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Ulipristal

Pronunciation

(ue li PRIS tal)

Index Terms

  • CDB-2914
  • Ulipristal Acetate

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral, as acetate:

Ella: 30 mg

Brand Names: U.S.

  • Ella

Pharmacologic Category

  • Contraceptive
  • Progestin Receptor Modulator

Pharmacology

Prevents progestin from binding to the progesterone receptor. Ulipristal postpones follicular rupture when administered prior to ovulation, thereby inhibiting or delaying ovulation. May also alter the normal endometrium, impairing implantation. When used for the treatment of signs and symptoms of uterine fibroids, ulipristal reduces the size of uterine fibroids by inhibiting cellular proliferation and inducing apoptosis.

Absorption

Rapid

Metabolism

Hepatic via CYP3A4; forms monodemethylated metabolite (active) and inactive metabolites

Excretion

Feces (primary route of elimination); urine (<10%)

Time to Peak

Serum: 1 hour (ulipristal and monodemethylated metabolite)

Half-Life Elimination

Ulipristal: ~32 to 38 hours; Monodemethylated metabolite: ~27 hours

Protein Binding

Ulipristal: >98% to plasma proteins including albumin, alpha1-acid glycoprotein, high-density lipoprotein, and low-density lipoprotein

Special Populations: Race

Exposure in South Asian patients may exceed that in white and black patients. However, no difference in efficacy and safety was observed.

Use: Labeled Indications

Emergency contraceptive (Ella): Prevention of pregnancy following unprotected intercourse or a known or suspected contraceptive failure. Ulipristal is not intended for routine use as a contraceptive.

Uterine fibroids (Fibristal [Canadian product]): Treatment of moderate-to-severe signs/symptoms of uterine fibroids in premenopausal adult women eligible for surgery. Note: Treatment duration is 2 courses with each course limited to 3 months.

Contraindications

Ella:

US labeling: Known or suspected pregnancy.

Canadian labeling: Hypersensitivity to ulipristal or any component of the formulation; known or suspected pregnancy.

Fibristal [Canadian product]: Hypersensitivity to ulipristal or any component of the formulation; pregnancy; breast-feeding; genital bleeding of unknown etiology or for reasons other than uterine fibroids; cancer of the breast, cervix, uterus, or ovaries

Dosing: Adult

Emergency contraception (Ella): Oral: 30 mg as soon as possible, but within 120 hours (5 days) of unprotected intercourse or contraceptive failure.

Uterine fibroids (Fibristal [Canadian product]): Females (premenopausal): Oral: 5 mg once daily for 3 consecutive months. Note: Treatment duration is 2 courses, with each course limited to 3 months. Initiate the first treatment course within the first 7 days of menstruation; initiate the second treatment course, at the earliest, the first week of the second menstruation following completion of the prior treatment course. The recommended treatment-free interval between treatment courses is 2 menstrual cycles.

Dosing: Geriatric

Not indicated for use in postmenopausal women.

Dosing: Pediatric

Emergency contraception (Ella): Oral:

Children and Adolescents (prepubertal): Not indicated for use prior to menarche.

Adolescents (postpubertal): Refer to adult dosing.

Dosing: Renal Impairment

Ella: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Fibristal [Canadian product]:

Mild impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); however, elimination of ulipristal is not expected to be significantly altered in renal impairment.

Moderate or severe impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); use is not recommended unless patient is monitored closely.

Dosing: Hepatic Impairment

Ella:

US labeling: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Canadian labeling:

Mild or moderate impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Severe impairment: Use is not recommended.

Fibristal [Canadian product]:

Mild or moderate impairment: No dosage adjustment necessary.

Severe impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); use is not recommended unless patient is monitored closely.

Administration

Oral:

Ella: Administer with or without food at anytime during menstrual cycle. If vomiting occurs within 3 hours of administration, consider repeating dose.

Fibristal [Canadian product]: Administer with water and with or without food; initiate during the first 7 days of menstrual cycle.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 3]).

Storage

Ella: Store at 20°C to 25°C (68°F to 77°F). Protect from light.

Fibristal [Canadian product]: Store at 15°C to 30°C (59°F to 86°F). Protect from light.

Drug Interactions

Barbiturates: May decrease the serum concentration of Ulipristal. Avoid combination

Bosentan: May decrease the serum concentration of Ulipristal. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Ulipristal. Avoid combination

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Ulipristal. Management: This is specific for when ulipristal is being used for signs/symptoms of uterine fibroids (Canadian indication). When ulipristal is used as an emergency contraceptive, patients receiving this combination should be monitored for ulipristal toxicity. Avoid combination

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Ulipristal. Management: This is specific for when ulipristal is being used for signs/symptoms of uterine fibroids (Canadian indication). When ulipristal is used as an emergency contraceptive, patients receiving this combo should be monitored for ulipristal toxicity. Avoid combination

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Efavirenz: May decrease the serum concentration of Ulipristal. Avoid combination

Felbamate: May decrease the serum concentration of Ulipristal. Avoid combination

Griseofulvin: May decrease the serum concentration of Ulipristal. Avoid combination

OXcarbazepine: May decrease the serum concentration of Ulipristal. Avoid combination

Progestins: Ulipristal may diminish the therapeutic effect of Progestins. Progestins may diminish the therapeutic effect of Ulipristal. Management: Ulipristal for uterine fibroids (Canadian indication): avoid progestins within 12 days of stopping ulipristal; as emergency contraceptive (U.S. indication): avoid progestins within 5 days of stopping ulipristal. Avoid combination

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

St John's Wort: May decrease the serum concentration of Ulipristal. Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Topiramate: May decrease the serum concentration of Ulipristal. Avoid combination

Adverse Reactions

Emergency contraception (Ella):

>10%:

Central nervous system: Headache (18% to 19%)

Endocrine & metabolic: Suppressed menstruation (≥7 days later than expected: 19%)

Gastrointestinal: Abdominal pain (8% to 15%), nausea (12% to 13%)

Genitourinary: Dysmenorrhea (7% to 13%)

1% to 10%:

Central nervous system: Fatigue (6%), dizziness (5%)

Endocrine & metabolic: Intermenstrual bleeding (9%)

Genitourinary: Early menses (≥7 days earlier than expected: 7%)

Postmarketing and/or case reports: Acne vulgaris

Treatment of moderate-to-severe signs/symptoms of uterine fibroids (Fibristal [Canadian product]):

>10%:

Central nervous system: Headache (1% to 16%)

Endocrine & metabolic: Hot flash (1% to 25%)

1% to 10%:

Cardiovascular: Edema (≤1%), hypotension (≤1%), sinus bradycardia (≤1%)

Central nervous system: Fatigue (≤4%), vertigo (≤4%), insomnia (≤2%), dizziness (1%), aggressive behavior (≤1%), drowsiness (≤1%), emotional lability (≤1%), migraine (≤1%), sleep disorder (≤1%)

Dermatologic: Night sweats (≤2%), acne vulgaris (≤1%), alopecia (≤1%), seborrhea (≤1%), xeroderma (≤1%)

Endocrine & metabolic: Hypercholesterolemia (3%), hypertriglyceridemia (≤3%), hypothyroidism (≤2%), obesity (1%), amenorrhea (≤1%), increased gamma-glutamyl transferase (≤1%), ovarian cyst (≤1%), ovarian hyperstimulation (≤1%), thyroid disease (≤1%)

Gastrointestinal: Nausea (3%), constipation (1%), dyspepsia (≤1%), upper abdominal pain (≤1%)

Genitourinary: Mastalgia (2%), pelvic pain (1% to 2%), endometrial hyperplasia (≤2%), genital bleeding (≤2%), breast swelling (≤1%), breast tenderness (≤1%), genital discharge (≤1%), uterine disease (≤1%), uterine hemorrhage (≤1%), vaginal dryness (≤1%), vulvovaginal candidiasis (≤1%)

Infection: Herpes virus infection (≤1%)

Neuromuscular & skeletal: Arthralgia (2%), muscle spasm (≤2%), back pain (≤1%), limb pain (≤1%)

Respiratory: Dyspnea (≤1%), epistaxis (≤1%), pharyngitis (≤1%)

Miscellaneous: Fever (≤1%)

Warnings/Precautions

Concerns related to adverse effects:

• Bleeding irregularities: Menstrual bleeding patterns may be altered (cycle length may be delayed or shortened by a few days), but returns to normal in subsequent cycles. Intermenstrual bleeding (spotting) has also been observed. The possibility of pregnancy should be considered if menstruation is delayed for >7 days of the expected menstrual period. In the treatment of uterine fibroids (Canadian labeling; not an approved indication in US labeling), a significant reduction in menstrual blood loss or amenorrhea is usually observed within 10 days of initiation; menses generally returns within 4 weeks after discontinuation.

• Endometrial thickening: Endometrial thickening has been observed with use of ulipristal in the treatment of uterine fibroids (Canadian labeling; not an approved indication in US labeling); effects are reversible following discontinuation of therapy. Persistent endometrial thickening (>3 months after discontinuation of therapy and return of menses) should be further evaluated. Changes in endometrial tissue observed with use are referred to as progesterone receptor modulator-associated endometrial changes (PAEC); may be mistaken for endometrial hyperplasia. Pathologists should be informed of ulipristal therapy when submitting endometrial tissue for histologic evaluation.

Disease related concerns:

• Asthma: Use of Fibristal [Canadian product] is not recommended in patients with severe uncontrolled asthma.

• Hepatic impairment: In patients with severe hepatic impairment, the Canadian labeling recommends avoiding use (Ella) or using only in closely monitored patients (Fibristal).

• Renal impairment: Use of Fibristal [Canadian product] is not recommended in moderate-to-severe renal impairment unless patient is monitored closely.

Special populations:

• Pediatric: Not for use prior to menarche.

• Postmenopausal women: Not indicated for use in postmenopausal women.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 3]).

Other warnings/precautions:

• Appropriate use: Not intended for routine contraception. Repeated use within the same menstrual cycle is not recommended.

• Ectopic pregnancy: A history of ectopic pregnancy is not a contraindication to use in emergency contraception. The possibility of ectopic pregnancy should be considered in patients if pregnancy occurs after treatment or in patients with lower abdominal pain after administration of ulipristal.

• Fertility: A return of fertility is likely to be rapid following treatment of ulipristal for emergency contraception. Efficacy of hormonal contraception may be decreased; hormonal contraception should be initiated ≥5 days after emergency contraception and barrier contraception is recommended immediately following use of ulipristal; barrier contraception should be continued throughout the same menstrual cycle. The Canadian labeling recommends a nonhormonal method of contraception for women receiving ulipristal for the treatment of uterine fibroids.

• HIV infection protection: Does not protect against HIV infection or other sexually-transmitted diseases.

• Pregnancy: Use is contraindicated in patients known or suspected to be pregnant. Exclude pregnancy prior to therapy via history, physical exam or pregnancy testing; not indicated for terminating an existing pregnancy.

Monitoring Parameters

Evaluate for pregnancy or ectopic pregnancy if menses is delayed for ≥1 week following emergency contraception, or if lower abdominal pain (3 to 5 weeks after administration) or persistent irregular bleeding develops.

Fibristal [Canadian product]: Rule out pregnancy prior to therapy initiation.

Pregnancy Risk Factor

X

Pregnancy Considerations

Adverse events have been observed in some animal reproduction studies. Exclude pregnancy prior to therapy; not indicated for terminating an existing pregnancy. A rapid return of fertility is expected following use for emergency contraception; routine contraceptive measures should be initiated or continued following use to ensure ongoing prevention of pregnancy. Barrier contraception is recommended immediately following emergency contraception and throughout the same menstrual cycle; efficacy of hormonal contraceptives may be decreased. The manufacturer labeling suggests that hormonal contraceptives may be less effective in females with BSA >30 kg/m2. When ulipristal is used for treatment of uterine fibroids (Canadian labeling; not in US labeling) a nonhormonal method of contraception is recommended.

Health care providers are encouraged to enroll women who were exposed to ulipristal during the cycle pregnancy started or anytime during pregnancy in the Ellipse II study (forms available at www.ellipse2.com).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, dizziness, loss of strength and energy, menstrual pain, menstrual irregularities, or hot flashes. Have patient report immediately to prescriber severe abdominal pain, abnormal vaginal bleeding, or groin or pelvic pain or edema (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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