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Raloxifene hydrochloride tablet 60 mg
(equivalent to 56 mg raloxifene).
Presentation
Evista tablets are white, elliptically-shaped, film-coated tablets intended for oral administration. Each tablet contains 60 mg raloxifene hydrochloride which is equivalent to 56 mg raloxifene. Evista tablets are imprinted with the identicode "4165".
Uses
Actions
Pharmacotherapeutic group: Raloxifene, a non-steroidal benzothiophene derivative, is a selective oestrogen receptor modulator (SERM).
Long-term Postmenopausal Health and the Role of Oestrogen
Oestrogen plays a number of critical roles in a woman's body, exerting positive effects in a wide variety of tissues. Of particular importance is the effect of oestrogen on the structure and integrity of bone, its protective effect against cardiovascular disease and its possible role in the central nervous system. Managing postmenopausal changes that are associated with decreased oestrogen is a challenge. Other conditions not related to decreased oestrogen levels, such as cancers of the breast and uterus, also increase postmenopause. The management of health issues in postmenopausal women can significantly impact their long-term health, strength and longevity.
Mechanism of Action
As a selective oestrogen receptor modulator (SERM) Evista therefore demonstrates selective agonist or antagonist activities on oestrogen receptive tissues. It acts as an agonist on bone and partially on cholesterol metabolism (decrease in total and LDL-cholesterol), but not in the hypothalamus or in the uterine or breast tissues.
Raloxifene reduces resorption of bone and decreases overall bone turnover due to oestrogen deficiency. These effects on bone are manifested as reductions in the serum and urine levels of bone turnover markers, evidence from radiocalcium kinetics studies for decreased bone resorption and increases in bone mineral density (BMD). The biological actions of raloxifene, like those of oestrogen, are mediated through high affinity binding to oestrogen receptors and regulation of gene expression. This binding results in differential expression of multiple oestrogen-regulated genes in different tissues. Recent data suggest that the oestrogen receptor can regulate gene expression by at least two distinct pathways which are ligand-, tissue-, and/or gene-specific.
Pharmacodynamic Effects
Effects on Bone
The decrease in oestrogen availability which occurs at menopause, leads to a marked increase in bone resorption, bone loss and risk of fracture. Bone loss is particularly rapid for the first 10 years after menopause when the compensatory increase in bone formation is inadequate to keep up with the resorptive losses. Other risk factors which may lead to the development of osteoporosis include early menopause; osteopenia (at least 1 SD below peak bone mass); thin body build; Caucasian or Asian ethnic origin; and a family history of osteoporosis. Replacement therapies generally reverse the excessive resorption of bone. In postmenopausal women, Evista reduces the incidence of fractures, preserves bone mass and increases BMD.
Clinical Trial Data
i. Incidence of fractures: In a study of 7,705 postmenopausal women with a mean age of 66 years and with osteoporosis or osteoporosis with an existing fracture, Evista treatment for three years reduced the incidence of vertebral fractures by 55% (RR 0.45, CI 0.29, 0.71, p<0.001) absolute risk reduction of 2.4% and 30% (RR 0.70, CI 0.56, 0.86; p<0.001) absolute risk reduction of 6.1% respectively. Although not statistically significant, the incidence of extravertebral fractures decreased with increasing exposure to Evista compared to placebo.
ii. Bone Mineral Density (BMD): The efficacy of Evista once daily in postmenopausal women aged up to 60 years and with or without a uterus was established over a two-year treatment period. The women were 2 to 8 years postmenopausal. Three trials included 1,764 postmenopausal women who were treated with Evista or placebo. In one of these trials the women had previously undergone hysterectomy. Evista produced significant increases in bone density of hip and spine as well as total body mineral mass compared to placebo. This increase was generally a 2% increase in BMD compared to placebo. A similar increase in BMD was seen in the treatment population. In the prevention trials, the percentage of subjects experiencing an increase or decrease in BMD during raloxifene therapy was: for the spine 37% decreased and 63% increased; and for the total hip 29% decreased and 71% increased.
iii. Calcium kinetics: Evista and oestrogen affect bone remodelling and calcium metabolism similarly. Evista was associated with reduced bone resorption and a mean positive shift in calcium balance of 60 mg per day, due primarily to decreased urinary calcium losses.
iv. Histomorphometry (bone quality): In a study comparing Evista with oestrogen, bone from patients treated with either medicine was histologically normal, with no evidence of mineralisation defects, woven bone or marrow fibrosis. Raloxifene decreases resorption of bone and returns bone turnover to the premenopausal range. These effects on bone are manifested as reductions in the serum and urine levels of bone turnover markers, decreases in bone resorption based on radiocalcium kinetics studies, increases in BMD and decreases in the incidence of fractures.
Effects on Lipid Metabolism and Cardiovascular Risk
Clinical trials showed that a 60 mg daily dose of Evista significantly decreased total cholesterol (3-6%), and LDL cholesterol (4-10%). Women with the highest baseline cholesterol levels had the greatest decreases. HDL cholesterol and triglyceride concentrations did not change significantly. After three years therapy Evista decreased fibrinogen (6.71%). In the osteoporosis treatment study, significantly fewer Evista treated patients required initiation of hypolipidaemic therapy compared to placebo.
The relative risk of venous thromboembolic events observed during raloxifene treatment was 2.34 (CI 1.26, 4.26) [absolute risk increase is 0.53%] when compared to placebo, and the relative risk was 1.0 (CI 0.3, 6.2) when compared to oestrogen or hormonal replacement therapy. The risk of a thromboembolic event was greatest in the first four months of therapy.
Effects on the Endometrium
In clinical trials, Evista did not stimulate the postmenopausal uterine endometrium. Compared to placebo, raloxifene was not associated with spotting or bleeding or endometrial hyperplasia. Nearly 3,000 transvaginal ultrasound (TVUs) examinations were evaluated from 831 women in all dose groups. Raloxifene treated women consistently had an endometrial thickness which was indistinguishable from placebo. After 3 years of treatment a = 5 mm increase in endometrial thickness, assessed with transvaginal ultrasound, was observed in 1.9% of the 211 women treated with raloxifene 60 mg/day compared to 1.8% of the 219 women who received placebo. There were no differences between the raloxifene and placebo groups with respect to the incidence of reported uterine bleeding.
Endometrial biopsies taken after six months therapy with Evista 60 mg daily demonstrated non-proliferative endometrium in all patients. In addition, in a study with 2.5 times the recommended daily dose of Evista there was no evidence of endometrial proliferation and no increase in uterine volume.
In the osteoporosis treatment trial, endometrial thickness was evaluated annually in a subset of the study population (1781 patients) for three years. Endometrial thickness measurements in Evista treated women were not different from baseline after 3 years of therapy. There was no difference between Evista and placebo treated women in the incidences of vaginal bleeding (spotting) or vaginal discharge. Fewer Evista treated women than placebo treated women required surgical intervention for uterine prolapse.
After 3 years, raloxifene did not increase the risk of endometrial or ovarian cancer.
Effects on Breast Tissue
Evista does not stimulate breast tissue. Across all placebo-controlled trials, Evista was indistinguishable from placebo with regard to frequency and severity of breast symptoms (no swelling, tenderness and breast pain).
In clinical trials with Evista involving over 12,000 patients, most of whom have been exposed to at least 42 months therapy, the relative risk of newly diagnosed breast cancer was significantly lower, 64% reduction (relative risk 0.36, CI 0.20, 0.65) [absolute risk reduction 0.56%] in Evista treated than in placebo treated postmenopausal women in a combined analysis of several studies. Overall the risk of an invasive oestrogen receptor (ER) positive breast cancer was reduced by 80% (relative risk 0.20, CI 0.09, 0.41) ) [absolute risk reduction 0.49%]. Evista has no effect on the risk of ER negative breast cancers. These observations support the conclusion that raloxifene has no intrinsic oestrogen agonist activity in breast tissue.
Effects on Cognitive Function
No adverse effects on cognitive function have been seen.
Pharmacokinetics
Pharmacokinetic Properties
Absorption
Raloxifene is absorbed rapidly after oral administration. Approximately 60% of an oral dose is absorbed. Presystemic glucuronidation is extensive. Absolute bioavailability of raloxifene is 2%. Bioavailability and the time to reach average maximum plasma concentration are functions of systemic interconversion and enterohepatic cycling of raloxifene and its glucuronide metabolites.
Distribution
Raloxifene is distributed extensively in the body. The volume of distribution is not dose dependent. Raloxifene and the monoglucuronide conjugates are highly bound to plasma proteins, including both albumin and alpha-1-acid-glycoprotein.
Metabolism
Raloxifene undergoes extensive first pass metabolism to the glucuronide conjugates: raloxifene-4´-glucuronide, raloxifene-6-glucuronide and raloxifene-4´,6-diglucuronide. No other metabolites have been detected. Raloxifene comprises less than 1% of the combined concentrations of raloxifene and the glucuronide metabolites. Raloxifene levels are maintained by enterohepatic recycling, giving a plasma half-life of 27.7 hours. Results from single oral doses of raloxifene predict multiple dose pharmacokinetics. Increasing doses of raloxifene result in slightly less than a proportional increase in the area under the plasma time concentration curve (AUC).
Excretion
The majority of a dose of raloxifene and its glucuronide metabolites are excreted within 5 days, primarily in the faeces, with less than 6% excreted in the urine.
Special Populations
Renal Insufficiency - Less than 6% of the total dose is eliminated in urine. In a population pharmacokinetic study, a 47% decrease in lean body mass adjusted creatinine clearance resulted in a 17% decrease in raloxifene clearance and a 15% decrease in the clearance of raloxifene conjugates.
Hepatic Insufficiency - The pharmacokinetics of a single dose of raloxifene in patients with cirrhosis and mild hepatic impairment (Child-Pugh class A) have been compared to that in healthy individuals. Plasma raloxifene concentrations were approximately 2.5-fold higher than in controls and correlated with bilirubin concentrations.
Indications
Evista is indicated for the treatment and prevention of osteoporosis in postmenopausal women, including those at risk of developing breast cancer, cardiovascular disease or uterine hyperplasia.
Dosage and Administration
The recommended dosage is one tablet daily by oral administration, which may be taken at any time of the day without regard to meals. No dose adjustment is necessary for the elderly. Due to the nature of this disease process, Evista is intended for long term use. Evista is to be administered in conjunction with supplementary calcium. Generally, calcium and vitamin D supplements are advised in women with a low dietary intake.
Contraindications
Evista must not be used in women of child bearing potential, as it may be associated with an increased risk of congenital defects.
Active or past history of venous thromboembolic events (VTE), including deep vein thrombosis, pulmonary embolism and retinal vein thrombosis.
Hypersensitivity to raloxifene or other ingredients in the tablet.
Hepatic impairment including cholestasis.
Unexplained uterine bleeding.
Evista should not be used in patients with signs and symptoms of endometrial or breast cancer as safety in these patient groups has not been adequately studied.
Warnings and Precautions
Raloxifene is associated with an increased risk for venous thromboembolic events that is similar to the reported risk associated with use of hormone replacement therapy. The risk-benefit balance should be considered in patients at risk of venous thromboembolic events of any aetiology. Evista should be discontinued in the event of an illness or a condition leading to a prolonged period of immobilisation. Discontinuation should happen as soon as possible in the case of illness, or from three days before the immobilisation occurs. Therapy should not be restarted until the initiating condition has resolved and the patient is fully mobile.
Raloxifene does not cause endometrial proliferation. Any uterine bleeding during Evista therapy is unexpected and should be fully investigated.
Raloxifene is metabolised primarily in the liver. Single doses of raloxifene given to patients with cirrhosis and mild hepatic impairment (Child-Pugh class A) produced plasma concentrations of raloxifene which were approximately 2.5 times the controls. The increase correlated with total bilirubin concentrations. Until safety and efficacy have been evaluated further in patients with impaired liver function, the use of Evista is not recommended in this patient population. Serum total bilirubin, gamma-glutamyl transferase, alkaline phosphatase, ALT and AST should be closely monitored during treatment if elevated values are observed.
As there is no experience with co-administration of systemic oestrogens (with or without progestogen), such use is not recommended.
In patients with a history of oral oestrogen-induced hypertriglyceridaemia (>5.6mmol/L), raloxifene may be associated with a marked increase in serum triglycerides. Patients with this medical history should have serum triglycerides monitored when taking raloxifene.
There is no indication for premenopausal use of raloxifene (see Contraindications).
There is no indication for use of raloxifene in males.
Carcinogenicity, Mutagenicity, Impairment of Fertility
In a 2-year carcinogenicity study in rats, an increase in ovarian tumors of granulosa/theca cell origin was observed in high-dose females (279 mg/kg/day). Systemic exposure (AUC) of raloxifene in this group was approximately 400 times that in postmenopausal women administered a 60 mg dose. In a 21-month carcinogenicity study in mice, there was an increased incidence of testicular interstitial cell tumours and prostatic adenomas and adenocarcinomas in males given 41 or 210 mg/kg, and prostatic leiomyoblastoma in males given 210 mg/kg. In female mice, an increased incidence of ovarian tumours in animals given 9 to 242 mg/kg (0.3 to 32 times the AUC in humans) included benign and malignant tumours of granulosa/theca cell origin and benign tumours of epithelial cell origin. The female rodents in these studies were treated during their reproductive lives, when their ovaries were functional and highly responsive to hormonal stimulation. In contrast to the highly responsive ovaries in this rodent model, the human ovary after menopause is relatively unresponsive to reproductive hormonal stimulation.
Raloxifene was not genotoxic in any of the conventional in vivo or in vitro routine test systems.
The reproductive and developmental effects observed in animals are consistent with the known pharmacological profile of raloxifene. No pregnancies occurred when raloxifene (greater than or equal to 5 mg/kg) was administered to male and female rats prior to and during mating. At doses of 0.1 to 10 mg/kg/day, raloxifene disrupted oestrous cycles of female rats during treatment, but did not delay fertile matings after treatment termination and only marginally reduced litter size, increased gestation length, and altered the timing of events in neonatal development. When given during the preimplantation period, raloxifene delayed and disrupted embryo implantation resulting in prolonged gestation and reduced litter size but development of offspring to weaning was not affected. Teratology studies were conducted in rabbits and rats. In rabbits, abortion and a low rate of ventricular septal defects (= 0.1 mg/kg) and hydrocephaly (= 10 mg/kg) were seen. In rats retardation of foetal development, wavy ribs and kidney cavitation occurred (= 1 mg/kg).
Raloxifene is a potent antioestrogen in the rat uterus and prevented growth of oestrogen-dependent mammary tumours in rats and mice.
Use in Pregnancy and Lactation
Pregnancy Category X. Evista is only for use in postmenopausal women. Evista must not be taken by women of child bearing potential. Raloxifene may cause foetal harm when administered to a pregnant woman. If this medicine is used mistakenly during pregnancy or the patient becomes pregnant while taking this medicine, the patient should be informed of the potential hazard to the foetus. (see Carcinogenicity, Mutagenicity & Impairment of Fertility).
Lactation
It is not known whether raloxifene is excreted in human milk. Its clinical use, therefore, cannot be recommended in lactating women. Evista may affect the development of the baby.
Effects on Ability to Drive and use Machinery
Raloxifene has no known effect on driving or the ability to use machinery.
Adverse Effects
Clinical Trial Data
In studies involving over 12,000 women all undesirable events were recorded, irrespective of causality. The duration of treatment in these studies ranged from 2 to 36 months. The majority of undesirable events has not usually required cessation of therapy.
The treatment-emergent events associated with the use of raloxifene that occurred with a significant difference (p<0.05) between raloxifene and placebo treatment are described below. Across all placebo-controlled clinical trials venous thromboembolic events, including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis occurred in a frequency of 3.25 cases per 1000 patient years. A relative risk of 2.34 (CI 1.26,4.26) [absolute risk increase is 0.53%] was observed in Evista-treated patients compared to placebo.
The frequency of superficial vein thrombophlebitis was 0.2% (reported in one raloxifene-treated patient) in the prevention trial and 1.3% in the treatment population.
Compared with placebo-treated patients the occurrence of vasodilatation (hot flushes) was modestly increased in Evista patients (clinical trials for the prevention of osteoporosis, 2 to 8 years postmenopausal, 24.3% Evista and 18.2% placebo; clinical trials for the treatment of osteoporosis, mean age 66, 9.7% Evista and 6.4% placebo). These events were most common in the first 6 months of treatment, and seldom occurred de novo after that time.
Another adverse reaction observed was leg cramps (5.5% Evista, 1.9% placebo in the prevention population and 7.0% Evista, 3.7% placebo in the treatment population).
One further change was seen which was not statistically significant (p>0.05), but which did show a significant dose trend. This was of peripheral oedema which occurred in the prevention population at an incidence of 3.1% Evista and 1.9% placebo ; and in the treatment population occurred at an incidence of 5.2% for Evista and 4.4% for placebo.
Slightly decreased (6-10%) platelet counts have been reported during raloxifene treatment.
In the prevention population discontinuations of therapy due to any clinical adverse experience occurred in 10.7% of 581 Evista-treated patients and 11.1% of 584 placebo-treated patients. In the treatment population discontinuations of therapy due to any clinical adverse experience occurred in 10.9% of 2557 Evista-treated patients and 8.8% of 2567 placebo-treated patients.
Evista (n=317) was compared with continuous combined (n=110) hormone replacement therapy (HRT) or cyclic (n=205) HRT patients in some clinical trials. The incidence of breast symptoms and uterine bleeding in raloxifene-treated women was significantly lower than in women treated with either form of HRT.
Rare cases of moderate increases in AST and/or ALT have been reported where a causal relationship to raloxifene can not be excluded. A similar frequency of increases was noted among placebo patients.
Flu syndrome was seen in 13.5% of Evista-treated patients and 11.4% of placebo-treated patients. There was no increase in discontinuation rates due to this event.
Compared with placebo, the following events were seen in significantly fewer numbers in Evista-treated patients: bradycardia, hypertension, hypercholesterolaemia, haematuria, breast neoplasm, breast carcinoma.
Overdosage
Incidents of overdosage in humans have not been reported. Daily doses of 600 mg administered during an 8 week study and 120 mg, used in clinical trials in more than 2500 postmenopausal women for three years, were well tolerated. There is no specific antidote for raloxifene hydrochloride.
Interactions
Antacids
Concurrent administration of either calcium carbonate or aluminium and magnesium hydroxide containing antacids do not affect the systemic exposure of raloxifene.
Warfarin
In vitro, Evista did not interact with the binding of warfarin. Co-administration of Evista and warfarin or other coumarin derivatives does not alter the pharmacokinetics of either compound. However, modest decreases in the prothrombin time have been observed, and if raloxifene is given concurrently with warfarin or other coumarin derivatives, the prothrombin time should be monitored. Effects on prothrombin time may develop over several weeks if Evista treatment is started in patients who are already on coumarin anticoagulant therapy.
Methylprednisolone
The chronic administration of raloxifene has no effect on the pharmacokinetics of methylprednisolone given as a single dose.
Digoxin
Raloxifene does not affect the steady-state AUC of digoxin. The Cmax of digoxin increased by less than 5%.
Phenytoin and Tamoxifen
In vitro, raloxifene did not interact with the binding of phenytoin or tamoxifen.
Cholestyramine
Raloxifene should not be co-administered with cholestyramine, an anion exchange resin, which significantly reduces the absorption and enterohepatic cycling of raloxifene. Although not specifically studied, it is anticipated that other anion exchange resins would have a similar effect.
Ampicillin
Peak concentrations of raloxifene are reduced with co-administration with ampicillin. However, since the overall extent of absorption and the elimination rate of raloxifene are not affected, raloxifene can be concurrently administered with ampicillin.
Hormones
Raloxifene modestly increases hormone-binding globulin concentrations, including sex steroid binding globulins (SHBG), thyroxine binding globulin (TBG), and corticosteroid binding globulin (CBG), with corresponding increases in total hormone concentrations. There is no evidence that these changes affect the concentrations of the corresponding free hormones.
Concomitant Medications
The influence of concomitant medication on raloxifene plasma concentrations was evaluated in the prevention and treatment trials. Frequently co-administered medicines included: paracetamol, non - steroidal anti-inflammatory medicines (such as acetylsalicylic acid, ibuprofen, and naproxen), oral antibiotics, H1 antagonists, H2 antagonists, and benzodiazepines. No clinically relevant effects of the co-administration of the agents on raloxifene plasma concentrations were identified.
Concomitant use of vaginal oestrogen preparations was commonplace in the clinical trial programme. No interaction was noted and compared to placebo there was no increased use in Evista-treated patients.
Pharmaceutical Precautions
Store below 30°C (86°F) in a dry place. Do not freeze and protect from excessive heat and sunlight. Shelf life: 2 years.
Incompatibilities: Not applicable
Package Quantities
Evista tablets are packed in 7 day calendar blisters. Individual cartons contain 28 tablets.
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