ELLA- ulipristal acetate tablet
Watson Pharma, Inc.
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use ella safety and effectively. See full prescribing information for ella.
ella (ulipristal acetate) tablet
Initial U.S. Approval: 2010
INDICATIONS AND USAGE
ella is a progesterone agonist/antagonist emergency contraceptive indicated for prevention of pregnancy following unprotected intercourse or a known or suspected contraceptive failure. ella is not intended for routine use as a contraceptive. (1)
DOSAGE AND ADMINISTRATION
DOSAGE FORMS AND STRENGTHS
WARNINGS AND PRECAUTIONS
The most common adverse reactions (≥ 5%) in the clinical trials were headache (18%), abdominal pain (12%), nausea (12%), dysmenorrhea (9%), fatigue (6%) and dizziness (5%). (6)
USE IN SPECIFIC POPULATIONS
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
FULL PRESCRIBING INFORMATION: CONTENTS *
7.1 Changes in Emergency Contraceptive Effectiveness Associated with Co-Administration of Other Products
ella is a progesterone agonist/antagonist emergency contraceptive indicated for prevention of pregnancy following unprotected intercourse or a known or suspected contraceptive failure. ella is not intended for routine use as a contraceptive.
Instruct patients to take one tablet orally as soon as possible within 120 hours (5 days) after unprotected intercourse or a known or suspected contraceptive failure.
The tablet can be taken with or without food.
If vomiting occurs within 3 hours of ella intake, consideration should be given to repeating the dose.
ella can be taken at any time during the menstrual cycle.
The ella tablet is supplied as a white to off-white, round, curved tablet containing 30 mg of ulipristal acetate and is marked “ella” on both sides.
ella is contraindicated for use in the case of known or suspected pregnancy. The risks to a fetus when ella is administered to a pregnant woman are unknown. If this drug is inadvertently used during pregnancy, the woman should be apprised of the potential hazard to the fetus. [See Use in Specific Populations (8.1).]
ella is not indicated for termination of an existing pregnancy. Pregnancy should be excluded before prescribing ella. If pregnancy cannot be excluded on the basis of history and/or physical examination, pregnancy testing should be performed. 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.
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 rapid return of fertility is likely following treatment with ella for emergency contraception; therefore, routine contraception should be continued or initiated as soon as possible following use of ella to ensure ongoing prevention of pregnancy. While there are no data about use of ella with regular hormonal contraceptives, due to its high affinity binding to the progesterone receptor, use of ella may reduce the contraceptive action of regular hormonal contraceptive methods. Therefore, 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.
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.
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).
|Most Common Adverse Reactions||Open-Label Study||
|N = 1,533||N = 1,104|
|Abdominal and upper abdominal pain||15||8|
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.
No drug interaction studies have been conducted for ella in vivo. However, in vitro data indicate that ella is predominantly metabolized by CYP3A4.
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:
CYP3A4 inhibitors such as itraconazole or ketoconazole may increase plasma concentrations of ella.
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 clinically relevant concentrations. Thus, co-administration of ulipristal acetate and P-gp substrates (e.g., dabigatran etexilate, digoxin) may increase the concentration of P-gp substrates.
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.
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.
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.
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.
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.
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:
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.
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).
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
|Mean (± SD)|
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.
Ulipristal acetate is highly bound (> 94%) to plasma proteins, including high density lipoprotein, alpha-l-acid glycoprotein, and albumin.
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.
The terminal half-life of ulipristal acetate in plasma following a single 30 mg dose is estimated to 32.4 ± 6.3 hours.
Carcinogenicity: Carcinogenicity studies with ulipristal acetate have not been conducted.
Genotoxicity: 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.
Two multicenter clinical studies evaluated the efficacy and safety of ella. An open-label study provided the primary data to support the efficacy and safety of ulipristal acetate for emergency contraception when taken 48 to 120 hours after unprotected intercourse. A single-blind comparative study provided the primary data to support the efficacy and safety of ulipristal acetate for emergency contraception when taken 0 to 72 hours after unprotected intercourse and provided supportive data for ulipristal acetate for emergency contraception when taken > 72 to 120 hours after unprotected intercourse. Women in both studies were required to have a negative pregnancy test prior to receiving emergency contraception. The primary efficacy analyses were performed on subjects less than 36 years of age who had a known pregnancy status after taking study medication.
| Open-Label Study
48 to 120 Hours*
| Single-Blind Comparative Study
0 to 72 Hours*
|N = 1,242||N = 844|
|Expected Pregnancy Rate**||5.5||5.6|
| Observed Pregnancy Rate**
(95% confidence interval)
* Time after unprotected intercourse when ella was taken
**Number of pregnancies per 100 women at risk for pregnancy
This study was a multicenter open-label trial conducted at 40 family planning clinics in the United States. Healthy women with a mean age of 24 years who requested emergency contraception 48 to 120 hours after unprotected intercourse received a dose of 30 mg ulipristal acetate (ella). The median BMI for the study subjects was 25.3 and ranged from 16.1 to 61.3 kg/m2.
Twenty-seven pregnancies occurred in 1,242 women aged 18 to 35 years evaluated for efficacy. The number of pregnancies expected without emergency contraception was calculated based on the timing of intercourse with regard to each woman’s menstrual cycle. ella statistically significantly reduced the pregnancy rate, from an expected rate of 5.5% to an observed rate of 2.2%, when taken 48 to 120 hours after unprotected intercourse.
This study was a multicenter, single-blind, randomized comparison of the efficacy and safety of 30 mg ulipristal acetate (ella) to levonorgestrel (another form of emergency contraception). Subjects were enrolled at 35 sites in the U.S., the United Kingdom and Ireland, with the majority (66%) having been enrolled in the U.S. Healthy women with a mean age of 25 years who requested emergency contraception within 120 hours of unprotected intercourse were enrolled and randomly allocated to receive ella or levonorgestrel 1.5 mg. The median BMI for the study subjects was 25.3 and ranged from 14.9 to 70.0 kg/m2.
In the ella group, 16 pregnancies occurred in 844 women aged 16 to 35 years when emergency contraception was taken 0 to 72 hours after unprotected intercourse. The number of pregnancies expected without emergency contraception was calculated based on the timing of intercourse with regard to each woman’s menstrual cycle; ella statistically significantly reduced the pregnancy rate, from an expected 5.6% to an observed 1.9%, when taken within 72 hours after unprotected intercourse. There were no pregnancies observed in the women who were administered ella more than 72 hours after unprotected intercourse (10% of women who received ella).
Data from the two studies were pooled to provide a total efficacy population of women treated with ulipristal acetate up to 120 hours after UPI. Time Trend analysis for the five 24-hour intervals from 0 to 120 hours between unprotected intercourse and treatment was conducted. There were no significant differences in the observed pregnancy rates across the five time intervals.
Subgroup analysis of the pooled data by BMI showed that for women with BMI > 30 kg/m2 (16% of all subjects), the observed pregnancy rate was 3.1% (95% CI: 1.7, 5.7), which was not significantly reduced compared to the expected pregnancy rate of 4.5% in the absence of emergency contraception taken within 120 hours after unprotected intercourse. In the comparative study, a similar effect was seen for the comparator emergency contraception drug, levonorgestrel 1.5 mg. For levonorgestrel, when used by women with BMI > 30 kg/m2, the observed pregnancy rate was 7.4% (95% CI: 3.9, 13.4), compared to the expected pregnancy rate of 4.4% in the absence of emergency contraception taken within 72 hours after unprotected intercourse.
ella (ulipristal acetate) tablet, 30 mg is supplied in a PVC-PE-PVDC-aluminum blister. The tablet is a white to off-white, round, curved tablet marked with "ella" on both sides.
NDC 52544-238-54 (1 tablet unit of use package)
Store at 20-25°C (68-77°F). [See USP controlled room temperature.]
Keep the blister in the outer carton in order to protect from light. Keep out of reach of children.
[See FDA-Approved Patient Labeling]
Information for Patients
| Patient Information
(ulipristal acetate) tablet
Read this Patient Information Leaflet before you take ella. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.
What is ella?
ella is a prescription emergency contraceptive that reduces your chance of becoming pregnant if your birth control fails or you have unprotected sex.
ella should not be used as your regular birth control. It is very important that you have a reliable form of birth control that is right for you.
ella will not protect you against HIV infection (AIDS) and other sexually transmitted diseases (STDs).
Who should not take ella?
What should I tell my healthcare provider before taking ella?
See "Who should not take ella?"
Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements.
Using some other medicines may have an effect on how ella or the other medicine works. These include St. John's Wort, phenytoin, rifampin, phenobarbital, dabigatran etexilate, digoxin and carbamazepine. Talk to your healthcare provider if you are currently using these medications.
Talk to your healthcare provider if you use hormonal birth control. Using ella may make your regular hormonal birth control method less effective. After using ella, you should use a reliable barrier method of birth control (such as a condom with spermicide) during any other times that you have sex in that same menstrual cycle.
Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.
When is it not appropriate to use ella?
How does ella work?
ella is thought to work for emergency contraception primarily by stopping or delaying the release of an egg from the ovary. It is possible that ella may also work by preventing attachment (implantation) to the uterus.
How should I take ella?
How effective is ella?
If ella is taken as directed, it will reduce the chance that you will get pregnant. ella is not effective in every case. ella is only to be used for a single episode of unprotected intercourse. Be sure to use a regular birth control method the next time you have sex.
ella and other emergency contraceptives may be less effective in women with a body mass index (BMI) > 30 kg/m2.
What if I am already pregnant and use ella?
ella should not be taken if you are already pregnant. There is little information on whether ella would harm a developing baby. Contact your healthcare provider if you think you may be pregnant and have taken ella.
ella is not for use to terminate an existing pregnancy.
What should I do if my menstrual period is delayed beyond 1 week or I have severe lower stomach (abdominal) pain?
After taking ella, your next menstrual period may begin a few days earlier or later than expected. If your period is more than 7 days later than expected, you may be pregnant. You should get a pregnancy test and follow up with your healthcare provider.
If you have severe lower stomach (abdominal) pain about 3 to 5 weeks after taking ella, you may have a pregnancy outside of the uterus (womb), which is called an ectopic or tubal pregnancy. An ectopic pregnancy is a serious condition that needs medical treatment right away. Call your healthcare provider or go to the nearest emergency room right away if you think you may have an ectopic pregnancy.
How often can I use ella?
ella is meant for emergency contraception only, and is not to be used frequently or as a regular birth control. If you need to use emergency contraception often, talk to your healthcare provider and learn about methods for birth control and sexually transmitted disease prevention that are right for you.
What are the possible side effects of ella?
The most common side effects of ella include:
Some women taking ella may have their next period earlier or later than expected. If your period is more than a week late, you should get a pregnancy test.
Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
These are not all the possible side effects of ella. For more information, ask your healthcare provider or pharmacist.
Call your healthcare provider for medical advice about side effects. You may report side effects to FDA 1-800-FDA-1088.
How should I store ella?
Do not use ella if the package is torn or broken.
Keep ella and all medicines out of the reach of children.
General information about the safe and effective use of ella:
Medicines are sometimes prescribed for purposes other than those in a Patient Information Leaflet. Do not use ella for a condition for which it was not prescribed. Do not give ella to other people, even if they have the same symptoms that you have. It may harm them.
In the case of an overdose, get medical help or contact a Poison Control Center right away at 1-800-222-1222. Overdose experience with ella is limited.
This Patient Information Leaflet summarizes the most important information about ella. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about ella that is written for health professionals.
For more information, go to www.ella-rx.com or you can contact Watson Medical Communications at 1-800-272-5525.
What are the ingredients in ella?
Active ingredients: ulipristal acetate, 30 mg
Inactive ingredients: lactose monohydrate, povidone, croscarmellose sodium, and magnesium stearate
For all medical inquiries contact:
Parsippany, NJ 07054
Watson Pharma, Inc.
Parsippany, NJ 07054 USA
Under License From:
Laboratoire HRA Pharma
75003 Paris, France
ella® is a registered trademark
of Laboratoire HRA Pharma
Cenexi, 95520 Osny, France; or
Laboratorios León Farma S.A., 24008 León, Spain
ulipristal acetate tablet
|Labeler - Watson Pharma, Inc. (966714656)|