ELLA Tablet Ref.[10802] Active ingredients: Ulipristal

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).

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) and 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):

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

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.

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

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 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 [see Warnings and Precautions (5.5) and Clinical Pharmacology (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 Clinical Pharmacology(12.2)].

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 ⅓ and ½ 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.

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.

Contraception

Ella and progestin-containing contraceptives' may interact and decrease the effectiveness 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 (5.5), Drug Interactions (7), and Clinical Pharmacology (2.2, 12.3)].

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.

No studies have been conducted to evaluate the effect of renal disease on the disposition of ella.

No studies have been conducted to evaluate the effect of hepatic disease on the disposition of ella.

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.