Ulipristal

G03A - Hormonal contraceptives for systemic use ATC G03AD02 Small molecule Natural product

JFDA label: Ecinq 30 mg Film Coated Tablet

Mechanism of Action

Modulator of Progesterone receptor — Progesterone receptor modulator

Target	Action	Gene / class
Progesterone receptor efficacy	MODULATOR	PGR

Indications

Approved

Emergency contraceptive (Ella)
Uterine fibroids (Fibristal [Canadian product])

Contraindications

Source: Lexicomp

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

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (3)

Common Edema · hypotension · sinus bradycardia

Nervous system disorders (10)

Very Common Headache

Common aggressive behavior · dizziness · drowsiness · emotional lability · Fatigue · insomnia · migraine · sleep disorder · vertigo

Renal and urinary disorders (13)

Very Common Dysmenorrhea

Common breast swelling · breast tenderness · Early menses · endometrial hyperplasia · genital bleeding · genital discharge · Mastalgia · pelvic pain · uterine disease · uterine hemorrhage · vaginal dryness · vulvovaginal candidiasis

Metabolism and nutrition disorders (12)

Very Common Hot flash · Suppressed menstruation

Common amenorrhea · Hypercholesterolemia · hypertriglyceridemia · hypothyroidism · increased gamma-glutamyl transferase · Intermenstrual bleeding · obesity · ovarian cyst · ovarian hyperstimulation · thyroid disease

Gastrointestinal disorders (5)

Very Common Abdominal pain · nausea

Common constipation · dyspepsia · upper abdominal pain

Skin and subcutaneous tissue disorders (4)

Common alopecia · Night sweats · seborrhea · xeroderma

Musculoskeletal and connective tissue disorders (4)

Common Arthralgia · back pain · limb pain · muscle spasm

Infections and infestations (1)

Common Herpes virus infection

General disorders and administration site conditions (1)

Common Fever

Other (1)

Not Known Acne vulgaris

Respiratory, thoracic and mediastinal disorders (3)

Common Dyspnea · epistaxis · pharyngitis

Dosing

Source: Lexicomp

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 (each course of therapy is limited to 3 months). Initiate the first treatment course within the first 7 days of menstruation; initiate subsequent treatment courses, 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. Repeated intermittent treatment has been studied up to 4 intermittent courses.

Emergency contraception (Ella): Oral: Children and Adolescents (prepubertal): Not indicated for use prior to menarche. Adolescents (postpubertal): Refer to adult dosing.

Not indicated for use in postmenopausal women.

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); however, dosage adjustment may not be necessary since renal elimination of ulipristal is minimal (Pohl 2013).

Ella: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied). Fibristal [Canadian product]: No dosage adjustment necessary in mild or moderate impairment; has not been studied in severe impairment (monitor closely if initiating therapy).

Warnings & Precautions

Source: Lexicomp

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 with Fibristal [Canadian product], 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 Fibristal [Canadian product] in the treatment of uterine fibroids; 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

Fibristal [Canadian product] is not recommended in patients with severe uncontrolled asthma. 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. 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 not be initiated until ≥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. Any nonhormonal contraceptive may be started immediately after uliprstal (Curtis 2016a). A nonhormonal method of contraception is recommended for women receiving Fibristal [Canadian product] 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.

Pregnancy & Lactation

Pregnancy

FDA category X Contraindicated

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

Lactation

Avoid

Ulipristal is excreted in breast milk. Following a single dose, mean breast milk concentrations within the first 24 hours were 22.7 ng/mL (ulipristal) and 4.49 ng/mL (active metabolite). Ulipristal concentrations decreased to less than 1 ng/mL by 96 to 120 hours after the dose, and were less than 1 ng/mL 24 to 48 hours after the dose for the active metabolite. Breastfeeding is not recommended by the manufacturer. Ulipristal may be used for emergency contraception in breastfeeding women, however,

Monitoring

Clinical pearl	Evaluate for pregnancy or ectopic pregnancy if expected 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. A pregnancy test is recommended if withdrawal bleeding does not occur within 3 weeks following use as an emergency contraceptive (Curtis 2015a). Fibristal [Canadian product]: Rule out pregnancy prior to therapy initiation; periodic monitoring of the endometrium; unexpected or persistent irregular bleeding

Clinical pearl

Evaluate for pregnancy or ectopic pregnancy if expected 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. A pregnancy test is recommended if withdrawal bleeding does not occur within 3 weeks following use as an emergency contraceptive (Curtis 2015a). Fibristal [Canadian product]: Rule out pregnancy prior to therapy initiation; periodic monitoring of the endometrium; unexpected or persistent irregular bleeding

Chemistry & Properties

Formula	C28H35NO3
Molecular weight	433.59 g/mol
IUPAC name	(8S,11R,13S,14S,17R)-17-acetyl-11-[4-(dimethylamino)phenyl]-17-hydroxy-13-methyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one
CAS	159811-51-5
PubChem CID	13559281
InChIKey	`HKDLNTKNLJPAIY-WKWWZUSTSA-N`
logP	4.97 (XLogP 2.9)
Polar surface area	57.61 Å²
H-bond acceptors / donors	4 / 1
Drug-likeness (QED)	0.73
Lipinski violations	0

SMILES

CC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(N(C)C)cc3)C[C@@]21C

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	10.0%
Half-life	1.458 h
Volume of distribution	1.626 L/kg
Protein binding	96.9%
BBB penetrant	Yes

Enzyme interactions

Enzyme	Role	Detail
CYP2B6	Inhibitor	—
CYP2C19	Inhibitor	—
CYP2C8	Inhibitor	—
CYP2C9	Inhibitor	—
CYP3A4	Inhibitor	—
CYP3A4	Substrate	—

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)MDR1 (Inhibitor)MRP1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)P-gp (Substrate)

Drug–drug interactions (70, DDInter)

Interacting drug	Severity	Management
Edoxaban	major
Venetoclax	major
Afatinib	moderate
Aminoglutethimide	moderate
Apixaban	moderate
Artesunate	moderate
Betrixaban	moderate
Bexarotene	moderate
Binimetinib	moderate
Brentuximab vedotin	moderate
Ceritinib	moderate
Cobimetinib	moderate
Cyclosporine	moderate
Daunorubicin	moderate
Daunorubicin (liposomal)	moderate
Deferasirox	moderate
Docetaxel	moderate
Doxorubicin	moderate
Doxorubicin (liposomal)	moderate
Epirubicin	moderate
Erlotinib	moderate
Etoposide	moderate
Everolimus	moderate
Fexofenadine	moderate
Fostamatinib	moderate
Gilteritinib	moderate
Griseofulvin	moderate
Idarubicin	moderate
Lapatinib	moderate
Larotrectinib	moderate
Lenalidomide	moderate
Loperamide	moderate
Lorlatinib	moderate
Lusutrombopag	moderate
Medroxyprogesterone acetate	moderate
Mitoxantrone	moderate
Naldemedine	moderate
Nilotinib	moderate
Paclitaxel	moderate
Paclitaxel (protein-bound)	moderate

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Registered Products (1)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Ecinq 30 mg Film Coated Tablet	Film-Coated Tablet Ulipristal Acetate 30.0 mg	1 tab	Sabbagh Drug Store	11.670