rifampin, decreases the plasma concentration of ella significantly. ella should not be administered with CYP3A4 inducers [see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY].
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 and CLINICAL PHARMACOLOGY].
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.
Sexually Transmitted Infections/HIV
ella does not protect against HIV infection (AIDS) or other sexually transmitted infections (STIs).
Patient Counseling Information
[See FDA-Approved PATIENT INFORMATION]
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.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
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.
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/m2). 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.
Use In Specific Populations
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 1/3, 1/2, and 3 times respectively, the human exposure at a dose of
30 mg [see 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.
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/m2). 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.
Ulipristal acetate and its active metabolite, monodemethyl-ulipristal acetate, are present in human milk in small amounts (see Data). Based on the levels of drug and active metabolite measured in breastmilk, a fully breastfed child would receive
a weight-adjusted dosage of approximately 0.8% of ulipristal acetate and monodemethyl-ulipristal acetate on Day 1 of drug administration and an approximate total of 1% of the maternal dose over a 5-day period after drug administration. There is no information on the effects on the breastfed child or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ella and any potential adverse effects on the breastfed child from ella or from the underlying maternal condition
The breast milk of 12 lactating women following administration of ella was collected in 24-hour increments to measure the concentrations of ulipristal acetate and the active metabolite monodemethyl-ulipristal acetate in breast milk. The mean daily concentrations of ulipristal acetate in breast milk were 22.7 ng/mL [0-24 hours], 2.96 ng/mL [24-48 hours], 1.56 ng/mL [48-72 hours], 1.04 ng/mL [72-96 hours], and 0.69 ng/mL [96-120 hours]. The mean daily concentrations of monodemethyl-ulipristal acetate in breast milk were 4.49 ng/mL [0-24 hours], 0.62 ng/mL [24-48 hours], 0.28 ng/mL [4872
hours], 0.17 ng/mL [72-96 hours], and 0.10 ng/mL [96-120 hours]. Using these data, a fully breastfed infant would receive approximately 4.1 mcg/kg of ulipristal acetate and monodemethyl-ulipristal acetate on Day 1 following drug administration and approximately 5.2 mcg/kg over a five day period following drug administartion.
Females And Males Of Reproductive Potential
ella and progestin-containing contaceptives may interact and decrease the effectivess of both products. Advise females to use a a reliable barrier method for subsequent acts of intercourse until her next menstrual period and to wait at least 5 days after taking ella to resume oral contraceptives [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS, and CLINICAL PHARMACOLOGY].
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.
While no formal studies have evaluated the effect of race, a cross-study comparison of two pharmacokinetic studies indicated that exposure in South Asians may exceed that in Caucasians and African Americans. However, no difference in efficacy and safety was observed for women of different races in clinical studies.
No studies have been conducted to evaluate the effect of hepatic disease on the disposition of ella.
No studies have been conducted to evaluate the effect of renal disease on the disposition of ella.