Ella

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 )

• 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) ].
• 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).

• 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.
• IN SPECIFIC POPULATIONS
• 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 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.
• 8.2 Lactation Risk Summary 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.
• Data 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 [48-72 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 administration.
• 8.3 Females and Males of Reproductive Potential Contraception Progestin-containing contraceptives may impair the ability of ella to delay ovulation.
• Advise females to use a reliable barrier method for subsequent acts of intercourse until her next menstrual period.
• 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 of contraception 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) , Drug Interactions (7) , and Clinical Pharmacology (12.2 , 12.3) ] .
• 8.4 Pediatric Use 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.
• 8.5 Geriatric Use This product is not intended for use in postmenopausal women.
• 8.6 Race 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.
• 8.7 Hepatic Impairment No studies have been conducted to evaluate the effect of hepatic disease on the disposition of ella .
• 8.8 Renal Impairment No studies have been conducted to evaluate the effect of renal disease on the disposition of ella .

• 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) ] .

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.