Fibristal: Indications, Dosage, Precautions, Adverse Effects
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Fibristal - Product Information

Manufacture: Actavis
Country: Canada
Condition: Uterine Fibroids
Class: Progesterone receptor modulators
Form: Tablets
Ingredients: ulipristal acetate, croscarmellose sodium, magnesium stearate, mannitol, microcrystalline cellulose, and talc

ulipristal acetate

Summary Product Information

Route of
Administration
Dosage Form /
Strength
Clinically Relevant Nonmedicinal
Ingredients
Oral Tablet, 5 mg Lactose
For a complete listing see Dosage Forms,
Composition and Packaging Section

Indications and Clinical Use

Fibristal (ulipristal acetate) is indicated for;

  • Treatment of moderate to severe signs and symptoms of uterine fibroids in adult women of reproductive age who are eligible for surgery. The duration of treatment is limited to 3 months.

Geriatrics (≥ 65 years of age)

Safety and efficacy of Fibristal have not been established in women ≥ 65 years of age.

Pediatrics (< 18 years of age)

Safety and efficacy of Fibristal have not been established in women < 18 years of age.

Contraindications

  • Fibristal is contraindicated in women who are hypersensitive to ulipristal acetate or to any ingredient in the formulation. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph.
  • Fibristal is contraindicated for use during pregnancy and in women who are breastfeeding.
  • Fibristal is contraindicated in women with genital bleeding of unknown etiology or for reasons other than uterine fibroids.
  • Fibristal is contraindicated in women with uterine, cervical, ovarian or breast cancer.
  • Due to lack of long-term safety data, the duration of treatment should not be longer than 3 months of continuous use.

Warnings and Precautions

Ulipristal acetate should only be prescribed after careful diagnosis. Pregnancy should be precluded prior to treatment.

Contraception

Concomitant use of progestagen-only pills, a progestagen-releasing intrauterine device or combined oral contraceptive pills is not recommended. Although a majority of women taking a therapeutic dose of ulipristal acetate have anovulation, a non-hormonal contraceptive method is recommended during treatment.

Hepatic Impairment

Ulipristal acetate is not recommended in patients with mild, moderate, or severe hepatic impairment unless the patient is closely monitored.

Renal Impairment

Renal impairment is not expected to significantly alter the elimination of ulipristal acetate. In the absence of specific studies, ulipristal acetate is not recommended for patients with moderate and severe renal impairment unless the patient is closely monitored.

Concomitant Treatments

No dose adjustment is recommended in patients receiving Fibristal with mild CYP3A4 inhibitors. Co-administration of moderate or potent CYP3A4 inhibitors (e.g., clarithromycin, ketoconazole, erythromycin) and ulipristal acetate is not recommended.

When prescribing ulipristal acetate to patients receiving CYP3A4 inducers, plasma levels of ulipristal acetate may be reduced. Concomitant use of ulipristal acetate and potent enzyme inducers (e.g., rifampicin, carbamazepine, phenytoin, St John´s wort) is not recommended.

Asthma Patients

Use in women with severe asthma insufficiently controlled by oral glucocorticoids is not recommended.

Endometrial Changes

Ulipristal acetate has a specific pharmacodynamic action on the endometrium. Increase in thickness of the endometrium may occur. If the endometrial thickening persists beyond 3 months following the end of treatment and return of menstruations, this may need to be investigated as per usual clinical practice to exclude underlying conditions.

Changes in the histology of the endometrium may be observed in patients treated with ulipristal acetate. These changes are reversible after treatment cessation.

These histological changes are denoted as “Progesterone Receptor Modulator Associated Endometrial Changes” (PAEC) and should not be mistaken for endometrial hyperplasia. In absence of safety data for a period longer than 3 months or on repeat courses of treatment, the risk of adverse impact on the endometrium is unknown if treatment is continued; therefore, treatment duration should not exceed 3 months.

Bleeding Pattern

Patients should be informed that treatment with ulipristal acetate usually leads to a significant reduction in menstrual blood loss or amenorrhea within the first 10 days of treatment. Should the excessive bleeding persist, patients should notify their physician. Menstrual periods will generally return within 4 weeks after the end of the treatment course.

Special Populations

Pregnant Women

Use of Fibristal is contraindicated during an existing or suspected pregnancy. The extent of exposure in pregnancy during clinical trials is very limited.

Nursing Women

It is not known if ulipristal acetate is excreted in human milk. However, ulipristal acetate is detected in milk of lactating rats. Because many drugs are excreted in human milk, risk to the breast-fed child cannot be excluded. Breastfeeding while taking Fibristal is not recommended.

Pediatrics (< 18 years of age)

Safety and efficacy of Fibristal have not been established in women < 18 years of age.

Geriatrics (≥ 65 years of age)

Safety and efficacy of Fibristal have not been established in women ≥ 65 years of age.

Monitoring and Laboratory Tests

Pregnancy should be excluded before prescribing Fibristal. If pregnancy cannot be excluded on the basis of history and/or physical examination, pregnancy testing should be performed. If there is any doubt concerning the general health or pregnancy status of any woman after taking Fibristal, further investigation may be warranted.

Adverse Reactions

Adverse Drug Reaction Overview

The most common adverse drug reactions (≥ 5%) in the clinical trials for women receiving Fibristal 5 mg were hot flash (13.0% overall) and headache (8.3% overall).

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Fibristal was studied in a randomized, double-blind, placebo-controlled multicenter trial (Study 1) and in a randomized, double-blind, active comparator-controlled multicenter trial (Study 2). In these studies, a total of 393 (192 + 201) women in 5 mg and 10 mg ulipristal acetate groups, respectively, were included in the safety analysis. The mean age of women who received ulipristal acetate in Study 1 was 42 years and the body mass index (BMI) was 25.3. The racial demographics of those enrolled were 88% Caucasian and 12% Asian. The mean age of women who received ulipristal acetate in Study 2 was 40 years and the mean BMI was 25.5. The racial demographics of those enrolled were 85% Caucasian, 10% Black, 1% Asian, and 5% other.

Adverse drug reactions reported in at least 1% of subjects in any treatment group, in either study are shown in Table 1.

Table 1: Adverse Drug Reactions Occurring in ≥ 1% of Subjects in Any Treatment Group in Clinical Trials
System Organ
Class
Adverse Reactions
(MedDRA)
Study 1 Study 2
Ulipristal
acetate
5 mg/day
N = 95
Ulipristal
acetate
10 mg/day
N = 98
Placebo
N = 48
Ulipristal
acetate
5 mg/day
N = 97
Ulipristal
acetate
10 mg/day
N = 103
Leupro-
lide acetate
N = 101
Cardiac
disorders
Sinus bradycardia 1 (1.1) - - - - -
Ear and
labyrinth
disorders
Vertigo - - - 4 (4.1) 3 (2.9) 1 (1.0)
Endocrine
disorders
Hyperprolactinemia - - 1 (2.1) - - -
Hypothyroidism 2 (2.1) 1 (1.0) - - - -
Thyroid disorder 1 (1.1) - - - - -
Gastrointestinal
disorders
Abdominal pain - - - - 4 (3.9) 4 (4.0)
Nausea - 2 (2.0) - 3 (3.1) 4 (3.9) 4 (4.0)
Constipation - - - 1 (1.0) 1 (1.0) 1 (1.0)
Abdominal pain upper - - - 1 (1.0) 1 (1.0) -
Dyspepsia - - - 1 (1.0) - -
General
disorders and
administration
site conditions
Fatigue - - - 4 (4.1) 4 (3.9) 3 (3.0)
Asthenia - - - - 2 (1.9) 1 (1.0)
Irritability - - - - 2 (1.9) -
Edema 1 (1.1) - - - - -
Generalized edema - - - 1 (1.0) - -
Pyrexia - - - 1 (1.0) - -
Infections and
infestations
Vaginal infection - - - - - 2 (2.0)
Vulvovaginal candidiasis 1 (1.1) 1 (1.0) - - - -
Herpes virus infection - 1 (1.0) - 1 (1.0) - -
Pharyngitis - - - 1 (1.0) - -
Investigations Weight increased - 2 (2.0) - - - -
Gamma-glutamyltransferase increased 1 (1.1) - - - - -
Activated partial thromboplastin time prolonged - 1 (1.0) - - - -
Metabolism and
nutrition
disorders
Hypercholesterolemia 3 (3.2) 2 (2.0) 1 (2.1) 3 (3.1) - 1 (1.0)
Hypertriglyceridemia 3 (3.2) - - - - -
Obesity 1 (1.1) - - 1 (1.0) - -
Fluid retention - 1 (1.0) - - - -
Musculoskeletal
and connective
tissue
Arthralgia - - - 2 (2.1) 3 (2.9) 2 (2.0)
Muscle spasms - - - 2 (2.1) - -
Back pain - - - 1 (1.0) 1 (1.0) -
Pain in extremity - - - 1 (1.0) 1 (1.0) -
Nervous system
disorders
Headache 1 (1.1) 3 (3.1) - 15 (15.5) 6 (5.8) 8 (7.9)
Migraine - - - 1 (1.0) 2 (1.9) 2 (2.0)
Somnolence - - - 1 (1.0) 1 (1.0) 2 (2.0)
Dizziness 1 (1.1) 1 (1.0) - 1 (1.0) - -
Neoplasms
benign,
malignant and
unspecified (incl
cysts and
polyps)
Ectopic ACTH syndrome - 1 (1.0) - - - -
Psychiatric
disorders
Insomnia - - - 2 (2.1) 2 (1.9) 5 (5.0)
Depression - - - - - 2 (2.0)
Affect lability - - - 1 (1.0) - 1 (1.0)
Aggression - - - 1 (1.0) - -
Sleep disorder - - - 1 (1.0) - -
Reproductive
system and
breast disorders
Hot flush 1 (1.1) 1 (1.0) - 24 (24.7) 25 (24.3) 63 (62.4)
Ovarian cyst - 1 (1.0) - 1 (1.0) 4 (3.9) 1 (1.0)
Breast tenderness - 3 (3.1) - 1 (1.0) - -
Endometrial hypertrophy - - - - 3 (2.9) -
Breast pain 2 (2.1) 2 (2.0) - 2 (2.1) 1 (1.0) 2 (2.0)
Dysmenorrhea - - 1 (2.1) - - -
Endometrial hyperplasia 2 (2.1) - - - - -
Genital hemorrhage - - - 2 (2.1) 2 (1.9) 2 (2.0)
Pelvic pain 2 (2.1) 1 (1.0) - 1 (1.0) - -
Menometrorrhagia - - 1 (2.1) - - -
Metrorrhagia - - 1 (2.1) 1 (1.0) 1 (1.0) 2 (2.0)
Uterine hemorrhage 1 (1.1) 1 (1.0) - - 1 (1.0) -
Amenorrhea 1 (1.1) - - - - -
Ovarian hyperfunction 1 (1.1) - - - - -
Uterine disorder 1 (1.1) - - - - -
Breast discomfort - 1 (1.0) - - - -
Vulvovaginal dryness - - - 1 (1.0) - 1 (1.0)
Breast swelling - - - 1 (1.0) - -
Genital discharge - - - 1 (1.0) - -
Respiratory,
thoracic and
mediastinal
disorders
Dyspnea - - - 1 (1.0) - -
Epistaxis - - - 1 (1.0) - -
Skin and
subcutaneous
tissue
Night sweats - - - 2 (2.1) 3 (2.9) -
Acne 1 (1.1) 2 (2.0) - - 5 (4.9) 4 (4.0)
Hyperhidrosis - 2 (2.0) - - - 3 (3.0)
Seborrhea 1 (1.1) - - - - -
Dry skin - - - 1 (1.0) 1 (1.0) 1 (1.0)
Alopecia - - - 1 (1.0) - -
Vascular
disorders
Hyperaemia - - 1 (2.1) - - -
Hypertension - - 1 (2.1) - - -
Hypotension - - - 1 (1.0) - -

Description of selected adverse reactions

Endometrial thickening

In 10-15% of patients, thickening of the endometrium (>16 mm by ultrasound or MRI at end of treatment) was observed with ulipristal acetate; this reverses when treatment is stopped and menstrual periods resume.

In addition, reversible changes to the endometrium are denoted PAEC and are different from endometrial hyperplasia. If hysterectomy or endometrial biopsy specimens are sent for histology, then the pathologist should be informed that the patient has taken ulipristal acetate.

Hot flush

Hot flushes were reported by 4 patients. In the placebo-controlled study, the rate of hot flushes was 1.7% for ulipristal acetate and 0% for placebo.

Headache

Mild or moderate severity headache was reported in 6.4% of patients.

Ovarian cyst

Functional ovarian cysts were observed during and after treatment in 1.5% of patients and in most of the cases spontaneously disappeared within a few weeks.

Uterine hemorrhage

Patients with heavy menstrual bleeding due to uterine fibroids are at risk of excessive bleeding, which may require surgical intervention. A few cases have been reported during ulipristal acetate treatment or within 2-3 months after ulipristal acetate treatment was stopped.

During clinical trials, the majority of adverse reactions were mild or moderate in severity. In Study 1, there were no subjects that discontinued the study due to adverse events. Additionally, in Study 2, Fibristal 5 mg demonstrated a lower rate of study discontinuation due to adverse events than the active comparator (1% for 5 mg ulipristal acetate vs. 5% for active comparator).

Drug Interactions

Drug-Food Interactions

Hormonal Contraceptives

Effect of Hormonal Contraceptives on Ulipristal Acetate

Ulipristal acetate has a steroid structure and acts as a selective progesterone receptor modulator with predominantly inhibitory effects on the progesterone receptor. Thus, hormonal contraceptives and progestogens are likely to reduce Fibristal efficacy.

Effect of Ulipristal Acetate on Hormonal Contraceptives

Ulipristal acetate may interfere with the action of hormonal contraceptive products (progestogen only, progestogen releasing devices or oral contraceptive pills) and progestogen administered for other reasons. Therefore concomitant administration of medicinal products containing progestogen is not recommended. Medicinal products containing progestogen should not be taken within 12 days after cessation of Fibristal treatment. Patients should be advised to use an alternative reliable barrier contraceptive method (such as a condom) while taking Fibristal.

CYP3A4 Inhibitors

Following administration of the moderate CYP3A4 inhibitor erythromycin propionate (500 mg twice daily for 9 days) to healthy female volunteers, Cmax and AUC of ulipristal acetate increased 1.2- and 2.9-fold, respectively; the Cmax of the active metabolite decreased (0.52-fold change), while the AUC of PGL4002, the mono-N-demethylated active metabolite of ulipristal acetate, increased 1.5-fold.

In the presence of the potent CYP3A4 inhibitor ketoconazole (400 mg once a day for 7 days), mean ulipristal acetate Cmax and AUC0-inf were increased by 1.96-fold and 5.86-fold, respectively. PGL4002 Cmax in the presence of ketoconazole was decreased by 0.53-fold while AUC0-inf was increased by 2.4-fold.

No dose adjustment is considered necessary for administration of ulipristal acetate to patients receiving concomitant mild CYP3A4 inhibitors. Co-administration of moderate or potent CYP3A4 inhibitors and ulipristal acetate is not recommended.

CYP3A4 Inducers

Patients receiving concomitant CYP3A4 inducers may have reduced plasma levels of ulipristal acetate. Concomitant use of ulipristal acetate and potent CYP3A4 inducers (e.g., rifampicin, carbamazepine, phenytoin, St John´s wort) is not recommended.

P-gp Substrates

Following the co-administration of ulipristal acetate and fexofenadine (60 mg), mean fexofenadine AUCand Cmax were all minimally decreased in the presence of ulipristal acetate, with no effect on the time to maximum fexofenadine concentration. The co-administration of ulipristal acetate is not expected to result in a clinically relevant effect on the pharmacokinetics of P-gp substrates.

Oral Iron

The co-administration of ulipristal acetate and oral ferrous sulfate resulted in a 32% reduction in ulipristal acetate Cmax but only a 10% decrease in ulipristal acetate AUC with no affect on the time to achieve Cmax (Tmax) compared to ulipristal acetate administration without iron. A similar effect was seen for PGL4002, the mono-N-demethylated active metabolite of ulipristal acetate.

Drug-Herb Interactions

Fibristal can be taken with or without food (see “Absorption” section under “Pharmacokinetics”).

Drug-Laboratory Interactions

Interactions with herbal products have not been established nevertheless St. John’s wort as a CYP3A4 inducer may decrease the plasma concentrations of ulipristal acetate, and may decrease its effectiveness (see section “Drug-Drug Interactions”).

Drug-Laboratory Test Interactions

No laboratory test interactions were observed during clinical evaluations.

Dosage and Administration

The usual dose is one 5 mg tablet per day, for 3 months of continuous use. Instruct the patient to start taking Fibristal during the first 7 days of her menstrual period.

The tablet should be swallowed with water and can be taken with or without food.

Missed Dose

If the patient misses a dose, she should take it as soon as it is remembered. However, if it is time for the next tablet, the patient should skip the missed tablet and take only a single tablet as usual.

Overdosage

Experience with ulipristal acetate overdose is limited.

Single doses up to 200 mg and daily doses of 50 mg for 10 consecutive days were administered to a limited number of subjects, and no severe or serious adverse reactions were reported.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Action and Clinical Pharmacology

Mechanism of Action

Ulipristal acetate (which is the first, in a new class called selective progesterone receptor modulators [SPRM]) is an orally-active selective progesterone receptor modulator characterized by a tissue-specific, partial progesterone antagonist effect. Ulipristal acetate exerts a direct effect on the endometrium and exerts a direct action on fibroids reducing their size through inhibition of cell proliferation and induction of apoptosis.

A daily dose of ulipristal acetate inhibits ovulation and partially suppresses FSH levels but serum estradiol levels are maintained in the mid-follicular range in the majority of patients.

Electrocardiography

A double-blind ECG assessment study was conducted in 186 healthy female volunteers evaluating the potential effects of Fibristal on the QT/QTc interval using a 4-arm (Fibristal 10 mg [n=47], Fibristal 50 mg [n=47], placebo [n=47], moxifloxacin [n=45]), parallel group design. Fibristal did not significantly prolong or shorten the QTc interval at supratherapeutic oral doses of 10 mg/day or 50 mg/day for 8 days.

Pharmacokinetics

Absorption

Following single-dose oral administration of 5 mg, ulipristal acetate is rapidly absorbed, with a Cmax of 23.5 ± 14.2 ng/mL occurring approximately 1 hour after ingestion, and with an AUC0-∞ of 68.5 ± 33.0 ng·h/mL. Ulipristal acetate is rapidly transformed into PGL4002, the pharmacologically active mono-N-demethylated active metabolite with a Cmax of 9.0 ± 4.4 ng/mL also occurring approximately 1 hour after ingestion, and with an AUC0-∞ of 29.1 ± 12.9 ng·h/mL.

Administration of ulipristal acetate after a high-fat meal resulted in a slower rate of ulipristal acetate absorption as indicated by a 26 - 27% decrease in Cmax and a delay of about 1.5 hours in median Tmax for both ulipristal acetate and PGL4002. However, the extent of absorption was increased in the presence of food as evidenced by an increase in AUC0-∞ of 26% compared to that observed after ulipristal acetate administration in the fasted state. Because of the modest degree of these changes, ulipristal may be taken without regard to food.

The rate of absorption of ulipristal acetate is pH-dependent. Administration of ulipristal acetate together with the proton pump inhibitor esomeprazole (20 mg daily for 6 days) resulted in approximately 65% lower mean Cmax, a delayed tmax (from a median of 0.75 hours to 1.0 hours) and 13% higher mean AUC (close to bioequivalence levels). Similar results were obtained for the active mono-N-demethylated metabolite. This kinetic effect of medicinal products that increase gastric pH is not expected to be of clinical relevance for daily administration of Fibristal tablets.

Distribution

Ulipristal acetate is highly bound (>98%) to plasma proteins, including albumin, alpha-l-acid glycoprotein, high density lipoprotein and low density lipoprotein.

Metabolism

Ulipristal acetate is metabolized to mono-N-demethylated (PGL4002) and di-N-demethylated (PGL4004) metabolites. In vitro data indicate that this is predominantly mediated by CYP3A4. The mono-demethylated metabolite is pharmacologically active.

Excretion

Due to the CYP-mediated metabolism, hepatic impairment is expected to alter the elimination of ulipristal acetate, resulting in increased exposure. The main route of elimination is through feces and less than 10% is excreted in the urine. The terminal half-life of ulipristal acetate in plasma following a single dose is estimated to be about 38 hours, with a mean oral clearance (CL/F) of about 100 L/h.

Special Populations and Conditions

Pediatrics and Geriatrics

No pharmacokinetic studies with ulipristal acetate have been performed in the pediatric or geriatric populations.

Hepatic and Renal Insufficiency

No pharmacokinetic studies with ulipristal acetate have been completed in women with impaired renal or hepatic function.

Storage and Stability

Store at controlled room temperature (15 to 30° C).

Tablets packaged in blisters: Keep the blister cards inside the outer carton in order to protect from light.

Tablets packaged in bottles with desiccant: Keep tablets inside the bottle in order to protect from light.

Keep out of reach of children.

Special Handling Instructions

There are no special handling instructions.

Dosage Forms, Composition and Packaging

Fibristal (ulipristal acetate) tablet, 5 mg is supplied in two packaging options:

  • Blister packages containing 7 or 15 tablets.
  • Bottles containing 7, 30, or 90 tablets.

The tablet is a white to off-white, round and biconvex tablet marked with “ES5” on one side.

The inactive ingredients are croscarmellose sodium, magnesium stearate, mannitol microcrystalline cellulose, and talc.