English
A B C D E F G H I J K L M N O P Q R S T U V W X Y Z

Fablyn (lasofoxifene tartrate) – Summary of product characteristics - G03

Updated on site: 06-Oct-2017

Medication nameFablyn
ATC CodeG03
Substancelasofoxifene tartrate
ManufacturerDr. Friedrich Eberth Arzneimittel GmbH

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.

4.

authorised

CLINICAL PARTICULARS

4.1

Therapeutic indications

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

FABLYN is indicated for the treatment of osteoporosis in p stmenopausal women at increased risk of

 

no

fracture. A significant reduction in the incidence f vertebrallongerand non-vertebral fractures but not hip

fractures has been demonstrated (see section 5.1).

product

 

When determining the choice of FABLYN or o her therapies, including estrogens, for a

postmenopausal woman, consideration sho ld 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 f administration

MedicinalAdult (postmenopausal women):

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.

Suppl m ntal calcium and/or vitamin D should be added to the diet if daily intake is inadequate. Postm nopausal 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 section 5.1).

4.3 Contraindications

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

Unexplained uterine bleeding.

authorised

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

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 lactati g women (see section 4.6).

4.4 Special warnings and precautions for use

longer

In clinical trials, FABLYN-treated women had annoi creased risk of venous thromboembolic events (deep

vein thrombosis and pulmonary embolism) compared to placebo. Other venous thromboembolic events could also occur. A less seriousproductevent, superfi ial hrombophlebitis, 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 thr mb embolic events independent of therapy, FABLYN should be discontinued at least 3 weeks p i to and during prolonged immobilization (e.g., post-surgical recovery, prolonged bed rest), and thera y should be resumed only after the patient is fully ambulatory. In addition,

section 5.1).

women taking FABLYN should be advised to move about periodically during prolonged travel. AnyMedicinalunexplained v gi l bleeding should be investigated as clinically indicated. FABLYN-treated and placebo-treated groups had similar incidences of endometrial hyperplasia and endometrial cancer (see

Lasofoxif ne has been associated with benign endometrial effects. These included, in some subjects, a small xc ss 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 hypertriglyceri emia (> 5.6 mmol/l), lasofoxifene may be associated with a marked increase in serum triglycerides. Pati nts with 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 wi caution in these

patients.

 

Safety and efficacy of FABLYN have not been evaluated in patients with severe renal insufficiency;

 

authorised

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 alactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

CYP isoforms are unlikely to produce lini ally meaningful alterations in FABLYN exposure and no dose adjustments are required.

4.5 Interaction with other medicinal products and ther forms of interaction

 

 

longer

Based on the absence of clinically relevant effects f ch lestyramine (anion exchange resin),

fluconazole (CYP2C9 inhibitor), ketoconazole (CYP3A4/5 inhibitor) and paroxetine (CYP2D6

 

no

 

inhibitor) on lasofoxifene pharmacokineti s, o her anion exchange resins and other inhibitors of these

product

 

 

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 steady-

state concentrations and may result in reduced efficacy.

KetoconazoleMedicinal- 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 child- bearing 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

authorised

 

FABLYN is only for use in postmenopausal women. FABLYN must not be taken during lactat on ( ee 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 machin s.

4.8 Undesirable effects

 

The safety of FABLYN in the treatment of osteoporosis was assessed in a large (8,556 patients)

 

no

double-blind, randomized, placebo-controlled multinatilongernal 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.

product

 

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, ulmonary embolism, and retinal vein thrombosis). Through 5 years of

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

follow-up, 37 FABLYN-treated women (1.3%, or 2.90 per 1,000 patients years) had a VTE compared toMedicinal18 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).

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

Infections and infestations

 

 

Uncommon:

Urinary tract infection, vaginal candidiasis, vaginal infection, vulvovaginit

Rare:

Arthritis infective, bronchitis, cellulitis, cervicitis, diverticulitis, fungal infect on,

 

furuncle, genital candidiasis, herpes simplex ophthalmic, impetigo, laby inthitis,

 

pyelonephritis, pyometra

 

 

Neoplasms

benign, malignant and unspecified (including cysts and polyps)

Uncommon:

Fibroma, uterine leiomyoma

 

 

Rare:

Benign breast neoplasm, breast fibroma, chronic lymphocytic leukaemia, endometrial

 

neoplasm, female reproductive neoplasm, haemangioma, hepaticauthorisedneoplasm malignant,

 

leiomyoma, melanocytic naevus, multiple myeloma, n oplasm, parathyroid tumour

 

benign

 

 

 

Blood and

lymphatic system disorders

 

 

Uncommon:

Anaemia, macrocytosis, thrombocytopenia

Rare:

Anaemia megaloblastic, hypochromasia

longer

Immune system disorders

 

 

Rare:

Seasonal allergy

no

 

Endocrine disorders

 

 

 

Rare:

Hyperparathyroidism

 

 

Metabolism

and nutrition disor ers

 

 

Uncommon:

Diabetes mellitus

 

 

Rare:

Anorexia, dec eased appetite, hypertriglyceridaemia, hypoalbuminaemia,

 

hypophosphataemia, increased appetite, tetany, type 2 diabetes mellitus

 

 

product

 

 

Psychiatric

disorders

 

 

 

Rare:

Ab orm l dreams, cyclothymic disorder

 

Medicinal

 

 

 

Nervous system d sorders

 

 

Uncommon:

Burning sensation, cerebral infarction, headache, restless legs syndrome

Rare:

Amnesia, dementia Alzheimer’s type, dizziness postural, dysgeusia, epilepsy,

 

hydrocephalus, hypogeusia, memory impairment, migraine, migraine with aura, motor

 

neurone disease, nerve compression, paresis, presyncope, sciatica, vascular headache

Eye disorders

Uncommon: Dry eye

Rare: Aphakia, chorioretinopathy, conjunctival haemorrhage, conjunctival hyperaemia, eye haemorrhage, eye pruritus, eyelid oedema, keratoconjunctivitis sicca, macular degeneration, ocular hyperaemia, pupils unequal, retinal detachment, retinal vascular disorder, retinopathy, visual acuity reduced, visual disturbance

Ear and labyrinth disorders

Rare: Ear discomfort, inner ear disorder, vertigo positional

Cardiac disorders

Uncommon: Palpitations, tachycardia

Rare: Cardiac failure, cardiomegaly, cor pulmonale, sinus arrest, supraventricular extrasystoles, tricuspid valve incompetence

Vascular disorders

Common: Hot flush

Uncommon: Deep vein thrombosis, flushing, phlebitis, thrombophlebitis, thrombophlebitis superficial, venous stasis

Rare:

Aortic aneurysm, arterial occlusive disease, capillary disorder, embolism, haematoma,

 

haemorrhage, intermittent claudication, lymphostasis, thrombosis, vascular stenosis,

 

venous thrombosis, venous thrombosis limb

 

Respiratory, thoracic and mediastinal disorders

 

Uncommon:

Cough, pulmonary embolism, rhinitis allergic

 

Rare:

Chronic obstructive pulmonary disease, pulmonary granuloma, vasomotor rhinitis

Gastrointestinal

disorders

 

 

Common:

Constipation

 

 

Uncommon:

Abdominal pain, abdominal pain lower, abdominal pain upper, dry m uth, flatulence,

 

gastritis, irritable bowel syndrome

 

 

Rare:

Abdominal tenderness, anal fissure, anal spasm, cheilitis, cheilosis, colitis ulcerative,

 

duodenal ulcer, duodenitis, dysphagia, gastric polyps, inguin l hernia, mouth ulceration,

 

oesophagitis, oral pain, rectal polyp, rectal ulcer, stomach discomfort

 

 

 

 

authorised

Hepatobiliary disorders

 

 

Uncommon:

Cholelithiasis, hepatic steatosis

 

 

Rare:

Bile duct stone, cholecystitis, hepatitis, jaundice, liver disorder

Skin and

subcutaneous tissue disorders

 

 

Common

Hyperhidrosis

 

 

 

longer

 

Uncommon:

Alopecia, erythema, night sweats, pruritus

 

Rare:

Angioedema, dry skin, hair texture ab ormal, nail disorder, onychoclasis,

 

photosensitivity reaction, pruri us generalized, rash maculo-papular, rash pruritic,

 

 

 

no

 

 

rosacea, skin irritation, skin lesion, skin hyperpigmentation, skin oedema, urticaria

Musculoskeletal, connective tissue and bone disorders

 

Very

Muscle spasms

 

 

common:

 

 

 

 

Uncommon:

Back pain, neck ain, pain in extremity

 

Rare:

Arthropathy, bursitis, clubbing, coccydynia, costochondritis, dactylitis, exostosis,

 

 

product

 

 

 

extremity contracture, haemarthrosis, joint stiffness, muscle contracture, muscle

 

twitchi g, musculoskeletal discomfort, pain in jaw, periarthritis, rheumatoid arthritis,

 

rotator cuff syndrome, tenosynovitis

 

Renal and ur nary disorders

 

 

Uncommon:

Micturition urgency, nocturia, pollakiuria, urethral disorder, urinary incontinence

Rar :

Calculus bladder, hypercalciuria, hypertonic bladder, nephrosclerosis, urethral

 

haemorrhage, urinary bladder polyp, urinary tract disorder

 

Reproductive

system and breast disorders

 

 

Medicinal

 

 

 

Common:

Cystocele, endometrial disorder, endometrial hypertrophy* (sonographic endometrial

 

thickness), uterine polyp, vaginal discharge, vaginal disorder

Uncommon: Breast disorder female, breast induration, breast pain, cervix disorder, cervical dysplasia, cervical polyp, colpocele, endometrial hyperplasia** (based on investigator reporting), genital discharge, genital haemorrhage, hydrometra, metrorrhagia, postmenopausal haemorrhage, rectocele, uterine cervical erosion, uterine prolapse, vaginal haemorrhage, vaginal prolapse, vulvovaginal pruritus

Rare: Adenomyosis, adnexa uteri cyst, adnexa uteri mass, breast discharge, breast engorgement, breast fibrosis, enlarged clitoris, fallopian tube cyst, nipple disorder, nipple

4.9 Overdose

pain, perineal laceration, pruritus genital, uterine cervical squamous metaplasia, uterine haemorrhage, uterine mass, vaginal erosion, vaginal inflammation, vaginal pain, vaginal wall congestion, varicose veins vulval, vulvar disorder

Congenital, familial and genetic disorders

Rare: Malformation venous

General disorders and administration site conditions

Common: Therapeutic response unexpected

Uncommon: Chest pain, fatigue, feeling hot, oedema peripheral

Rare: Chest discomfort, feeling drunk, hyperthermia, inflammation, mass, oedema, polyp

Investigations

Common:

Aspartate aminotransferase increased

 

 

Uncommon:

Alanine aminotransferase increased, blood glucose increased, smear cervix abnormal,

 

transaminases increased, weight increased

 

 

Rare:

5′ nucleotidase increased, blood albumin decreased, blood creatinine abno mal, blood

 

triglycerides increased, blood urine present, bone density decreased, chest X-ray

 

abnormal, electrocardiogram T wave abnormal, gamma-glutamyl ransferase increased,

 

hepatitis B surface antigen positive, high density lipoprotein decreased, low density

 

lipoprotein increased, pedal pulse decreased, platelet count decre sed, ultrasound breast

 

abnormal, ultrasound ovary abnormal

 

authorised

Injury and

poisoning

 

 

 

Rare:

Excoriation, genital injury, limb injury, skeletal injury, soft tissue injury, spinal fracture,

 

thoracic vertebral fracture, tooth fracture

longer

 

 

 

 

 

* Endometrial hypertrophy is a MedDRA dictionary term that represents sonographic endometrial

thickness findings.

 

 

 

** Endometrial hyperplasia events based on i

vestigator reporting rather than histopathology findings

and did not require histological confirmation.

no

 

 

 

product

 

 

 

 

 

 

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 recommendedMedicinaldose) for up to one year without dose-related serious adverse reactions.

There is no spe f c a tidote for FABLYN. In the event of overdose, general supportive measures should be n t ated based on the patient’s signs and symptoms.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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:

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

in a sub-study of the PEARL study.

authorised

markers of bone turnover (e.g., C-telopeptide and markers of bone formation: os eocalcin, procollagen

type 1 N-terminal propeptide, and bone-specific alkaline phosphatase). The s ppression of bone

turnover markers was evident by 3 months and persisted throughout the 36-month observation period

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

bone biomarkers in postmenopausal women with osteoplongerr sis were examined through 3 years in the PEARL study. The study population consisted of 8,556 postmenopausal women with osteoporosis as

The effects of FABLYN on fracture incidence (table 2) were examined through 5 years; and BMD and

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 his study had a median age of 67 years (range 59 to 80)

no

 

 

 

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 p stmenopausal women over 5 years

 

 

 

 

 

product

FABLYN

Placebo

Relative risk reduction (95%

 

 

CI) vs. placebo

New radiographic vertebr l fractures

n=2,748

n=2,744

41%a

Percentage of pat e ts with new fracture

5.6%

9.3%

(28%, 52%)

New radiograph vertebral fracture in patients with ≥

n=778

n=774

42%b

1 baseline fra ture

8.7%

14.2%

(21%, 57%)

Percentage of patients with new fracture

 

 

 

New radiographic vertebral fracture in patients

n=1,970

n=1,970

41%c

without any prevalent fracture at baseline

4.4%

7.4%

(23%, 55%)

Percentage of patients with new fracture

 

 

 

Medicinal

 

 

d

n=2,852

n=2,852

24%

Non-vertebral fractures

Percentage of patients with non-vertebral fracture

8.1%

10.4%

(9%, 36%)

All clinical fractures

n=2,852

n=2,852

25%e

Percentage of patients with clinical fracture

9.3%

12.1%

(12%, 36%)

Abbreviations: n= number of patients; CI = Confidence Intervals a p < 0.0001; b p = 0.0004; c p = 0.0002; d p = 0.0020; e p = 0.0004

-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).

(as determined by the Genant scale) compared to women treated with placeboauthorised(5.2% placebo-treated women versus 3.3% FABLYN-treated women; p = 0.0006).

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 ve teb al fractures

-Non-vertebral fractures

FABLYN significantly decreased the incidence of non-vertebral fractu es from 10.4% for placebo to

8.1% for FABLYN (relative risk reduction = 24%, p = 0.0020). This d crease 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 r BMD T-score-3) (p = 0.0183).

-All clinical fractures

longer

 

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

 

 

no

9.3% for FABLYN (relative risk reduction = 25%, p = 0.0004). This decrease was observed through

the first year and maintained through 5 years.

 

-Bone mineral density

product

 

 

 

In a 3-year substudy of the PEARL study (n=760), FABLYN significantly increased BMD (compared

Significant increases in BMD were observed as early as 3 months for lumbar spine and total hip.

to placebo) at lumbar spine (3.3%), total hip (3.0%), femoral neck (3.3%), greater trochanter (3.6%), intertrochantericMedicinalarea (2.6%), Ward’s triangle (5.9%) and forearm (1.8%) at 3 years. FABLYN also significantly incre sed whole body bone mineral content (BMC), compared to placebo, at 3 years.

An analys s was conducted of the subjects who were referred to their physician for consideration of treatm nt with an alternative osteoporosis medicinal product if one of the following was observed: a) ≥7% BMD loss at LS or ≥10% BMD loss at femoral neck at Month 12; b) ≥11% BMD loss at lumbar spine (LS) or ≥14% BMD loss at femoral neck at Month 24; c) ≥2 on-study radiographic vertebral fractures by Month 24. These referrals were significantly less frequent in the FABLYN group (0.9%) than in the placebo group (3.3%).

Results from one-year trial in Asian subjects

The effects of FABLYN on BMD in postmenopausal Japanese, Korean and Taiwanese women with osteoporosis were also examined in a one-year, randomized, placebo-controlled, double-blind osteoporosis treatment trial. The study population consisted of 497 women with osteoporosis as defined by low vertebral BMD (T-score ≤ 2.5). Women in this study had a median age of 63 years (range 44 to 79) and a median time since menopause of 13 years. All women in the study received calcium (600-1200 mg/day) and Vitamin D (400-800 IU/day).

In this study, FABLYN significantly increased spine and hip (total hip and all subcomponents of the hip) BMD by 2 to 4%. It also reduced markers of bone turnover.

Bone histomorphometry

Bone formed during two years’ administration of lasofoxifene is of normal quality. To assess bone quality, bone biopsies were obtained from 71 postmenopausal women enrolled in BMD trials after 2 years of treatment. There was no evidence of osteomalacia, marrow fibrosis, cellular toxicity, woven bone or other abnormalities affecting the quality of the bone following lasofoxifene treatment.

ultrasound and histological benign cystic atrophy (a variant of atrophic endometrium),authorisedcontributing to approximately 1.5 mm increase in mean endometrial thickness. In clinical practice, these benign

Effects on the endometrium:

The following results of the effects of FABLYN on the endometrium through 5 years of expo ure are reported from the PEARL study.

There was no difference between FABLYN- and placebo-treated women in the incidences of endometrial carcinoma and endometrial hyperplasia.

Lasofoxifene may be associated with benign endometrial effects: endometri l cystic change viewed on

The incidence of endometrial cystic change and endometriallongerthickness was analyzed in a subset of the study population (298 patients) with an annual transvaginal ultrasound (TVU) through 3 years. Placebo-treated women had a 1.9% incidence in cystic change over 3 years, whereas the FABLYN-

findings do not warrant further evaluation in women with no vaginal bl eding, in accordance with guidelines for postmenopausal women (see section 4.4).

treated women had a 20.4% incidence. All histolnogy findings were benign. Placebo-treated women had a 0.7 mm mean decrease from baseline in e dometrial thickness over 3 years, whereas the FABLYN-treated women had a 1.4 mm mean increase. The increase was observed at 12 months, and

did not significantly increase through 3 years. In some cases, these findings were observed to resolve spontaneously on treatment.

In all women with a uterus at baseline, histologically benign endometrial polyps were reported in 34 of 2,302 (1.5%) FABLYN-treated women versus 18 of 2,309 (0.8%) placebo-treated women. In a subset

of the study population designed to look at endometrial histology (1,080 patients) with a TVU at 3

 

product

years, histologically benign endometrial polyps were reported in 20 of 366 (5.5%) FABLYN-treated

women and 12 of 360 (3.3%) placebo-treated women.

The overall n

dence of vaginal bleeding was low (≤ 2.6% in all treatment groups). Vaginal bleeding

was reported

n 74 (2.6%) FABLYN-treated women versus 37 (1.3%) placebo-treated women. The

numbMedicinalr of subjects discontinuing treatment as a result of vaginal bleeding was low [FABLYN: 4 (0.1%), placebo: 0].

The number of hysterectomies in the FABLYN-treated group (27/2,302 patients, 1.2%) and the placebo-treated group (24/2,309 patients, 1.0%) were similar. To assess the effect of FABLYN on diagnostic uterine procedures (i.e., hysteroscopy, saline infused sonohysterogram, endometrial biopsy, polypectomy or dilation and curettage), an analysis was conducted on women without planned TVU surveillance (4,055 patients). More FABLYN-treated patients (7.0%) had a diagnostic procedure compared to placebo-treated patients (2.7%). Diagnostic uterine procedures were performed in a greater number of FABLYN-treated patients as a result of vaginal bleeding (as mandated by the protocol) and asymptomatic endometrial findings (e.g., suspected uterine polyps, endometrial thickness).

Effects on breast:

Effects on lipid metabolism and cardiovascular risk:

Over the 5 years of the PEARL study (involving 8,556 patients), FABLYN treatment compared to placebo reduced the risk of invasive breast cancer by 85% (placebo: 20 (0.7%), FABLYN: 3 (0.1%); HR 0.15 (CI 0.04, 0.50)), the risk of all breast cancer by 79% (placebo: 24 (0.9%), FABLYN: 5 (0.2%); HR 0.21 (CI 0.08, 0.55)), the risk of estrogen receptor (ER) positive invasive breast cancer by 83% (placebo: 18 (0.7%), FABLYN: 3 (0.1%); HR 0.17 (CI 0.05, 0.57)) and the risk of estrogen receptor (ER) positive breast cancer by 81% (placebo: 21 (0.8%), FABLYN: 4 (0.1%); HR 0.19 (CI 0.07, 0.56)). FABLYN has no effect on the risk of ER negative breast cancer or ER negative invasive breast cancers. These observations support the conclusion that lasofoxifene has no intrinsic estrogen agonist activity in breast tissue.

decreased total cholesterol, LDL cholesterol, LDL-associated apolipoprotein B-100, and high

The effect of FABLYN on the lipid profile was evaluated in a 3-year substudyauthorisedof the PEARL tudy; the substudy enrolled 1,014 postmenopausal women. Relative to placebo, FABLYN sign f cantly

sensitivity C-reactive protein (median changes -10.4%, -15.8%, -11.8%, -12.5%, respectively); no

significant changes versus placebo were seen for HDL cholesterol or VLDL choles erol. Statistically

significant increases were seen for apolipoprotein A-1, which is associated wi h HDL cholesterol, and serum triglycerides (median changes vs. placebo 6.1% and 4.9%, respectively).

placebo-treated patients (HR 0.68; 95% CI 0.50, 0.93, p=longer0.016). In the same study at 5 years, there was no increase in the risk of stroke including hemorrhagic, ischemic, embolic stroke, stroke type

At 5 years in the overall study population (N=8,556), the incidence of major coronary events,

including coronary death, non-fatal myocardial infarction, new isch mic heart disease, hospitalization for unstable angina, and revascularisation procedures, was si nificantly lower. There were 0.51

events/100 patient-years for FABLYN-treated patients compared to 0.75 events/100 patient-years in

unspecified and transient ischemic attacks in FABLYNno -treated patients. There were 0.48 events/100

patient years in the placebo group and 0.36 eve ts/100 patient years among FABLYN-treated patients

(HR = 0.75; 95% CI 0.51, 1.10, p = 0.140). Effects on vulvar and vaginalproductatrophy (VVA):

The efficacy of FABLYN in the treatment of VVA was investigated in two 12-week Phase 3 studies in postmenopausal women with m derate or severe signs and symptoms of VVA, regardless of

osteoporosis status (involving 889 patients). In both studies, it decreased the severity of the subject’s Medicinalmost bothersome base ine VVA symptom, decreased vaginal pH, decreased the percentage of vaginal parabasal cells from the maturation index (MI) and increased the percentage of vaginal superficial

cells from the MI. Simil r results for vaginal pH and MI were observed in the PEARL study.

5.2 Pharma okinetic properties

The disposition of lasofoxifene was evaluated in 758 subjects in conventional clinical pharmacology studi s. 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:

Linearity/non-linearity:

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 α1-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

intermediates by methylation and glucuronidation); oxidation at the pyrrolidine ring; and ph nyl hydroxylation. Three metabolites of lasofoxifene were detected in plasma: the direct glucu onide conjugate, the glucuronide of a hydroxylated metabolite, and the methylated catech l.

administration of 14C-labeled lasofoxifene. Lasofoxifene is extensively metabolized in humans. Five metabolic pathways of lasofoxifene have been identified: direct glucuronidation;authoriseddirect sulfation; hydroxylation at the phenyl tetraline moiety (with subsequent conjugative metabolism of the cat chol

The binding affinities of the major circulating metabolites of lasofoxifene were at least 31-fold and 18- fold less than those of lasofoxifene for the estrogen receptor alpha and the es rogen 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 mechanismslongerof elimination of lasofoxifene from the systemic circulation. The apparent oral clearance (CL/F) of lasofoxif ne in postmenopausal women is approximately 6.6 l/hr.

Elimination:

excreted in feces, with a minor component of urinarynoexcretion of active substance-related material.

Lasofoxifene has a half-life of approximately 6 days. Lasofoxifene and its metabolites are primarily

Following oral administration of 14C-labeled lasofoxifene in solution to humans, approximately 72% of the radioactive dose wasproductrecovered by day 24 (approximately 66% in feces and 6% in urine). Less than 2% of the administered dose was re overed in the urine as unchanged lasofoxifene.

Lasofoxifene exhibits linear ha macokinetics 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 lasofoxifeneMedicinalare consistent with expectations from its single-dose pharmacokinetics.

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

Pa diatric:

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

Renally impaired patients:

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:

moderate hepatic impairment. Plasma lasofoxifene exposure was approximately the same in h althy subjects as in subjects with mild hepatic impairment (Child-Pugh Class A) and was mode tly

Lasofoxifene was studied, as a single 0.25 mg dose, in healthy subjects andauthorisedsubjects with mild or

increased (38%) in subjects with moderate hepatic impairment (Child-Pugh Class B) c mpa ed to healthy subjects. These differences are not considered to be clinically meaningful. No d se 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).

Since less than 2% of lasofoxifene is recovered in urine as unchang d 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 pharmacokinetics between postmenopausal women with estimated creatinine clearance as low as 32 m /min and those with normal creatinine

clearance. No dose adjustment for FABLYN is necessary f r patients with mild or moderate renal

insufficiency (see section 4.4).

no

longer

 

5.3 Preclinical safety data

 

 

product

 

 

Lasofoxifene was not genotoxic in any of the battery of tests applied. In two-year carcinogenicity studies conducted in rats (≥1 mg/kg/ ay; 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 tum u s f 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

their relevance for humans is currently unknown. Based on 3- and 5-year human data in the clinical trials, the n den e of cancer during treatment with lasofoxifene was not higher than for placebo.

plasma AUC), there was an increased incidence of adrenal cortical adenoma and carcinoma, interstitial cellMedicinaltumors 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,

Lasofoxif ne was not teratogenic in rats up to a dose of 10mg/kg (approximately 53 times the AUC in humans) or rabbits up to a dose of 3 mg/kg (below the level of systemic exposure in humans). 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 PARTICULARS

6.1 List of excipients

Tablet core:

 

 

 

 

 

Lactose anhydrous

 

 

 

 

 

Microcrystalline cellulose

 

 

 

authorised

Hypromellose

 

 

 

 

Croscarmellose sodium

 

 

 

 

Silica, colloidal anhydrous

 

 

 

 

Magnesium stearate

 

 

 

 

 

Tablet coating:

 

 

 

 

 

Sunset yellow FCF aluminium lake (E110)

 

longer

 

Triacetin

 

 

 

 

Lactose monohydrate

 

 

 

 

Titanium dioxide (E171)

 

no

 

 

6.2

Incompatibilities

 

 

 

 

 

 

 

Not applicable.

 

 

 

 

 

6.3

Shelf life

 

product

 

 

 

4 years

 

 

 

 

 

 

 

 

 

Medicinal

 

 

 

 

6.4

Special prec

utions for storage

 

 

 

This medicine does

ot require any special storage conditions.

 

6.5 Nature and contents of container

 

 

 

FABLYN film-coated tablets are supplied in PVC blisters with aluminum foil backing or HDPE 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.

6.6Special 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

 

 

authorised

10. DATE OF REVISION OF THE TEXT

 

 

Detailed information on this medicinal product is availablelongeron the website of the European Medicines

Agency (EMEA) http://www.emea.europa.eu/.

 

product

no

Medicinal

 

EU/1/08/500/004

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

24 February 2009

Comments

A B C D E F G H I J K L M N O P Q R S T U V W X Y Z
  • Help
  • Get it on Google Play
  • About
  • Info on site by:

  • Presented by RXed.eu

  • 27558

    prescription drugs listed