Ella (Page 2 of 4)

7.1 Changes in Emergency Contraceptive Effectiveness Associated with Co-Administration of Other Products

Drugs or herbal products that induce enzymes, including CYP3A4, may decrease the plasma concentrations of ella , and may decrease its effectiveness. Some drugs or herbal products that may decrease the effectiveness of ella include:

  • barbiturates
  • bosentan
  • carbamazepine
  • felbamate
  • griseofulvin
  • oxcarbazepine
  • phenytoin
  • rifampin
  • St. John’s Wort
  • topiramate

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.

7.3 Effects of ella on Co-Administered Drugs

In vitro studies demonstrated that ella does not induce or inhibit the activity of cytochrome P450 enzymes. P-glycoprotein (P-gp) transporters: In vitro data indicate that ulipristal may be an inhibitor of P-gp at clnically relevant concentrations. Thus, co-administration of ulipristal and P-gp substrates (e.g., dabigatran etexilate, digoxin) may increase the concentration of P-gp substrates.

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

It is not known if ulipristal acetate is excreted in human milk. However, ulipristal acetate is detected in milk of lactating rats. Because many drugs are excreted in human milk, risk to the breast-fed child cannot be excluded. 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. Safety and efficacy are expected to be the same for postpubertal adolescents less than 18 years and for users 18 years and older. 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. Administration at the time of the luteinizing hormone peak delays follicular rupture by 5 to 9 days. Dosing in the early luteal phase does not significantly delay endometrial maturation but decreases endometrial thickness by 0.6 ± 2.2 mm (mean ± SD).

12.3 Pharmacokinetics

Absorption

Following a single dose administration of ella in 20 women under fasting conditions, maximum plasma concentrations of ulipristal acetate and the active metabolite, monodemethyl-ulipristal acetate, were 176 and 69 ng/ml and were reached at 0.9 and 1 hour, respectively.

Figure 1: Mean (± SD) Plasma Concentration-time Profile of Ulipristal Acetate and Monodemethyl-ulipristal Acetate Following Single Dose Administration of 30 mg Ulipristal Acetate

Figure 1: Mean ((± SD) plasma concentration-time profile of ulipristal acetate and monodemethyl-ulipristal acetate following single dose administration of 30 mg ulipristal acetate
(click image for full-size original)
Table 2: Pharmacokinetic Parameter Values Following Administration of ella (ulipristal acetate) Tablet 30 mg to 20 Healthy Female Volunteers under Fasting Conditions
Mean (± SD)

Cmax (ng/ml)

AUC0-t (ng•hr/ml)

AUC0-∞ (ng•hr/ml)

tmax (hr)*

t1/2 (hr)

Ulipristal acetate

176(89)

548(259)

556(260)

0.9(0.5-2.0)

32(6.3)

Monodemethyl-ulipristal acetate

69(26)

240(59)

246(59)

1.00(0.8-2.0)

27(6.9)

Cmax = maximum concentration
AUC0-t = area under the drug concentration curve from time 0 to time of last determinable concentration
AUC0-∞ = area under the drug concentration curve from time 0 to infinity
tmax = time to maximum concentration
t1/2 = elimination half-life * Median (range)

Effect of food: Administration of ella together with a high-fat breakfast resulted in approximately 40-45% lower mean Cmax , a delayed tmax (from a median of 0.75 hours to 3 hours) and 20-25% higher mean AUC0-∞ of ulipristal acetate and monodemethyl-ulipristal acetate compared with administration in the fasting state. These differences are not expected to impair the efficacy or safety of ella to a clinically significant extent; therefore, ella can be taken with or without food.

Distribution

Ulipristal acetate is highly bound (> 94%) to plasma proteins, including high density lipoprotein, alpha-l-acid glycoprotein, and albumin.

Metabolism

Ulipristal acetate is metabolized to mono-demethylated and di-demethylated metabolites. In vitro data indicate that this is predominantly mediated by CYP3A4. The mono-demethylated metabolite is pharmacologically active.

Excretion

The terminal half-life of ulipristal acetate in plasma following a single 30 mg dose is estimated to 32.4 ± 6.3 hours.

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2020. All Rights Reserved.