Ella (Page 2 of 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
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.

7 DRUG INTERACTIONS

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 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 Pharmacodynamics (12.2)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category X. [See Contraindications (4).]

Use of ella is contraindicated during an existing or suspected pregnancy.There are no adequate and well controlled studies in pregnant women.

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.

8.3 Nursing Mothers

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 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].

The effect of this exposure on newborns/infants has not been studied; therefore, risk to the breast-fed child cannot be excluded. Therefore, use of ella by breastfeeding women is not recommended.

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.

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.

10 OVERDOSAGE

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.

11 DESCRIPTION

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:

Ulipristal acetate structural formula
(click image for full-size original)

C30 H37 NO4

12 CLINICAL PHARMACOLOGY

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.

12.2 Pharmacodynamics

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 depends 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:

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 who received ella plus the COC [33.3% (13/39)] and the group who received a placebo plus the COC [32.4% (12/37)]. [see Warnings and Precautions (5.5) and Drug Interactions (7.3)].

The initiation of a desogestrel 75 µg “progestin-only pill” 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 Warnings and Precautions (5.5) and Drug Interactions (7.1; 7.3)].

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