Ulipristal - Drug Monograph

Introduction

Ulipristal acetate is a selective progesterone receptor modulator (SPRM) that represents a significant advancement in emergency contraception and gynecological therapeutics. Originally approved by the FDA in 2010, ulipristal has demonstrated efficacy in both emergency contraception and management of uterine fibroids, though its fibroid indication has been subject to regulatory restrictions in some regions due to safety concerns.

Mechanism of Action

Ulipristal functions as a selective progesterone receptor modulator with antagonistic and partial agonistic effects. Its primary mechanism in emergency contraception involves:

• Inhibition or delay of ovulation by suppressing follicular rupture
• Direct action on the endometrium, creating an unfavorable environment for implantation
• Modulation of progesterone receptors in the hypothalamus, disrupting the luteinizing hormone (LH) surge
• Unlike levonorgestrel-based emergency contraception, ulipristal maintains efficacy even when administered after the LH surge has begun

Indications

• Emergency contraception within 120 hours (5 days) of unprotected intercourse or contraceptive failure

• Preoperative treatment of moderate to severe symptoms of uterine fibroids in adult women of reproductive age (Note: This indication has been suspended in several countries due to hepatic safety concerns)

• Management of endometriosis (investigational)
• Treatment of uterine bleeding disorders

Dosage and Administration

• Single 30 mg oral dose taken as soon as possible within 120 hours of unprotected intercourse
• Administration with or without food
• If vomiting occurs within 3 hours of ingestion, consider repeating the dose

• Renal impairment: No dosage adjustment necessary
• Hepatic impairment: Use with caution in severe impairment
• Pediatrics: Safety and efficacy established for females of reproductive potential
• Geriatrics: Not indicated for use in postmenopausal women

Pharmacokinetics

• Rapidly absorbed with peak plasma concentrations achieved within 1 hour
• Absolute bioavailability: Approximately 76%
• Food may delay absorption but does not significantly affect overall exposure

• Protein binding: >98% (primarily to albumin)
• Volume of distribution: ~86 L
• Crosses the blood-brain barrier to a limited extent

• Extensive hepatic metabolism via CYP3A4-mediated oxidation
• Forms active metabolites (monodemethylated and didemethylated derivatives)
• No significant inhibition or induction of CYP enzymes

• Elimination half-life: ~38 hours (ulipristal); ~27 hours (active metabolite)
• Primarily fecal excretion (90%) with minimal renal elimination
• Clearance: Approximately 100 L/hour

Contraindications

• Known hypersensitivity to ulipristal acetate or any component of the formulation
• Pregnancy (except when used as emergency contraception)
• Severe hepatic impairment
• Undiagnosed abnormal genital bleeding
• Uterine or cervical cancer

Warnings and Precautions

• Cases of serious liver injury, including liver failure requiring transplantation, have been reported
• Regular liver function monitoring recommended during repeated use
• Contraindicated in patients with existing liver disease

• Exclude ectopic pregnancy in patients who become pregnant or complain of severe abdominal pain

• Concomitant use of CYP3A4 inducers may significantly decrease ulipristal concentrations
• Progestin-containing contraceptives may reduce efficacy

• May cause changes in menstrual cycle timing and flow
• Subsequent menses may be early or delayed by several days

Drug Interactions

• Strong CYP3A4 inducers (rifampin, carbamazepine, St. John's wort): ↓ ulipristal concentrations
• Moderate CYP3A4 inducers: Potential ↓ efficacy
• Gastric pH modifiers (PPIs, H2 antagonists, antacids): Potential ↓ absorption

• Weak to moderate CYP3A4 inhibitors: Unlikely to require dose adjustment
• Oral contraceptives: May reduce effectiveness of both medications

Adverse Effects

• Headache (13-18%)
• Nausea (12-15%)
• Abdominal pain (10-12%)
• Dysmenorrhea (10%)
• Fatigue (6-10%)

• Dizziness
• Breast tenderness
• Mood changes
• Acne
• Altered menstrual bleeding patterns

• Hepatic injury and enzyme elevations
• Severe allergic reactions
• Ectopic pregnancy (rare)

Monitoring Parameters

• Pregnancy test
• Liver function tests (if considering repeated use)
• Assessment of contraindications

• Pregnancy test if next menses is delayed beyond 1 week
• Liver function monitoring with repeated use (every 2-3 months)
• Assessment of adverse effects

• Follow-up pregnancy test if indicated
• Monitoring of subsequent menstrual cycles

Patient Education

• Take as soon as possible after unprotected intercourse (within 120 hours)
• Does not protect against sexually transmitted infections
• May cause changes in menstrual cycle timing and flow
• Use barrier contraception until next menstrual period
• Seek medical attention if severe abdominal pain occurs (possible ectopic pregnancy)
• Not intended for routine contraception
• Inform healthcare provider of all medications being taken
• Report any signs of liver problems (jaundice, dark urine, abdominal pain)

• 98% effective when taken within 24 hours
• 85% effective when taken within 120 hours
• More effective than levonorgestrel emergency contraception beyond 72 hours

References

1. FDA Prescribing Information: Ella® (ulipristal acetate) tablets 2. Gemzell-Danielsson K, et al. Emergency contraception: mechanisms of action. Contraception. 2013;87(3):300-308. 3. Fine P, et al. Ulipristal acetate taken 48-120 hours after intercourse for emergency contraception. Obstet Gynecol. 2010;115(2 Pt 1):257-263. 4. European Medicines Agency. PRAC recommends restricting use of ulipristal acetate for uterine fibroids. 2020. 5. Glasier AF, et al. Ulipristal acetate versus levonorgestrel for emergency contraception: a randomised non-inferiority trial. Lancet. 2010;375(9714):555-562. 6. Levy DP, et al. Ulipristal acetate for emergency contraception: postmarketing experience after use by more than 1 million women. Contraception. 2014;89(5):431-433. 7. Medical Eligibility Criteria for Contraceptive Use, WHO, 5th edition, 2015