ella

ella

ulipristal

Manufacturer:

HRA Pharma

Distributor:

Firma Chun Cheong
/
Orient Europharma
Full Prescribing Info
Contents
Ulipristal acetate.
Description
ella also contains the following inactive ingredients: Lactose monohydrate 237 mg, povidone K30, croscarmellose sodium and magnesium stearate.
Action
Pharmacotherapeutic Group: Sex hormones and modulators of the genital system, emergency contraceptives. ATC Code: G03AD02.
Pharmacology: Pharmacodynamics: Ulipristal acetate is an orally-active synthetic selective progesterone receptor modulator which acts via high-affinity binding to the human progesterone receptor. The primary mechanism of action is inhibition or delay of ovulation. Pharmacodynamic data show that even when taken immediately before ovulation is scheduled to occur, ulipristal acetate is able to postpone follicular rupture in some women.
Ulipristal acetate also has high affinity for the glucocorticoid receptor and in vivo, in animals, antiglucocorticoid effects have been observed. However, in humans, no such effect has been observed even after repeat administration at the daily dose of 10 mg. It has minimal affinity to the androgen receptor and no affinity for the human estrogen or mineralocorticoid receptors.
Results from 2 independent randomized controlled trials (see table as follows) showed the efficacy of ulipristal acetate to be non-inferior to that of levonorgestrel in women who presented for emergency contraception between 0 hr and 72 hrs after unprotected intercourse or contraceptive failure. When the data from the 2 trials were combined via meta-analysis, the risk of pregnancy with ulipristal acetate was significantly reduced compared to levonorgestrel (p=0.046).

Click on icon to see table/diagram/image

Two trials provide efficacy data on ella used up to 120 hrs after unprotected intercourse. In an open-label clinical trial, which enrolled women who presented for emergency contraception and were treated with ulipristal acetate between 48 hrs and 120 hrs after unprotected intercourse, a pregnancy rate of 2.1% (26/1241) was observed. In addition, the second comparative trial described previously also provides data on 100 women treated with ulipristal acetate from 72-120 hrs after unprotected intercourse, in whom no pregnancies were observed.
Pharmacokinetics: Absorption: Following oral administration of a single 30 mg dose, ulipristal acetate is rapidly absorbed, with a peak plasma concentration of 176±89 ng/mL occurring approximately 1 hr (0.5-2 hrs) after ingestion and with an AUC0-∞ of 556±260 ng·hr/mL.
Administration of ulipristal acetate together with a high-fat breakfast resulted in approximately 45% lower mean Cmax, a delayed Tmax (from a median of 0.75-3 hrs) and 25% higher mean AUC0-∞ compared with administration in the fasted state. Similar results were obtained for the active mono-demethylated metabolite.
The absorption of ulipristal acetate is pH-dependent and may be reduced in situations where gastric pH is increased irrespective of cause.
Distribution: Ulipristal acetate is highly bound (>98%) to plasma proteins, including albumin, α-1-acid glycoprotein and high density lipoprotein (HDL).
Metabolism/Elimination: Ulipristal acetate is extensively metabolized to mono-demethylated, di-demethylated and hydroxylated metabolites. The mono-demethylated metabolite is pharmacologically active. In vitro data indicate that this is predominantly mediated by CYP3A4, and to a small extent by CYP1A2 and CYP2D6. The terminal half-life of ulipristal acetate in plasma following a single 30 mg dose is estimated to 32.4±6.3 hrs, with a mean oral clearance (CL/F) of 76.8±64 L/hr.
Special Populations: No pharmacokinetic studies with ulipristal acetate have been performed in females with impaired renal or hepatic function.
Interactions: In vitro data indicate that ulipristal acetate and its active metabolite do not significantly inhibit CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A4, at clinically relevant concentrations. After single dose administration, induction of CYP1A2 and CYP3A4 by ulipristal or its active metabolite is not likely. Thus, administration of ulipristal acetate is unlikely to alter the clearance of medicinal products that are metabolized by these enzymes.
Toxicology: Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity. Most findings in general toxicity studies were related to its mechanism of action as a modulator of progesterone and glucocorticoid receptors, with antiprogesterone activity observed at exposures similar to therapeutic levels.
Reproduction toxicity data are insufficient due to lack of human and animal pharmacokinetic data. Due to its mechanism of action, ulipristal acetate has an embryolethal effect in rats, rabbits (at repeated doses above 1 mg/kg) and in monkeys. The safety for a human embryo is unknown. At doses which were low enough to maintain gestation in the animal species, no teratogenic potential was observed.
Carcinogenicity studies with ulipristal acetate have not been conducted.
Indications/Uses
Emergency contraception within 120 hrs (5 days) of unprotected sexual intercourse or contraceptive failure.
Dosage/Direction for Use
The treatment consist of 1 tablet to be taken orally as soon as possible, but no later than 120 hrs (5 days) after unprotected intercourse or contraceptive failure.
If vomiting occurs within 3 hrs of ella intake, another tablet should be taken.
ella can be taken at any moment during the menstrual cycle.
Pregnancy should be excluded before ella is administered.
Children and Adolescents: A limited number of women <18 yr were included in clinical trials of ella.
Renal or Hepatic Impairment: In the absence of specific studies, no specific dose recommendations for ella can be made.
Severe Hepatic Impairment: In the absence of specific studies, ella is not recommended.
Administration: The tablet can be taken with or without food.
Overdosage
Experience with ulipristal acetate overdose is limited. Single doses up to 200 mg were administered to a limited number of subjects, and no severe or serious adverse reactions were reported.
Contraindications
Hypersensitivity to ulipristal acetate or to any of the excipients of ella.
Use in pregnancy: ella is contraindicated during an existing or suspected pregnancy.
Extremely limited data are available on the health of the foetus/newborn in case a pregnancy is exposed to ulipristal acetate. Although no teratogenic potential was observed, animal data are insufficient with regard to reproduction toxicity (see Toxicology: Preclinical Safety Data under Actions).
Patients and health care providers are encouraged to report any pregnancy exposure to ella by contacting the product license holder.
Special Precautions
Concomitant use with an emergency contraceptive containing levonorgestrel is not recommended (see Interactions).
Use in women with severe asthma insufficiently controlled by oral glucocorticoid is not recommended.
Emergency contraception with ella is an occasional method. It should in no instance replace a regular contraceptive method. In any case, women should be advised to adopt a regular method of contraception.
Although the use of ella does not contraindicate the continued use of regular hormonal contraception, ella may reduce its contraceptive action (see Interactions). Therefore, after using emergency contraception, it is recommended that subsequent acts of intercourse be protected by a reliable barrier method until next menstrual period starts.
Repeated administration of ella within the same menstrual cycle is not advisable, as safety and efficacy of ella after repeated administration within the same menstrual cycle has not been investigated.
Emergency contraception with ella does not prevent pregnancy in every case. No data is available on the efficacy of ella for women who have had unprotected intercourse >120 hrs before ella intake. In case of doubt, delay of  >7 days in next menstrual period, abnormal bleeding at the expected date of menses, or symptoms of pregnancy, pregnancy should be excluded by a pregnancy test.
If pregnancy occurs after treatment with ella, as for all pregnancies, the possibility of an ectopic pregnancy should be considered. Ectopic pregnancy may continue, despite the occurence of uterine bleeding.
After ella intake, menstrual periods can sometimes occur earlier or later than expected by a few days. In approximately 7% of the women, menstrual periods occurred  >7 days earlier than expected. In 18.5% of the women, a delay of >7 days occurred and in 4% the delay was >20 days.
Concomitant use of ella and the following active subtances are not recommended due to potential interaction: P-gp substrates (eg dabigatran, etexilate, digoxin), CYP3A4 inducers (eg, rifampicin, phenytoin, phenobarbital, carbamazepine, St John's wort/Hypericum perforatum), drugs that increase gastric pH (eg, proton pump inhibitors, antacids and H2-receptor antagonists), and prolonged use of ritonavir. (See Interactions.)
Excipients: ella contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take ella.
Effects on the Ability to Drive or Operate Machinery: No studies on the effect on the ability to drive and use machines have been performed.
ella may have minor or moderate influence on the ability to drive or use machines: Mild to moderate dizziness is common after ella intake, somnolence and blurred vision are uncommon; disturbance in attention has been reported.
Use in lactation: It is unknown whether ulipristal acetate is excreted in human or animal breast milk. Ulipristal acetate is a lipophilic compound and may theoretically be excreted in breast milk. A risk to the breastfed child cannot be excluded. After intake of ella, breastfeeding is not recommended for at least 36 hrs.
Use In Pregnancy & Lactation
Use in pregnancy: ella is contraindicated during an existing or suspected pregnancy.
Extremely limited data are available on the health of the foetus/newborn in case a pregnancy is exposed to ulipristal acetate. Although no teratogenic potential was observed, animal data are insufficient with regard to reproduction toxicity (see Toxicology: Preclinical Safety Data under Actions).
Patients and health care providers are encouraged to report any pregnancy exposure to ella by contacting the product license holder.
Use in lactation: It is unknown whether ulipristal acetate is excreted in human or animal breast milk. Ulipristal acetate is a lipophilic compound and may theoretically be excreted in breast milk. A risk to the breastfed child cannot be excluded. After intake of ella, breastfeeding is not recommended for at least 36 hrs.
Adverse Reactions
The most commonly reported adverse reactions were headache, nausea, abdominal pain and dysmenorrhea.
Safety of ulipristal acetate has been evaluated in 4,718 women during the clinical development program.
The adverse reactions reported in the phase III program of 2,637 women are stated as follows. The vast majority of adverse reactions were mild or moderate and resolved spontaneously.
Adverse reactions are classified as: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000) and system organ class. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Infections and Infestations: Uncommon: Vaginitis, nasopharyngitis, influenza, urinary tract infection. Rare: Infective conjunctivitis, hordeolum, pelvic inflammatory disease.
Metabolism and Nutrition Disorders: Uncommon: Appetite disorders. Rare: Dehydration.
Psychiatric Disorders: Common: Mood disorders. Uncommon: Emotional disorder, anxiety, insomnia, hyperactivity disorder, libido changes. Rare: Disorientation.
Nervous System Disorders: Common: Headache, dizziness. Uncommon: Somnolence, migraine. Rare: Tremor, disturbance in attention, dysguesia, poor quality of sleep, parosmia, syncope.
Eye disorders: Uncommon: Visual disturbance. Rare: Abnormal sensation in eye, ocular hyperemia, photophobia.
Ear and Labyrinth Disorders: Rare: Vertigo.
Vascular Disorders: Uncommon: Hot flush. Rare: Haemorrhage.
Respiratory, Thoracic and Mediastinal Disorders: Rare: Upper respiratory tract, congestion, cough, dry throat, epistaxis.
Gastrointestinal Disorders: Common: Nausea, abdominal pain (NOS), upper abdominal pain, abdominal discomfort, vomiting. Uncommon: Lower abdominal pain, diarrhea, dry mouth, constipation, dyspepsia, flatulence. Rare: Gastro-esophageal reflux disease, toothache.
Skin and Subcutaneous Tissue Disorders: Uncommon: Acne, skin lession, pruritus. Rare: Urticaria, genital pruritus.
Musculoskeletal and Connective Tissue Disorders: Common: Myalgia, back pain. Rare: Pain in extremity, arthralgia.
Renal and Urinary Disorders: Rare: Urinary tract disorder, chromaturia, nephrolithiasis, renal pain, bladder pain.
Reproductive System and Breast Disorders: Common: Dysmenorrhea, pelvic pain, breast tenderness. Uncommon: Menorrhagia, vaginal discharge, menstrual disorder, metrorrhagia, vaginal haemorrhage, hot flush, premenstrual syndrome. Rare: Genital pruritus, dysfunctional uterine bleeding, dyspareunia, ruptured ovarian cyst, vulvovaginal pain, menstrual discomfort, hypomenorrhea.
General Disorders and Administration Site Conditions: Common: Fatigue. Uncommon: Pain, irritability, chills, malaise, pyrexia. Rare: Chest discomfort, inflammation, thrist.
The majority of women (74.6%) in the phase III studies had their next menstrual period at the expected time or within ±7 days, while 6.8% experienced menses >7 days earlier than expected and 18.5% had a delay of >7 days beyond the anticipated onset of menses. The delay was >20 days in 4% of the women.
A minority (8.7%) of women reported intermenstrual bleeding lasting an average of 2.4 days. In a majority of cases (88.2%), this bleeding was reported as spotting. Among the women who received ella in the phase III studies, only 0.4% reported heavy intermenstrual bleeding.
In the phase III studies, 82 women entered a study more than once and therefore received >1 dose of ella (73 women enrolled twice and 9 enrolled 3 times). There were no safety differences in these subjects in terms of incidence and severity of adverse events, change in duration or volume of menses or incidence of intermenstrual bleeding.     
Drug Interactions
Potential for other drugs to affect ulipristal acetate: No specific drug interaction studies have been performed in vivo.
Ulipristal acetate is metabolized by CYP3A4 in vitro. CYP3A4 inducers (eg, rifampicin, phenytoin, phenobarbital, carbamazepine, St John's wort/Hypericum perforatum) may therefore reduce plasma concentrations of ulipristal acetate and may result in decrease in efficacy. Concomitant use is therefore not recommended (see Precautions).
The CYP3A4 inhibitor ritonavir can also have an inducing effect on CYP3A4 when ritonavir is used for a longer period. In such cases, ritonavir may reduce plasma concentrations of ulipristal acetate. Concomitant use is therefore not recommended (see Precautions). Enzyme induction wears off slowly and effects on the plasma concentrations of ulipristal acetate may occur even if a woman has stopped taking an enzyme inducer within the last 2-3 weeks.
Conversely, potent CYP3A4 inhibitors (eg, ketoconazole, itraconazole, ritonavir, telithromycin, clarithromycin, nefazodone) may increase exposure to ulipristal acetate. The clinical relevance is unknown.
Concomitant administration of medicinal products that increase gastric pH (eg proton pump inhibitors, antacids and H2-receptor antagonists) may reduce plasma concentrations of ulipristal acetate and may result in decrease in efficacy. Concomitant use therefore not recommended (see Precautions).
Potential for ulipristal acetate to affect other medicinal products: P-glycoprotein transporters: In vitro data indicate that ulipristal may be an inhibitor of P-gp at clinically relevant concentrations. Thus, in the absence of clinical data, coadministration of ulipristal acetate and P-gp substrates (eg, dabigatran, etexilate, digoxin) is not recommended. (See Precautions.)
Because ulipristal acetate binds the progesterone receptor with high affinity, it may interfere with the action of progestogen-containing medicinal products: Contraceptive action of combined hormonal contraceptives and progestogen-only contraception may be reduced; concomitant use of ulipristal acetate and emergency contraception containing levonorgestrel is not recommended. (See Precautions.)
Incompatibilities: Not applicable.
MIMS Class
ATC Classification
G03AD02 - ulipristal ; Belongs to the class of emergency contraceptives. Used as systemic contraceptives.
Presentation/Packing
Tab (white to off-white, round curved, engraved with code "ella" on both faces) 30 mg x 1's.
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