Active ingredients: Ulipristal (Ulipristal acetate)
Esmya 5 mg tablets
Why is Esmya used? What is it for?
Esmya contains the active substance ulipristal acetate. It is used to treat moderate to severe symptoms of uterine fibroids (also called myomas), which are benign tumors of the uterus.
Esmya is used in adult women (over 18 years of age) who have not reached menopause.
In some women, uterine fibroids can cause heavy menstrual bleeding ("menstruation"), pelvic pain (discomfort in the lower abdomen), and pressure on other organs.
This medicine works by modifying the activity of progesterone, a naturally occurring hormone in the body. It is used before surgery to remove fibroids or for long-term treatment of fibroids to reduce their size, stop or reduce bleeding, and increase the level of red blood cells.
Contraindications When Esmya should not be used
You should know that most women do not have menstrual bleeding (menstruation) during treatment and for a few weeks thereafter.
Do not take Esmya
- if you are allergic to ulipristal acetate or any of the other ingredients of Esmya
- if you are pregnant or breastfeeding;
- if you have vaginal bleeding not caused by uterine fibroids;
- if you have cancer of the uterus, cervix (the neck of the womb), ovaries or breasts.
Precautions for use What you need to know before taking Esmya
- If you are taking a hormonal contraceptive (such as the birth control pill) (see "Other medicines and Esmya"), you must use a reliable alternative barrier method of contraception (such as a condom) while taking Esmya.
- If you have liver or kidney disease, tell your doctor or pharmacist before taking Esmya.
- If you have severe asthma, Esmya may not be suitable for you. Discuss this with your doctor.
Treatment with Esmya generally causes a significant reduction in menstrual bleeding (menstruation) or can even stop it within the first 10 days of treatment. However, if you continue to have excessive bleeding, tell your doctor.
Menstruation will usually resume within 4 weeks of ending treatment with Esmya. The lining of the uterus may thicken or change as a result of treatment with Esmya. These changes disappear after treatment is stopped and menstruation resumes.
Children and adolescents
Children under the age of 18 should not take Esmya.
Interactions Which drugs or foods can change the effect of Esmya
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
If you are taking any of the medicines listed below, tell your doctor or pharmacist, as these medicines can interact with Esmya:
- Some medicines used to treat heart problems (e.g. digoxin).
- Some medicines used to prevent strokes and blood clots (e.g. dabigatran ethexylate).
- Some medicines used in the treatment of epilepsy (eg phenytoin, fosphenytoin, phenobarbital, carbamazepine, oxcarbazepine, primidone).
- Some medicines used in the treatment of HIV infection (eg ritonavir, efavirenz, nevirapine).
- Medicines used to treat some bacterial infections (e.g. rifampicin, telithromycin, clarithromycin, erythromycin, rifabutin).
- Some medicines used in the treatment of fungal infections (e.g. ketoconazole (except shampoo), itraconazole).
- Herbal remedies containing St. John's Wort (Hypericum perforatum), used in the treatment of depression or anxiety.
- Some medicines used in the treatment of depression (e.g. nefazodone).
- Some medicines used in the treatment of hypertension (eg verapamil).
Esmya is likely to reduce the effectiveness of some hormonal contraceptives. Hormonal contraceptives and progestogens (eg norethindrone or levonorgestrel) are also likely to reduce the effectiveness of Esmya. Consequently, hormonal contraceptives are not recommended and you must use a reliable alternative barrier method of contraception, such as a condom, during treatment with Esmya.
Esmya with food and drink
You should avoid drinking grapefruit juice while taking Esmya.
Warnings It is important to know that:
Pregnancy and breastfeeding
Do not take Esmya if you are pregnant. Treatment during pregnancy can affect its course (we do not know if Esmya can harm the fetus or cause a miscarriage). If you become pregnant while taking Esmya, you must stop taking Esmya immediately and contact your doctor or pharmacist.
Esmya is likely to reduce the effectiveness of some hormonal contraceptives (see "Other medicines and Esmya"). Esmya is excreted in breast milk. You should therefore not breastfeed while taking Esmya.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
Esmya may cause mild dizziness (see section 4 "Possible side effects"). If you experience these symptoms, do not drive or use machines.
Dose, Method and Time of Administration How to use Esmya: Posology
Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
The recommended dose is one 5 mg tablet per day for treatment cycles of up to 3 months each. If you have been prescribed several courses of 3-month treatment with Esmya, you should start each course as soon as possible during the second menstrual cycle following the completion of the previous treatment.
You should always start taking Esmya in the first week of your menstrual cycle.
The tablet should be swallowed with water and can be taken with or without food.
Overdose What to do if you have taken too much Esmya
If you take more Esmya than you should
Experience with taking several doses of Esmya at once is limited. No serious harmful effects have been reported when taking multiple doses of this medicine concomitantly. However, if you take more Esmya than you should, it is recommended that you consult your doctor or pharmacist about it.
If you forget to take Esmya
If you forget a dose that you were supposed to take less than 12 hours ago, take it as soon as you notice. If more than 12 hours have passed, skip the missed dose and take only one tablet as usual. Do not take a double dose to make up for a forgotten tablet.
If you stop taking Esmya
Esmya should be taken daily during treatment cycles of up to 3 months. During each course of treatment, do not stop taking the tablets without your doctor's advice, even if you feel better, as symptoms may return later.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Side Effects What are the side effects of Esmya
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Very common side effects (affecting more than 1 in 10 people):
- reduction or absence of menstrual bleeding (amenorrhea)
- thickening of the lining of the uterus (thickening of the endometrium)
Common side effects (affecting up to 1 in 10 people):
- headache
- feeling dizzy (vertigo)
- stomach pain, feeling sick (nausea)
- acne
- pain in muscles and bones (musculoskeletal)
- sac of fluid in the ovaries (ovarian cyst), breast tension / pain, pain in the lower abdomen (pelvic)
- hot flashes
- tiredness (fatigue)
- weight gain.
Uncommon side effects (affecting up to 1 in 100 people):
- anxiety
- mood swings
- dizziness
- dry mouth, constipation
- hair loss, dry skin, increased sweating
- backache
- urine loss
- bleeding of the uterus (uterine haemorrhage), vaginal discharge, abnormal vaginal bleeding, breast discomfort
- swelling due to water retention (edema)
- extreme tiredness (asthenia)
- increase in blood cholesterol detected with tests, increase in blood fats (triglycerides) detected with tests.
Rare side effects (affecting up to 1 in 1,000 people):
- nosebleeds
- indigestion, bloating
- rupture of fluid sac in the ovaries (rupture of ovarian cyst)
- breast swelling.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton and blister after "EXP." The expiry date refers to the last day of that month.
Keep the blister in the outer carton to protect the medicine from light.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
What Esmya contains
- The active ingredient is ulipristal acetate. One tablet contains 5 mg of ulipristal acetate.
- The other ingredients are microcrystalline cellulose, mannitol, croscarmellose sodium, talc and magnesium stearate.
Description of what Esmya looks like and contents of the pack
Esmya is a white to off-white 7 mm curved round tablet with "ES5" debossed on one side.
Esmya is available in Al / PVC / PE / PVDC blisters in cardboard boxes containing 28, 30 and 84 tablets or in Al / PVC / PVDC blisters in cardboard boxes containing 28 and 84 tablets.
Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
ESMYA 5 MG TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
One tablet contains 5 mg of ulipristal acetate.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Tablet.
Round, white to off-white, 7 mm biconvex tablet, debossed with "ES5" on one side.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Ulipristal acetate is indicated for the pre-operative treatment of moderate to severe symptoms of uterine fibroids in adult women of reproductive age.
Ulipristal acetate is indicated for the intermittent treatment of moderate to severe symptoms of uterine fibroids in adult women of reproductive age.
04.2 Posology and method of administration
Dosage
The treatment consists of one 5 mg tablet to be taken by mouth once a day for treatment cycles of up to 3 months each.
Treatments should only begin when menstruation has occurred:
- The first course of treatment should start during the first week of menstruation.
- Subsequent courses should begin as early as possible during the first week of the second menstruation following completion of the previous treatment course.
The attending physician must explain to the patient that the treatment withdrawal intervals must be respected.
Intermittent repeat treatment has been studied for up to 4 intermittent treatment cycles.
If a patient forgets to take a dose, she should take ulipristal acetate as soon as possible. If more than 12 hours have passed since the missed dose, the patient should no longer take the missed dose, but simply resume her usual dosing schedule.
Special populations
Kidney failure
No dose adjustment is recommended in patients with mild or moderate renal impairment. In the absence of specific studies, ulipristal acetate is not recommended in patients with severe renal impairment unless the patient is closely monitored (see sections 4.4 and 5.2).
Hepatic insufficiency
No dose adjustment is recommended in patients with mild hepatic impairment. In the absence of specific studies, ulipristal acetate is not recommended in patients with moderate or severe hepatic impairment unless the patient is closely monitored (see sections 4.4 and 5.2).
Pediatric population
There is no indication for a specific use of ulipristal acetate in the pediatric population. The safety and efficacy of ulipristal acetate have only been determined in women of at least 18 years of age.
Method of administration
The tablets can be taken with or without food.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Pregnancy and breastfeeding.
Vaginal bleeding of unknown etiology or for reasons other than uterine fibroid.
Uterine, cervical, ovarian or breast cancer.
04.4 Special warnings and appropriate precautions for use
Ulipristal acetate should only be prescribed after careful diagnosis. Before treatment it is necessary to exclude pregnancy. Perform a pregnancy test if pregnancy is suspected before starting a new course of treatment.
Contraception
Concomitant use of a progestogen-releasing intrauterine device, a progestogen-releasing intrauterine device, or a combined oral contraceptive pill is not recommended (see section 4.5). Although the majority of women taking a therapeutic dose of ulipristal acetate experience anovulation, during treatment recommends the use of a non-hormonal method of contraception.
Endometrial alterations
Ulipristal acetate exerts a specific pharmacodynamic action on the endometrium:
Changes in the histology of the endometrium may be observed in patients treated with ulipristal acetate. These changes are reversible after cessation of treatment.
These histological changes are referred to as "progesterone receptor modulator associated endometrial changes" (PAEC) and should not be mistaken for endometrial hyperplasia (see sections 4.8 and 5.1).
A reversible increase in the thickness of the endometrium may also occur during the course of treatment.
In case of repeated intermittent treatment, periodic monitoring of the endometrium is recommended. This includes an annual ultrasound scan, to be performed after the resumption of menstruation during the treatment suspension period.
If there is a thickening of the endometrium that persists after the resumption of menstruation during the treatment withdrawal periods or for more than 3 months after the end of the treatment courses and / or an altered bleeding profile is observed (see "bleeding profile" "), investigations including endometrial biopsy should be performed to rule out other underlying conditions, including endometrial malignancy.
In case of hyperplasia (without atypia), monitoring according to usual clinical practice is recommended (e.g. follow-up check after 3 months). In cases of atypical hyperplasia, the investigations and procedures required by usual clinical practice must be performed.
Treatment courses should not exceed 3 months each, as the risk of adverse effects on the endometrium if continued without interruption of treatment is unknown.
Bleeding profile
Patients should be advised that treatment with ulipristal acetate generally results in a significant reduction in menstrual blood loss or amenorrhea within the first 10 days of treatment. If excessive bleeding persists, the patient should inform her physician. Menstruation will generally recur within 4 weeks of the end of each treatment cycle.
If, during repeated intermittent treatment, after initial bleeding reduction or amenorrhea, a persistent or unexpected altered bleeding pattern, such as intermenstrual bleeding, is detected, further investigations of the endometrium, including endometrial biopsy, should be performed to rule out other underlying conditions, including endometrial malignancy.
Intermittent repeat treatment has been studied for up to 4 intermittent treatment cycles.
Kidney failure
Renal insufficiency is not expected to significantly alter the elimination of ulipristal acetate. In the absence of specific studies, ulipristal acetate is not recommended in patients with severe renal impairment unless the patient is strictly monitored (see section 4.2).
Hepatic insufficiency
There is no therapeutic experience with ulipristal acetate in patients with hepatic insufficiency. Hepatic insufficiency is expected to alter the elimination of ulipristal acetate, resulting in increased exposure (see section 5.2). This effect is not considered clinically relevant for patients with mild hepatic impairment. The use of ulipristal acetate in patients with moderate or severe hepatic impairment unless the patient is closely monitored (see section 4.2).
Concurrent treatments
Co-administration of moderate (e.g. erythromycin, grapefruit juice, verapamil) or potent (e.g. ketoconazole, ritonavir, nefazodone, itraconazole, telithromycin, clarithromycin) inhibitors of CYP3A4 and ulipristal acetate is not recommended (see section 4.5).
Concomitant use of ulipristal acetate and strong CYP3A4 inducers (eg rifampicin, rifabutin, carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, primidone, St. John's wort, efavirenz, nevirapine, long-term use of ritonavir) is not recommended (see section 4.5).
Asthmatic patients
Use in women with severe asthma inadequately controlled by oral glucocorticoids is not recommended.
04.5 Interactions with other medicinal products and other forms of interaction
Potential for other drugs to interfere with ulipristal acetate:
Hormonal contraceptives
Ulipristal acetate has a steroid structure and acts as a selective progesterone receptor modulator, with predominantly inhibitory effects on the progesterone receptor. Hormonal and progestogen contraceptives are therefore likely to reduce the efficacy of ulipristal acetate due to a competitive action on the progesterone receptor. Concomitant administration of progestogen-containing medicinal products is therefore not recommended (see sections 4.4 and 4.6).
CYP3A4 inhibitors
Following administration of the moderate CYP3A4 inhibitor erythromycin propionate (500 mg twice daily for 9 days) to healthy volunteers, ulipristal acetate Cmax and AUC increased 1.2- and 2.9-fold, respectively; of the active metabolite of ulipristal acetate increased 1.5-fold, while the Cmax of the active metabolite decreased (0.52-fold change).
Following administration of the potent CYP3A4 inhibitor ketoconazole (400 mg once daily for 7 days) to healthy volunteers, Cmax and AUC of ulipristal acetate increased 2- and 5.9-fold, respectively; the AUC of the active metabolite of ulipristal acetate increased 2.4-fold while the Cmax of the active metabolite decreased (0.53-fold change).
No dose adjustment is required when ulipristal acetate is administered to patients who are concomitantly receiving mild CYP3A4 inhibitors. Concomitant administration of moderate or strong inhibitors of CYP3A4 and ulipristal acetate is not recommended (see section 4.4).
CYP3A4 inducers
Administration of the strong CYP3A4 inducer rifampicin (300 mg twice daily for 9 days) to healthy volunteers significantly reduced Cmax and AUC of ulipristal acetate and its active metabolite by 90% or more and reduced the half-life of ulipristal. acetate 2.2-fold, corresponding to an approximately 10-fold decrease in exposure to ulipristal acetate. Concomitant use of ulipristal acetate and potent CYP3A4 inducers (eg rifampicin, rifabutin, carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, primidone, St. John's wort, efavirenz, nevirapine, long-term use of ritonavir) is not recommended (see section 4.4).
Medicinal products affecting gastric pH
Administration of ulipristal acetate (10 mg tablets) in combination with the proton pump inhibitor esomeprazole (20 mg daily for 6 days) produced an approximately 65% reduction in mean Cmax, a delay in Tmax (from a median of 0.75 hours to 1.0 hours) and a 13% increase in the mean value of AUC. This effect of medicinal products that increase gastric pH is not expected to be clinically relevant in the daily administration of ulipristal acetate in tablets.
Potential for ulipristal acetate to interfere with other medicinal products:
Hormonal contraceptives
Ulipristal acetate may interfere with the action of hormonal contraceptive products (progestogens only, progestogen releasing devices or combined oral birth control pills) and progestogens administered for other reasons. Concomitant administration of progestogen-containing medicinal products is therefore not recommended (see sections 4.4 and 4.6) Medicinal products containing progestogens should not be taken for 12 days after cessation of treatment with ulipristal acetate.
P-gp substrates
Data in vitro indicate that ulipristal acetate may be an inhibitor of P-gp at clinically relevant concentrations on the gastrointestinal wall during absorption. Simultaneous administration of ulipristal acetate and a substrate of P-gp has not been studied and an interaction cannot be excluded. The results in vivo show that ulipristal acetate (administered as a single 10 mg tablet) 1.5 hours prior to administration of the P-gp substrate fexofenadine (60 mg) has no clinically relevant effect on the pharmacokinetics of fexofenadine. It is therefore recommended that the co-administration of ulipristal acetate and P-gp substrates (e.g. dabigatran ethexylate, digoxin, fexofenadine) be spaced out by at least 1.5 hours.
04.6 Pregnancy and lactation
Female contraception
Ulipristal acetate is likely to interact negatively with progestogen-only pills, progestogen-releasing devices, or combined oral birth control pills; Concomitant use is therefore not recommended. Although the majority of women taking a therapeutic dose of ulipristal acetate exhibit anovulation, the use of a non-hormonal method of contraception is recommended during treatment (see sections 4.4 and 4.5).
Pregnancy
Ulipristal acetate is contraindicated during pregnancy (see section 4.3).
There are no or limited data on the use of ulipristal acetate in pregnant women.
Although no teratogenic potential was found, data on animal species are insufficient for an assessment of reproductive toxicity (see section 5.3).
Feeding time
Available toxicological data in animals have shown that ulipristal acetate is excreted in milk (for details see section 5.3). Ulipristal acetate is excreted in human milk. Effects on infants have not been studied. The presence of risks for the newborn cannot be excluded. Ulipristal acetate is contraindicated during lactation (see sections 4.3 and 5.2).
Fertility
The majority of women taking a therapeutic dose of ulipristal acetate exhibit anovulation, however, the level of fertility while taking multiple doses of ulipristal acetate has not been studied.
04.7 Effects on ability to drive and use machines
Ulipristal acetate may slightly impair the ability to drive or use machines, since mild dizziness has been observed after taking ulipristal acetate.
04.8 Undesirable effects
Summary of the safety profile
The safety of ulipristal acetate was evaluated in 1,053 women with uterine fibroids treated with 5 mg or 10 mg of ulipristal acetate during Phase III studies. The most common effect in clinical trials was amenorrhea (79.2%), which was considered a desirable outcome for patients (see section 4.4).
The most frequent adverse reaction was hot flash. The vast majority of adverse reactions were mild and moderate (95.0%), did not cause discontinuation of the medicinal product (98.0%) and resolved spontaneously.
In this group of 1,053 women, the safety of repeated intermittent treatment courses (each limited to 3 months) was evaluated in 551 women with uterine fibroids treated with 5 or 10 mg of ulipristal acetate in two phase III studies (including 457 exposed women four courses of intermittent treatment), in which the drug exhibited a safety profile similar to that seen with only one course of treatment.
Table of adverse reactions
Based on pooled data from four Phase III studies in patients with uterine fibroids treated for 3 months, the following adverse reactions were reported. Adverse reactions listed below are classified by frequency and by system organ. Within each frequency class, adverse reactions are listed in order of decreasing severity. Frequencies are defined as very common (≥1 / 10), common (≥1 / 100 to
* see section "Description of some adverse reactions"
** the literal term "mild hair loss" has been codified with the term "alopecia"
When comparing repeated treatment courses, the frequency of adverse reactions was overall lower in subsequent treatment cycles than in the first course and each adverse reaction was less frequent or remained in the same frequency category (except for dyspepsia which was classified as uncommon in treatment cycle 3 as it occurred in one patient).
Description of some adverse reactions
Thickening of the endometrium
In 10-15% of patients, thickening of the endometrium (> 16 mm by ultrasound or MRI at the end of treatment) was observed with ulipristal acetate at the end of the first 3-month treatment course. of the endometrium was less frequent (4.9% and 3.5% of patients, respectively at the end of the second and fourth treatment cycles). The thickening of the endometrium disappears when treatment is stopped and menstrual cycles resume.
Furthermore, the reversible alterations of the endometrium are termed PAEC and differ from endometrial hyperplasia. If submitting hysterectomy or endometrial biopsy specimens for histological examination, the pathologist should be informed that the patient has taken ulipristal acetate (see sections 4.4 and 5.1).
Hot flush
Hot flashes were reported by 8.1% of patients, but the frequency was different from trial to trial. In the active comparator controlled study, rates were 24% (10.5% moderate or severe) with ulipristal acetate and 60.4% (39.6% moderate or severe) for leuprorelin-treated patients. In the placebo-controlled study, the hot flash rate was 1.0% for ulipristal acetate and 0% for placebo. In the first 3-month treatment cycle of the two long-term Phase III trials, the frequency was 5.3% and 5.8% with ulipristal acetate, respectively.
Headache
Headache of mild or moderate severity was reported by 5.8% of patients.
Ovarian cyst
Functional ovarian cysts were observed during and after treatment in 1.0% of patients; in most cases the cysts disappeared spontaneously within a few weeks.
Uterine bleeding
Patients with heavy menstrual bleeding due to uterine fibroids are at risk of excessive bleeding, which may require surgery. A few cases have been reported during treatment with ulipristal acetate and within 2-3 months of stopping treatment with ulipristal acetate.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. in "Annex V.
04.9 Overdose
Experience with ulipristal acetate overdose is poor.
A limited number of subjects were given single doses of the drug up to 200 mg and daily doses of 50 mg for 10 consecutive days without observing any serious or serious adverse reactions.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: sex hormones and modulators of the genital system, progesterone receptor modulators.
ATC code: G03XB02.
Ulipristal acetate is an orally active synthetic selective progesterone receptor modulator characterized by a tissue-specific partial antagonistic effect against progesterone.
Endometrium
Ulipristal acetate exerts a direct effect on the endometrium.If the daily administration of a 5 mg dose is started during a menstrual cycle, most people (including patients with myoma) will complete their first period but will not have their next period until treatment is finished. Once treatment with ulipristal acetate is stopped, menstrual cycles usually resume within 4 weeks.
The direct action on the endometrium causes specific histological alterations of this category of drugs and defined PAEC. Typically, the histological aspect is an inactive and weakly proliferating epithelium associated with asymmetry of stromal and epithelial growth that produces prominent glands with cystic dilatation and combined estrogenic (mitotic) and progestin (secretory) epithelial effects. This pattern was observed in approximately 60% of patients treated with ulipristal acetate for 3 months. These changes are reversible after cessation of treatment. These changes should not be confused with endometrial hyperplasia.
Approximately 5% of reproductive age patients with heavy menstruation have an endometrial thickness greater than 16 mm. In approximately 10-15% of patients treated with ulipristal acetate, the endometrium may thicken (> 16 mm) during the first 3-month treatment course. In case of repeated treatment courses, the frequency of endometrial thickening was found to be minor (4.9% of patients after the second treatment course and 3.5% after the fourth treatment course). The thickening disappears after discontinuation of treatment and the resumption of menstruation. In the event that endometrial thickening persists after the resumption of menstruation during the treatment withdrawal period or beyond the 3 months following the end of the treatment cycles, it may be necessary to carry out further investigations according to usual clinical practice to rule out other pathologies underlying.
Fibroids
Ulipristal acetate exerts a direct action on fibroids reducing their size by inhibiting cell proliferation and inducing apoptosis.
Pituitary gland
A daily dose of 5 mg ulipristal acetate inhibits ovulation in the majority of patients, as indicated by constant progesterone levels around 0.3 ng / mL.
A daily dose of 5 mg ulipristal acetate partially suppresses FSH levels, but serum estradiol levels are maintained in the mid-follicular range in the majority of patients and are similar to levels found in patients receiving placebo.
Ulipristal acetate does not affect serum TSH, ACTH or prolactin levels.
Clinical efficacy and safety
Pre-operative use:
The efficacy of fixed doses of ulipristal acetate 5 mg and 10 mg once daily was evaluated in two 13-week randomized, double-blind Phase 3 studies in patients with heavy menstruation associated with uterine fibroids. Study 1 was double-blind, placebo-controlled trial. Patients in this trial were expected to be anemic at study entry (Hb iron by mouth, 80 mg Fe ++, plus investigational drug. Study 2 included an active comparator, leuprorelin 3.75 mg administered once monthly with an intramuscular injection. A double placebo was used to maintain blinded Study 2. In both studies, menstrual blood loss was assessed using the Pictorial Bleeding Assessment Chart, PBAC) A PBAC value> 100 in the first 8 days of menstruation was considered indicative of excessive menstrual blood loss.
In Study 1, a statistically significant difference was observed in the reduction in menstrual blood loss in favor of patients treated with ulipristal acetate compared to placebo (see Table 1 below), which resulted in a faster and more efficient correction of the anemia. compared to iron alone. Similarly, patients treated with ulipristal acetate showed greater reduction in myoma size on MRI.
In Study 2, the reduction in menstrual blood loss was similar in patients treated with ulipristal acetate and the gonadotropin-releasing hormone (leuprorelin) agonist. Most of the patients treated with ulipristal acetate stopped losing blood within the first week of treatment (amenorrhea).
The size of the three largest myomas was assessed with ultrasound at the end of treatment (Week 13) and for an additional 25 weeks without treatment in patients not undergoing a hysterectomy or myomectomy. The reduction in myoma size was generally maintained during this. follow-up period in patients treated with ulipristal acetate, while some regrowth occurred in patients treated with leuprorelin.
Table 1: Results of primary efficacy assessments and some secondary efficacy assessments in Phase III studies
a In Study 1, change from baseline in total myoma volume was measured by MRI. In Study 2, the change in volume of the three largest myomas was measured by ultrasound. Values in bold in the shaded boxes indicate a significant difference in comparisons between ulipristal acetate and the control. These differences were always in favor of ulipristal acetate.
P-values: 1 =
Intermittent repeated use:
The efficacy of repeated treatment courses with fixed doses of ulipristal acetate 5 mg or 10 mg once daily was evaluated in two Phase 3 studies analyzing up to 4 intermittent 3-month treatment cycles in patients with very heavy menstruation associated with uterine fibroids. Study 3 was an open-label study evaluating ulipristal acetate 10 mg, in which each 3-month treatment was followed by 10 days of double-blind progestogen or placebo treatment. Study 4 was a randomized clinical study double-blind study that evaluated ulipristal acetate 5 or 10 mg.
Studies 3 and 4 demonstrated efficacy in controlling the symptoms of uterine fibroids (eg uterine bleeding) and in reducing the size of the fibroid after 2 and 4 courses of treatment.
In study 3, treatment efficacy was demonstrated for longer than 18 months of repeated intermittent treatment (4 courses of 10 mg once daily); 89.7% of patients had amenorrhea at the end of the course of treatment 4.
In study 4, 61.9% and 72.7% of patients had amenorrhea at the end of treatment cycles 1 and 2 combined (5 mg dose and 10 mg dose, respectively, p = 0.032); 48.7% and 60.5% of patients had amenorrhea at the end of all four treatment cycles (5 mg dose and 10 mg dose, respectively, p = 0.027). At the end of treatment cycle 4, 158 subjects (69.6%) and 164 subjects (74.5%) had amenorrhea with the 5 mg and 10 mg dose, respectively (p = 0.290).
Table 2: Results of primary efficacy assessments and some secondary efficacy assessments in long-term Phase III studies
a Treatment cycle 2 assessment corresponds to treatment cycle 2 plus one menstrual bleeding.
b Patients for whom data were missing were excluded from the analysis.
c N and% include withdrawn patients
d Controlled bleeding was defined as no episodes of heavy bleeding and a maximum of 8 days of bleeding (excluding spotting days) during the last two months of a treatment course.
Endometrial findings:
In all Phase III studies, including intermittent repeat treatment studies, a total of 7 cases of hyperplasia were observed in 789 patients with adequate biopsies (0.89%). In the vast majority of cases, the endometrium spontaneously returned to normal after the resumption of menstruation during the treatment withdrawal period. The incidence of hyperplasia did not increase with repeated courses of treatment. The observed frequency corresponds to that of the control groups and to the prevalence reported in the literature for symptomatic premenopausal women of this age group (mean of 40 years).
The European Medicines Agency has waived the obligation to submit the results of studies with Esmya in all subsets of the pediatric population in uterine fibroids (see section 4.2 for information on pediatric use).
05.2 Pharmacokinetic properties
Absorption
Following oral administration of a single 5 or 10 mg dose, ulipristal acetate is rapidly absorbed, with Cmax of 23.5 ± 14.2 ng / mL and 50.0 ± 34.4 ng / mL approximately 1 hour after l "ingestion, and with AUC0-∞ of 61.3 ± 31.7 ng.h / mL and 134.0 ± 83.8 ng.h / mL, respectively. Ulipristal acetate is rapidly transformed into a pharmacologically active metabolite with Cmax of 9.0 ± 4.4 ng / mL and 20.6 ± 10.9 ng / mL, again approximately 1 hour after ingestion, and AUC0-∞ of 26.0 ± 12.0 ng.h / mL and 63 , 6 ± 30.1 ng.h / mL, respectively.
Administration of ulipristal acetate (30 mg tablet) accompanied by a high-fat breakfast resulted in a reduction in mean Cmax of approximately 45%, a delay in Tmax (median 0.75 to 3 hours) and a 25% increase in mean AUC0-∞ value compared to dosing in the fasted state. Similar results were obtained for the active mono-N-desmethyl metabolite. This kinetic effect of food is not expected to be clinically relevant in the daily administration of ulipristal acetate tablets.
Distribution
Ulipristal acetate binds strongly (> 98%) to plasma proteins, including albumin, alpha-1-acid glycoprotein, high-density lipoprotein and low-density lipoprotein.
Ulipristal acetate and its active mono-N-demethylated metabolite are excreted in breast milk with a milk / plasma AUCt ratio of 0.74 ± 0.32 for ulipristal acetate.
Biotransformation / Elimination
Ulipristal acetate is rapidly converted to its mono-N-demethylated and subsequently to its di-N-demethylated metabolites. The data in vitroindicate that this conversion is predominantly mediated by the cytochrome P450 isoform 3A4 (CYP3A4). The primary route of elimination is via the faeces and less than 10% is excreted in the urine. The estimated terminal half-life of ulipristal acetate in plasma after a single The 5 or 10 mg dose is estimated to be approximately 38 hours, with a mean oral clearance (CL / F) of approximately 100 L / h.
The data in vitro indicate that ulipristal acetate and its active metabolite do not inhibit CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A4, nor do they induce CYP1A2 at clinically relevant concentrations. Therefore, ulipristal acetate is unlikely to alter the clearance of medicinal products metabolised by these enzymes.
The data in vitro indicate that ulipristal acetate and its active metabolite are not substrates of P-gp (ABCB1).
Special populations
Pharmacokinetic studies of ulipristal acetate have not been conducted in women with impaired renal or hepatic function. Due to CYP-mediated metabolism, hepatic insufficiency is expected to alter the elimination of ulipristal acetate, resulting in increased exposure (see sections 4.2 and 4.4).
05.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.
Most of the results obtained in general toxicity studies related to action on progesterone receptors (and higher concentrations on glucocorticoid receptors) and showed antiprogesterone activity at exposures similar to therapeutic levels. In a 39-week study in cynomolgus monkeys PAEC-like histological changes were noted at low doses.
Due to its mechanism of action, ulipristal acetate has an embryolethal effect in rats, rabbits (at repeated doses above 1 mg / kg), guinea pigs and monkeys. There is no data on the safety of the human embryo. At doses low enough to maintain gestation in animal species, no teratogenic potential was observed.
Reproduction studies conducted in rats at doses such as to produce exposure similar to the dose used in humans showed no evidence of damage to fertility caused by ulipristal acetate in treated animals or in the offspring of treated females.
Carcinogenicity studies (in rats and mice) showed that ulipristal acetate is not carcinogenic.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Microcrystalline cellulose
Mannitol
Croscarmellose sodium
Talc
Magnesium stearate
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years.
06.4 Special precautions for storage
Keep the blisters in the outer carton to protect the medicine from light.
06.5 Nature of the immediate packaging and contents of the package
Al / PVC / PE / PVDC or Al / PVC / PVDC blisters.
Packs of 28, 30 and 84 tablets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
Gedeon Richter Plc.
Gyömroi út 19-21.
1103 Budapest
Hungary
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/12/750/001
042227013
EU / 1/12/750/002
042227025
EU / 1/12/750/003
042227037
EU / 1/12/750/004
042227049
EU / 1/12/750/005
042227052
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 23 February 2012
10.0 DATE OF REVISION OF THE TEXT
D.CCE May 2015
