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Drug Details

Fablyn

• Presentation
  Film-coated tablet. Triangular, peach-coloured, film-coated tablets debossed with “Pfizer” on one side and “OPR 05” on the other side.
• Description
  Each film-coated tablet contains lasofoxifene tartrate, equivalent to 500 micrograms lasofoxifene. Excipient: Each film-coated tablet contains 71.34 mg lactose.
• 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.

  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.

• Adult Dosage
  

  Adult (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.

  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.

• Child Dosage
  

  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.

• Elderly Dosage
  

  Elderly women (65 years and older)

  No dose adjustment is necessary in elderly female patients.

  Hepatic insufficiency:
  No dose adjustment is required in patients with mild to moderate hepatic insufficiency. 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. 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.

• Contra Indications
  

  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.

• Special Precautions
  

  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.

  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.

  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.

  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.

  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 hypertriglyceridemia (> 5.6 mmol/l), lasofoxifene may be associated with a marked increase in serum triglycerides. Patients 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. 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.

  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.

• Interactions
  

   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 steady-state 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.

• Adverse Drug Reactions
  

  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.

  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.

  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, vulvovaginitis
  Rare: Arthritis infective, bronchitis, cellulitis, cervicitis, diverticulitis, fungal infection, furuncle, genital candidiasis, herpes simplex ophthalmic, impetigo, labyrinthitis, 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, hepatic neoplasm malignant, leiomyoma, melanocytic naevus, multiple myeloma, neoplasm, parathyroid tumour benign

  Blood and lymphatic system disorders
  Uncommon: Anaemia, macrocytosis, thrombocytopenia
  Rare: Anaemia megaloblastic, hypochromasia

  Immune system disorders
  Rare: Seasonal allergy

  Endocrine disorders
  Rare: Hyperparathyroidism
  
  Metabolism and nutrition disorders
  Uncommon: Diabetes mellitus
  Rare: Anorexia, decreased appetite, hypertriglyceridaemia, hypoalbuminaemia, hypophosphataemia, increased appetite, tetany, type 2 diabetes mellitus

  Psychiatric disorders
  Rare: Abnormal dreams, cyclothymic disorder

  Nervous system disorders
  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 mouth, flatulence, gastritis, irritable bowel syndrome
  Rare: Abdominal tenderness, anal fissure, anal spasm, cheilitis, cheilosis, colitis ulcerative, duodenal ulcer, duodenitis, dysphagia, gastric polyps, inguinal hernia, mouth ulceration, oesophagitis, oral pain, rectal polyp, rectal ulcer, stomach discomfort

  Hepatobiliary disorders
  Uncommon: Cholelithiasis, hepatic steatosis
  Rare: Bile duct stone, cholecystitis, hepatitis, jaundice, liver disorder

  Skin and subcutaneous tissue disorders
  Common: Hyperhidrosis
  Uncommon: Alopecia, erythema, night sweats, pruritus
  Rare: Angioedema, dry skin, hair texture abnormal, nail disorder, onychoclasis, photosensitivity reaction, pruritus generalized, rash maculo-papular, rash pruritic, rosacea, skin irritation, skin lesion, skin hyperpigmentation, skin oedema, urticaria

  Musculoskeletal, connective tissue and bone disorders
  Very common: Muscle spasms
  Uncommon: Back pain, neck pain, pain in extremity
  Rare: Arthropathy, bursitis, clubbing, coccydynia, costochondritis, dactylitis, exostosis, extremity contracture, haemarthrosis, joint stiffness, muscle contracture, muscle twitching, musculoskeletal discomfort, pain in jaw, periarthritis, rheumatoid arthritis, rotator cuff syndrome, tenosynovitis

  Renal and urinary disorders
  Uncommon: Micturition urgency, nocturia, pollakiuria, urethral disorder, urinary incontinence
  Rare: Calculus bladder, hypercalciuria, hypertonic bladder, nephrosclerosis, urethral haemorrhage, urinary bladder polyp, urinary tract disorder

  Reproductive system and breast disorders
  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 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 abnormal, blood triglycerides increased, blood urine present, bone density decreased, chest X-ray abnormal, electrocardiogram T wave abnormal, gamma-glutamyltransferase increased, hepatitis B surface antigen positive, high density lipoprotein decreased, low density lipoprotein increased, pedal pulse decreased, platelet count decreased, ultrasound breast abnormal, ultrasound ovary abnormal

  Injury and poisoning
  Rare: Excoriation, genital injury, limb injury, skeletal injury, soft tissue injury, spinal fracture, thoracic vertebral fracture, tooth fracture

  * 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.