Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Eli Lilly Nederland B.V., Papendorpseweg 83, 3528 BJ Utrecht, The Netherland
Pharmacotherapeutic group: Selective Oestrogen Receptor Modulator
ATC code: G03XC01
As a selective oestrogen receptor modulator (SERM), raloxifene has selective agonist or antagonist activities on tissues responsive to oestrogen. 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’s biological actions, 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. Data suggests that the oestrogen receptor can regulate gene expression by at least two distinct pathways which are ligand-, tissue-, and/or genespecific.
The decrease in oestrogen availability which occurs at menopause, leads to marked increases 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 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 with osteoporosis, Optruma reduces the incidence of vertebral fractures, preserves bone mass and increases bone mineral density (BMD).
Based on these risk factors, prevention of osteoporosis with Optruma is indicated for women within ten years of menopause, with BMD of the spine between 1.0 and 2.5 SD below the mean value of a normal young population, taking into account their high lifetime risk for osteoporotic fractures. Likewise, Optruma is indicated for the treatment of osteoporosis or established osteoporosis in women with BMD of the spine 2.5 SD below the mean value of a normal young population and/or with vertebral fractures, irrespective of BMD.
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, Optruma treatment for 3 years reduced the incidence of vertebral fractures by 47% (RR 0.53, CI 0.35, 0.79; p<0.001) and 31% (RR 0.69, CI 0.56, 0.86; p<0.001) respectively. Forty five women with osteoporosis or 15 women with osteoporosis with an existing fracture would need to be treated with Optruma for 3 years to prevent one or more vertebral fractures. Optruma treatment for 4 years reduced the incidence of vertebral fractures by 46% (RR 0.54, CI 0.38, 0.75) and 32% (RR 0.68, CI 0.56, 0.83) in patients with osteoporosis or osteoporosis with an existing fracture respectively. In the 4th year alone, Optruma reduced the new vertebral fracture risk by 39% (RR 0.61, CI 0.43, 0.88). An effect on non-vertebral fractures has not been demonstrated. From the 4th to the 8th year, patients were permitted the concomitant use of bisphosphonates, calcitonin and fluorides and all patients in this study received calcium and vitamin D supplementation. In the RUTH study overall clinical fractures were collected as a secondary endpoint. Optruma reduced the incidence of clinical vertebral fractures by 35% compared with placebo (HR 0.65, CI 0.47 0.89). These results may have been confounded by baseline differences in BMD and vertebral fractures. There was no difference between treatment groups in the incidence of new nonvertebral fractures. During the whole length of the study concomitant use of other bone-active medications was permitted.
ii) Bone Mineral Density (BMD): The efficacy of Optruma 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 Optruma and calcium or calcium supplemented placebo. In one of these trials the women had previously undergone hysterectomy. Optruma 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 who received Optruma for up to 7 years. 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. Optruma and oestrogen affect bone remodelling and calcium metabolism similarly. Optruma 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 Optruma with oestrogen, bone from patients treated with either medicinal product was histologically normal, with no evidence of mineralisation defects, woven bone or marrow fibrosis. Raloxifene decreases resorption of bone; this effect on bone is 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.
Clinical trials showed that a 60 mg daily dose of Optruma significantly decreased total cholesterol (3 to 6%), and LDL cholesterol (4 to 10%). Women with the highest baseline cholesterol levels had the greatest decreases. HDL cholesterol and triglyceride concentrations did not change significantly. After 3 years therapy Optruma decreased fibrinogen (6.71%). In the osteoporosis treatment study, significantly fewer Optruma-treated patients required initiation of hypolipidaemic therapy compared to placebo.
Optruma therapy for 8 years did not significantly affect the risk of cardiovascular events in patients enrolled in the osteoporosis treatment study. Similarly, in the RUTH study, raloxifene did not affect the incidence of myocardial infarction, hospitalized acute coronary syndrome, stroke or overall mortality, including overall cardiovascular mortality, compared to placebo (for the increase in risk of fatal stroke see section 4.4).
The relative risk of venous thromboembolic events observed during raloxifene treatment was 1.60 (CI 0.95, 2.71) when compared to placebo, and 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.
In clinical trials, Optruma 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, at least 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 Optruma 60 mg daily demonstrated nonproliferative endometrium in all patients. In addition, in a study with 2.5 x the recommended daily dose of Optruma 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 (1,644 patients) for 4 years. Endometrial thickness measurements in Optruma treated women were not different from baseline after 4 years of therapy. There was no difference between Optruma and placebo treated women in the incidences of vaginal bleeding (spotting) or vaginal discharge. Fewer Optruma treated women than placebo treated women required surgical intervention for uterine prolapse. Safety information following 3 years of raloxifene treatment suggests that raloxifene treatment does not increase pelvic floor relaxation and pelvic floor surgery.
After 4 years, raloxifene did not increase the risk of endometrial or ovarian cancer. In postmenopausal women who received raloxifene treatment for 4 years, benign endometrial polyps were reported in 0.9% compared to 0.3% in women who received placebo treatment.
Optruma does not stimulate breast tissue. Across all placebo-controlled trials, Optruma was indistinguishable from placebo with regard to frequency and severity of breast symptoms (no swelling, tenderness and breast pain).
Over the 4 years of the osteoporosis treatment trial (involving 7,705 patients), Optruma treatment compared to placebo reduced the risk of total breast cancer by 62% (RR 0.38; CI 0.21, 0.69), the risk of invasive breast cancer by 71% (RR 0.29, CI 0.13, 0.58) and the risk of invasive oestrogen receptor (ER) positive breast cancer by 79% (RR 0.21, CI 0.07, 0.50). Optruma 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.
No adverse effects on cognitive function have been seen.
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%. The time to reach average maximum plasma concentration and bioavailability are functions of systemic interconversion and enterohepatic cycling of raloxifene and its glucuronide metabolites.
Raloxifene is distributed extensively in the body. The volume of distribution is not dose dependent. Raloxifene is strongly bound to plasma proteins (98-99%).
Raloxifene undergoes extensive first pass metabolism to the glucuronide conjugates: raloxifene-4'-glucuronide, raloxifene-6-glucuronide, and raloxifene-6, 4′-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 proportional increase in the area under the plasma time concentration curve (AUC).
The majority of a dose of raloxifene and glucuronide metabolites are excreted within 5 days and are found primarily in the faeces, with less than 6% excreted in urine.
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.
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.
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 extensive battery of test systems applied. The reproductive and developmental effects observed in animals are consistent with the known pharmacological profile of raloxifene. At doses of 0.1 to 10 mg/kg/day in female rats, raloxifene disrupted estrous 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.
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