Fablyn - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

FABLYN 500 microgram film-coated tablets.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains lasofoxifene tartrate, equivalent to 500 micrograms lasofoxifene.

Excipient: Each film-coated tablet contains 71.34 mg lactose.

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet.

Triangular, peach-coloured, film-coated tablets debossed with “Pfizer” on one side and “OPR 05” on the other side.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

FABLYN is indicated for the treatment of osteoporosis in postmenopausal women at increased risk of fracture. A significant reduction in the incidence of vertebral and non-vertebral fractures but not hip fractures has been demonstrated (see section 5.1).

When determining the choice of FABLYN or other therapies, including estrogens, for a postmenopausal woman, consideration should be given to menopausal symptoms, effects on uterine and breast tissues, and cardiovascular risks and benefits (see section 5.1).

4.2 Posology and method of administration

Adult (postmenopausal

The recommended dose is one 500 microgram tablet daily.

The tablet may be taken any time of day without regard to food and beverage intake.

Supplemental calcium and/or vitamin D should be added to the diet if daily intake is inadequate.

Postmenopausal women require an average of 1,500 mg/day of elemental calcium. The recommended intake of vitamin D is 400–800 IU daily.

Children and adolescents below 18 years of age:

There is no indication for FABLYN in children and adolescents below 18 years of age since the medicinal product is for use in postmenopausal women only. Therefore safety and efficacy have not been studied (see section 5.2).

Elderly women (65 years and older):

No dose adjustment is necessary in elderly female patients (see section 5.2).

Hepatic insufficiency:

No dose adjustment is required in patients with mild to moderate hepatic insufficiency (see section 5.2). Safety and efficacy of lasofoxifene have not been evaluated in patients with hepatic insufficiency with liver function test > 1.5 ULN; therefore, FABLYN should be used with caution in these patients.

Renal insufficiency:

No dose adjustment is necessary in patients with mild or moderate renal insufficiency (see section 5.2). Safety and efficacy of lasofoxifene have not been evaluated in patients with severe renal insufficiency; therefore, FABLYN should be used with caution in these patients.

Due to the chronic nature of the disease process, FABLYN is intended for long-term use (see secti

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Active or past history of venous thromboembolic events, including deep vein thrombosis, pulmonary embolism and retinal vein thrombosis.

Unexplained uterine bleeding.

Pregnancy and lactation: FABLYN is only for use in postmenopausal women. It must not be taken by women of child-bearing potential, pregnant women and lactating women (see section 4.6).

4.4 Special warnings and precautions for use

In clinical trials, FABLYN-treated women had an increased risk of venous thromboembolic events (deep vein thrombosis and pulmonary embolism) compared to placebo. Other venous thromboembolic events could also occur. A less serious event, superficial thrombophlebitis, also has been reported more frequently with FABLYN compared to placebo. The risk-benefit balance should be considered in patients at risk of venous thromboembolic events of any aetiology (see sections 4.3 and 4.8). Because immobilization increases the risk for venous thromboembolic events independent of therapy, FABLYN should be discontinued at least 3 weeks prior to and during prolonged immobilization (e.g., post-surgical recovery, prolonged bed rest), and therapy should be resumed only after the patient is fully ambulatory. In addition, women taking FABLYN should be advised to move about periodically during prolonged travel.

Any unexplained vaginal bleeding should be investigated as clinically indicated. FABLYN-treated and placebo-treated groups had similar incidences of endometrial hyperplasia and endometrial cancer (see

• section 5.

Lasofoxifene has been associated with benign endometrial effects. These included, in some subjects, a small excess in the incidence of vaginal bleeding as well as endometrial cystic change viewed on ultrasound and histological benign cystic atrophy (a variant of atrophic endometrium). These cystic findings contributed to an approximate 1.5 mm increase in mean endometrial thickness. As a consequence of these benign effects, more FABLYN-treated patients had a diagnostic uterine procedure compared to placebo-treated patients in the PEARL trial (see section 5.1). However, in clinical practice, these benign findings do not warrant further evaluation in women with no vaginal bleeding (in accordance with guidelines for postmenopausal women), as the risks of diagnostic uterine procedures in asymptomatic women outweigh any benefits. Pathologists should be made aware of a history of lasofoxifene use when assessing endometrial histology, to ensure an accurate diagnosis of benign cystic atrophy when present.

The concurrent use of FABLYN and systemic estrogen or hormone therapy has not been studied and therefore concomitant use of FABLYN with systemic estrogens is not recommended.

FABLYN has not been studied in women with a prior history of breast cancer. No data are available on its concomitant use with agents used in the treatment of early or advanced breast cancer. Therefore, FABLYN should be used for the treatment of osteoporosis only after the treatment of breast cancer, including adjuvant therapy, has been completed.

Any unexplained breast abnormality occurring during FABLYN therapy should be investigated. FABLYN does not eliminate the risk of breast cancer (see section 5.1).

FABLYN may increase the incidence of hot flushes and is not effective in reducing hot flushes associated with estrogen deficiency. In some asymptomatic patients, hot flushes may occur upon beginning therapy.

Limited clinical data suggest that in patients with a history of oral oestrogen-induced hypertriglyceride (> 5.6 mmol/l), lasofoxifene may be associated with a marked increase in serum triglycerides. Patients this medical history should have serum triglycerides monitored when taking lasofoxifene.

Lasofoxifene is highly protein bound, predominantly cleared by metabolism and is likely to undergo enterohepatic circulation (see section 5.2). Safety and efficacy of FABLYN have not been evaluated in patients with liver function test > 1.5 ULN; therefore, FABLYN should be used with caution in these patients.

Safety and efficacy of FABLYN have not been evaluated in patients with severe renal insufficiency; therefore, FABLYN should be used with caution in these patients (see section 4.2 and section 5.2).

FABLYN contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

4.5 Interaction with other medicinal products and other forms of interaction

Based on the absence of clinically relevant effects of cholestyramine (anion exchange resin), fluconazole (CYP2C9 inhibitor), ketoconazole (CYP3A4/5 inhibitor) and paroxetine (CYP2D6 inhibitor) on lasofoxifene pharmacokinetics, other anion exchange resins and other inhibitors of these CYP isoforms are unlikely to produce clinically meaningful alterations in FABLYN exposure and no dose adjustments are required.

Lasofoxifene clearance may be increased in patients chronically treated with inducers of CYP3A4 and UGTs (eg, phenytoin, carbamazepine, barbiturates and St John’s Wort) resulting in reduced steadystate concentrations and may result in reduced efficacy.

Ketoconazole – The strong CYP3A4/5 inhibitor ketoconazole increased the systemic exposure of lasofoxifene by 20% which is not considered to be clinically meaningful.

Paroxetine – The strong CYP2D6 inhibitor paroxetine increased the systemic exposure of lasofoxifene by 35% which is not considered to be clinically meaningful.

Proton pump inhibitors – Data on the effect of concomitant administration of proton pump inhibitors (PPIs) with lasofoxifene is not available; thus, use of these agents with lasofoxifene should be considered with caution.

In clinical studies, lasofoxifene did not alter the metabolism of dextromethorphan (CYP2D6 substrate) and chlorzoxazone (CYP2E1 substrate) or the pharmacokinetics of warfarin (CYP2C9 substrate), methylprednisolone (CYP3A4 substrate) or digoxin (MDR1 P-glycoprotein substrate). Therefore FABLYN is unlikely to alter the pharmacokinetics of medicinal products that are cleared by metabolism via these CYP isoforms, or are transported by MDR1 P-glycoprotein.

Warfarin – Lasofoxifene had no effect on the pharmacokinetics of R- and S- warfarin. Mean international normalized ratio (INR) AUC and maximum value of INR after single-dose warfarin administration with lasofoxifene were approximately 8% and 16% lower, respectively, than after warfarin alone. These changes are not considered to be clinically meaningful.

• 4.6 Pregnancy and lactation

Pregnancy

FABLYN is only for use in postmenopausal women. FABLYN must not be taken by women of childbearing potential (see section 4.3). There are no adequate data from the use of lasofoxifene in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

Lactation

FABLYN is only for use in postmenopausal women. FABLYN must not be taken during lactation (see section 4.3). It is not known whether lasofoxifene is excreted in human milk. Animal studies have shown excretion of lasofoxifene in milk.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

FABLYN has no known influence on the ability to drive and use m

4.8 Undesirable effects

The safety of FABLYN in the treatment of osteoporosis was assessed in a large (8,556 patients) double-blind, randomized, placebo-controlled multinational Phase 3 fracture trial (the PEARL study).

The duration of treatment in postmenopausal women was 60 months, 2,852 were randomized to FABLYN and 2,852 were randomized to placebo.

Within this study, 12.9% of FABLYN-treated women and 12.3% of placebo-treated women discontinued therapy due to adverse events.

Venous Thromboembolic Events : The most serious adverse reaction related to FABLYN was VTE (deep venous thrombosis, pulmonary embolism, and retinal vein thrombosis). Through 5 years of follow-up, 37 FABLYN-treated women (1.3%, or 2.90 per 1,000 patients years) had a VTE compared to 18 placebo-treated women (0.6%, or 1.41 per 1,000 patients years) and the hazard ratio was 2.06 (95% CI: 1.17, 3.61).

As observed with other Selective Estrogen Receptor Modulators (SERMs), slightly decreased (approximately 4%) platelet counts were observed in lasofoxifene-treated patients in PEARL.

Common adverse reactions considered to be related to FABLYN therapy were muscle spasms, hot flush and vaginal discharge. Muscle spasms occurred in about one in 9 patients. Hot flush occurred in about one in 11 patients and was most commonly reported during the first 6 months of treatment.

Vaginal discharge occurred in about one in 26 patients.

The safety of FABLYN in the treatment of osteoporosis was also assessed in a Phase 2 placebo-controlled trial in Japanese, Korean and Taiwanese women. The duration of treatment in postmenopausal women was 12 months, 124 were exposed to FABLYN and 125 were exposed to placebo. Within this study, 3.2% of FABLYN-treated women and 8.0% of placebo-treated women discontinued therapy due to adverse events.

Table 1 lists adverse reactions occurring in the two osteoporosis treatment clinical trials that occurred at an incidence greater than placebo.

Most of the adverse reactions occurring during the studies were mild and generally did not require discontinuation of therapy.

Adverse reactions are listed by system organ class and frequency (very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100) and rare (>1/10,000 to <1/1,000)). In each system organ class and frequency, adverse reactions are not presented in order of decreasing seriousness but in alphabetical order.

Table 1 : Adverse reactions observed in placebo-controlled osteoporosis treatment clinical trials in more FABLYN-treated women than in placebo-treated women

• * Endometrial hypertrophy is a MedDRA dictionary term that represents sonographic endometrial thickness findings.

• * * Endometrial hyperplasia events based on investigator reporting rather than histopathology findings and did not require histological confirmation.

4.9 Overdose

No case of FABLYN overdose has been reported.

Lasofoxifene has been administered to postmenopausal women at single doses as high as 100 mg (200 times the recommended unit dose) and multiple doses as high as 10 mg/day (20 times the recommended dose) for up to one year without dose-related serious adverse reactions.

There is no specific antidote for FABLYN. In the event of overdose, general supportive measures should be initiated based on the patient’s signs and symptoms.

Pharmacotherapeutic group: Selective Estrogen Receptor Modulator (SERM), ATC code: {not yet assigned}

Decreases in estrogen levels after menopause or oophorectomy lead to accelerated bone loss due to increased bone turnover, where bone resorption exceeds bone formation. The increased turnover causes accelerated bone loss because the compensatory increase in bone formation is not sufficient to offset increased bone resorption. In some women, these changes will eventually lead to decreased bone mass, osteoporosis, and increased risk for fractures, particularly of the spine, hip, and wrist. Vertebral fractures are the most common type of osteoporotic fracture in postmenopausal wo­men.

Lasofoxifene is a SERM whose biological actions are largely mediated through binding to estrogen receptors. This binding results in the activation of some estrogenic pathways and a blockade of others. Lasofoxifene produces tissue and cell-specific effects in estrogen-responsive tissues.

Clinical data indicate that FABLYN has an estrogen-like agonist effect on bone as well as antagonistic effects on the breast. The effects of FABLYN on bone are manifested as reductions in the serum and urine levels of bone turnover markers, increases in bone mineral density (BMD), and decreases in incidence of fractures.

Skeletal effects:

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Bone turnover

In the osteoporosis treatment trials, FABLYN therapy resulted in consistent, statistically significant suppression of bone resorption and bone formation, as reflected by changes in serum and urine markers of bone turnover (e.g., C-telopeptide and markers of bone formation: osteocalcin, procollagen type 1 N-terminal propeptide, and bone-specific alkaline phosphatase). The suppression of bone turnover markers was evident by 3 months and persisted throughout the 36-month observation period in a sub-study of the PEARL study.

5-year results from large, multinational fracture trial (PEARL)

The effects of FABLYN on fracture incidence (table 2) were examined through 5 years; and BMD and bone biomarkers in postmenopausal women with osteoporosis were examined through 3 years in the PEARL study. The study population consisted of 8,556 postmeno­pausal women with osteoporosis as defined by low BMD (vertebral or hip BMD at least 2.5 standard deviations below the mean value for healthy young women). Women enrolled in this study had a median age of 67 years (range 59 to 80) and a median time since menopause of 20 years. All women in the study received calcium (1,000 mg/day) and Vitamin D (400–800 IU/day).

Table 2: Fracture incidence in postmenopausal women over 5 years

-Radiographic vertebral fractures

FABLYN significantly decreased the incidence of new radiographic vertebral fractures (excluding worsening of previous fractures) from 9.3% for placebo to 5.6% for FABLYN (relative risk reduction = 41%, p < 0.0001). This decrease was observed through the first year and was maintained through 5 years.

In women with a prevalent vertebral fracture at baseline, FABLYN significantly reduced the incidence of new vertebral radiographic fractures from 14.2% for placebo to 8.7% for FABLYN (relative risk reduction = 42%, p = 0.0004). In women without any prevalent vertebral fractures at baseline, the incidence of new radiographic vertebral fractures was significantly reduced from 7.4% for placebo to 4.4% for FABLYN (relative risk reduction = 41%, p = 0.0002).

Significantly fewer women experienced multiple radiographic vertebral fractures in the FABLYN treatment group versus the placebo group throughout 5 years of dosing (p < 0.0001).

Significantly fewer women treated with FABLYN experienced moderate or severe vertebral fractures (as determined by the Genant scale) compared to women treated with placebo (5.2% placebo-treated women versus 3.3% FABLYN-treated women; p = 0.0006).

-Non-vertebral fractures

FABLYN significantly decreased the incidence of non-vertebral fractures from 10.4% for placebo to 8.1% for FABLYN (relative risk reduction = 24%, p = 0.0020). This decrease was observed through the first year and was maintained through 5 years. The reduction in the incidence of non-vertebral fractures was also observed in postmenopausal women with severe osteoporosis (defined as a baseline lumbar spine BMD T-score < -2.5 + prevalent fracture or BMD T-score < -3) (p = 0.0183).

-All clinical fractures

FABLYN significantly decreased the incidence of all clinical fractures from 12.1% for placebo to

• 9.3% for FABLYN (relative risk reduction = 25%, p = 0.0004). This decrease was observed through the first year and maintaine

  d through 5 years.

  
  

• -Bone mineral density

  
  

5.2 Pharmacokinetic properties

The disposition of lasofoxifene was evaluated in 758 subjects in conventional clinical pharmacology studies. Pharmacokinetic data from over 2,000 postmeno­pausal women including patients in selected osteoporosis clinical trials contributed to a population pharmacokinetic analysis.

Absorption:

Lasofoxifene is slowly absorbed from the gastrointestinal tract with maximal plasma concentrations attained on average by approximately 6 hours after dosing. Ingestion of a high fat meal does not change the oral bioavailability of lasofoxifene. FABLYN may be administered any time of day without regard to food or beverage intake.

Distribution:

The apparent volume of distribution (V/F) of lasofoxifene in postmenopausal women is approximately 1,350 l.

Lasofoxifene is highly bound to proteins in human plasma (>99%). Lasofoxifene binds to both albumin and a1-acid glycoprotein; however, it does not affect the binding of either warfarin or propranolol.

Metabolism:

Biotransformation and disposition of lasofoxifene in humans have been determined following oral administration of 14C-labeled lasofoxifene. Lasofoxifene is extensively metabolized in humans. Five metabolic pathways of lasofoxifene have been identified: direct glucuronidation; direct sulfation; hydroxylation at the phenyl tetraline moiety (with subsequent conjugative metabolism of the catechol intermediates by methylation and glucuronidation); oxidation at the pyrrolidine ring; and phenyl hydroxylation. Three metabolites of lasofoxifene were detected in plasma: the direct glucuronide conjugate, the glucuronide of a hydroxylated metabolite, and the methylated catechol.

The binding affinities of the major circulating metabolites of lasofoxifene were at least 31-fold and 18fold less than those of lasofoxifene for the estrogen receptor alpha and the estrogen receptor beta, respectively, indicating that these metabolites are unlikely to contribute to the pharmacologic activity of lasofoxifene. Oxidation, by multiple cytochrome P450s including CYPs 2D6 and 3A4/5, and conjugation of lasofoxifene are the two primary mechanisms of elimination of lasofoxifene from the systemic circulation. The apparent oral clearance (CL/F) of lasofoxifene in postmenopausal women is approximately 6.6 l/hr.

Elimination:

Lasofoxifene has a half-life of approximately 6 days. Lasofoxifene and its metabolites are primarily excreted in feces, with a minor component of urinary excretion of active substance-related material. Following oral administration of 14C-labeled lasofoxifene in solution to humans, approximately 72% of the radioactive dose was recovered by day 24 (approximately 66% in feces and 6% in urine). Less than 2% of the administered dose was recovered in the urine as unchanged lasofoxifene.

Linearity/non-linearity:

Lasofoxifene exhibits linear pharmacokinetics over a wide dose range following single-dose (up to 100 mg) and multiple-dose (up to 20 mg once daily) administration. Steady-state pharmacokinetics of lasofoxifene are consistent with expectations from its single-dose pharmacokinetics.

At steady state, the half-life of lasofoxifene in postmenopausal women is approximately 6 days, resulting in small fluctuations in concentrations over the 24-hour dosing interval.

Paediatric:

The pharmacokinetics of lasofoxifene have not been evaluated in a paediatric population.

Elderly:

No clinically meaningful differences in lasofoxifene pharmacokinetic were observed over the age range of 40 to 80 years of age based on the results of a population pharmacokinetic analysis. No dose adjustment for FABLYN is necessary in elderly patients.

Race:

In a population pharmacokinetic analysis, no discernible difference in lasofoxifene pharmacokinetics was detected in different racial groups. This analysis included 2,049 postmeno­pausal women consisting of 85.5% Caucasian, 8.6% Hispanic, 3.4% Asian, and 1.9% African American. The results of a phase 1 study in Japanese and Caucasian women was consistent with the population pharmacokinetic analysis and showed no discernible difference in lasofoxifene pharmacokinetics in these two populations.

Gender:

Since FABLYN is indicated for use only in postmenopausal women, no assessment of the effect of gender on lasofoxifene pharmacokinetics has been made.

Hepatically impaired patients:

Lasofoxifene was studied, as a single 0.25 mg dose, in healthy subjects and subjects with mild or moderate hepatic impairment. Plasma lasofoxifene exposure was approximately the same in healthy subjects as in subjects with mild hepatic impairment (Child-Pugh Class A) and was modestly increased (38%) in subjects with moderate hepatic impairment (Child-Pugh Class B) compared to healthy subjects. These differences are not considered to be clinically meaningful. No dose adjustment for FABLYN is necessary for patients with mild or moderate hepatic insufficiency. Subjects with severe hepatic impairment have not been studied (see section 4.4).

Renally impaired patients:

Since less than 2% of lasofoxifene is recovered in urine as unchanged active substance, a study in subjects with renal insufficiency was not conducted. In a population pharmacokinetic analysis, there

were no clinically meaningful differences in lasofoxifene women with estimated creatinine clearance as low as 32 ml/min and those with normal creatinine clearance. No dose adjustment for FABLYN is necessary for patients with mild or moderate renal insufficiency (see section 4.4).

5.3 Preclinical safety data

Lasofoxifene was not genotoxic in any of the battery of tests applied. In two-year carcinogenicity studies conducted in rats (>1 mg/kg/day; 7 times systemic exposure following a human dose of 0.5 mg/day based on plasma AUC) an increased incidence of renal tubular adenoma and carcinoma in males and granulosa cell tumours of the ovary in females was noted. In the corresponding 2-year study in mice (>2 mg/kg/day; less than systemic exposure following a human dose of 0.5 mg/day based on plasma AUC), there was an increased incidence of adrenal cortical adenoma and carcinoma, interstitial cell tumors of the testis, benign and malignant ovarian tumors and benign uterine glandular polyps. Although all of these tumours are believed to be the result of rodent-specific hormonal mechanisms, their relevance for humans is currently unknown. Based on 3– and 5-year human data in the clinical trials, the incidence of cancer during treatment with lasofoxifene was not higher than for placebo.

Increased incidence of imperforate anus, hypoplastic tail, edema and limb flexures noted in fetuses of pregnant rats dosed at 100 mg/kg (approximately 400 times the AUC in humans) were associated with increased embryo-fetal lethality and generalized failure to thrive. In fertility studies conducted in rats with lasofoxifene, slight effects on male reproductive performance occurred at >10 mg/kg/day (approximately 42 times the AUC in humans) as evidenced by decreases in copulation index, implantation sites, and fetuses sired. Reduced fertility, and an increase in pre- and post-implantation loss leading to reduced litter size and prolonged gestation were observed in females treated at >0.01 mg/kg/day (below the level of systemic exposure in humans). In a prenatal and postnatal study in rats, at >0.01 mg/kg/day lasofoxifene delayed and/or disrupted parturition, increased pup mortality at birth, altered the achievement of developmental milestones, and reduced growth. Overall, the reproductive and developmental effects observed in animals are consistent with the SERM class of compounds.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Tablet core:

Lactose anhydrous

Microcrystalline cellulose

Croscarmellose sodium

Silica, colloidal anhydrous

Magnesium stearate

Tablet coating:

Sunset yellow FCF aluminium lake (E110)

Hypromellose

Lactose monohydrate

Titanium dioxide (E171)

Triacetin

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

4 years

6.4 Special precautions for storage

This medicine does not require any special storage conditions.

6.5 Nature and contents of container bottles with polyethylene/aluminum foil lined polypropylene child-resistant closures.

Blister packs of 7, 28 or 30 tablets and bottles of 90 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7. MARKETING AUTHORISATION HOLDER

Dr. Friedrich Eberth Arzneimittel GmbH

Am Bahnhof 2

92289 Ursensollen

Germany

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/08/500/001

EU/1/08/500/002

EU/1/08/500/003

EU/1/08/500/004

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

24 February 2009