Raloxifene
Raloxifene Uses, Dosage, Side Effects, Food Interaction and all others data.
Raloxifene is a selective estrogen receptor modulator (SERM). The biological actions of Raloxifene are largely mediated through binding to estrogen receptor. This binding results in activation of certain estrogenic pathways and blockade of others. Raloxifene reduces resorption of bone and decreases overall bone turnover. These effects on bone are manifested as reductions in the serum and urine levels of bone turnover markers. Clinical trials and data suggest that Raloxifene lacks estrogen like effects on the uterus and breast tissues. Raloxifene is rapidly absorbed after oral administration, metabolized in liver, and primarily excreted in faeces and rest in urine.
Raloxifene belongs to the selective estrogen receptor modulator (SERM) drug class that exhibits estrogenic effects on bone and lipid metabolism while mediating anti-estrogenic effects on uterine endometrium and breast tissues. On skeletal tissues, raloxifene stimulates bone-depositing osteoblasts and inhibits bone-resorbing osteoclasts to augument bone mineral density. Raloxifene produces estrogen-like effects on bone, reducing the resorption of bone and increasing bone mineral density in postmenopausal women, thus slowing the rate of bone loss. In three randomized, placebo-controlled trials in Europe, postmenopausal women receiving raloxifene at variable doses of 30 to 150 mg daily demonstrated significant increases in bone mineral density in the lumbar spine, total hip, femoral neck and total body compared to placebo. In the MORE and RUTH trials, there were fewer incidences of vertebral fractures in postmeopausal women receiving raloxifene compared to placebo. In a eight-week study evaluating short-term effects of raloxifene in healthy postmenopausal women, there was a decrease in the bone turnover markers, such as serum alkaline phosphatase level, serum osteocalcin level and urinary calcium excretion.
Raloxifene was shown to inhibit estrogen-dependent proliferation of human breast cancer cells in vitro and development of induced mammary tumors in rats in vivo. In adult female rats, raloxifene produced a greater regression of the mammary gland than tamoxifen. The MORE trial was a multicenter, randomized, double-blind clinical trial that investigated the long-term effects of the drug therapy in European and American postmenopausal women receiving raloxifene for 40 months. Additionally, a reduction in the incidence of invasive breast cancer was also demonstrates in the CORE and RUTH trials. Study findings demonstrated that compared to placebo, the risk of invasive breast cancer was decreased by 76% among postmenopausal women with osteoporosis. There was a decrease in the risk of estrogen receptor-positive breast cancer by 90% but there was no increase in the risk of endometrial cancer. Unlike hormone replacement therapy, raloxifene does not mediate proliferative or stimulatory effects on endometrial tissue. Findings from both animal and human studies demonstrated no significant changes in the histologic appearance of the endometrium.
Raloxifene promotes estrogen-like effects on lipid metabolism. In a European trial that evaluated lipid profiles following raloxifene therapy over the 24-month period, there were significant decreases in the serum concentrations of total and low-density lipoprotein (LDL) cholesterol over a 24-month period of raloxifene therapy. Raloxifene is not associated with causing alterations in the serum levels of HDL cholesterol or triglycerides. As the HDL choesterol level is considered a strong inverse predictor of cardiovascular disease in women, the cardioprotective effects of raloxifene were questioned. Due to limited data on the long-term trials, it is not possible to determine whether the small lipid effects produced by raloxifene correlate with a smaller degree of cardioprotective activity compared with hormone replacement therapy.
| Trade Name | Raloxifene |
| Availability | Prescription only |
| Generic | Raloxifene |
| Raloxifene Other Names | Raloxifène, Raloxifene, Raloxifeno, Raloxifenum |
| Related Drugs | Prolia, hydrochlorothiazide, alendronate, calcitonin, estradiol, Fosamax, Boniva, ibandronate, Reclast, Evista |
| Weight | 60mg |
| Type | Oral tablet |
| Formula | C28H27NO4S |
| Weight | Average: 473.583 Monoisotopic: 473.166079047 |
| Protein binding | About 95% of raloxifene and its glucuronide metabolites are bound to plasma proteins. Although this is a relatively high protein binding profile, in vitro studies suggest that raloxifene and its metabolites do not significantly interact with binding of highly protein-bound drugs. FDA Label still advises patients to use raloxifene with caution co-administering with other highly protein-bound drugs. |
| Groups | Approved, Investigational |
| Therapeutic Class | Other preparations: Inhibiting bone resorption |
| Manufacturer | |
| Available Country | United States |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Raloxifene is an estrogen agonist/antagonist used for:
- Treatment and prevention of osteoporosis in postmenopausal women
- Reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis
- Reduction in risk of invasive breast cancer in postmenopausal women at high risk for invasive breast cancer
Important Limitations: Raloxifene is not used for the treatment of invasive breast cancer, reduction of the risk of recurrence of breast cancer, or reduction of risk of noninvasive breast cancer
Raloxifene is also used to associated treatment for these conditions: Invasive Breast Cancer, Osteoporosis, Osteoporosis caused by glucocorticoid
How Raloxifene works
Raloxifene is a selective estrogen receptor modulator that acts as both an estrogen agonist and antagonist via differential effects on the tissue-specific estrogen receptors. Based on the findings of competitive binding assays, raloxifene displays binding affinity that is similar to that of estradiol, the predominant circulating estrogen. Estrogens play variable roles at different tissues in females, including the bone, breasts, uterus and liver, by binding to the steroid nuclear hormone receptors, Estrogen Receptor alpha (ERα) or Estrogen Receptor beta (ERβ). These receptors are normally bound to the Heat Shock Protein 90 (Hsp90) when unbound to the ligand. Ligand binding induces a conformational change in the receptor that promotes dissociation of the receptor from Hsp90, dimerization and translocation into the nucleus. This movement into the nucleus allows the receptor to bind to genomic locations based on sequence recognition of the DNA binding domain, also known as the Estrogen Response Elements (EREs).
In bones, endogenous estrogens normally modulate multiple DNA response elements, including the gene-encoding transforming growth factor-β3 (TGF-β3), which is a cytokine embedded in the bone matrix. TGF-β3 plays an important role in bone remodelling by working with other cytokines to induce production of osteoblasts, such as IL-6, and attenuate the activity of osetoclasts. Estrogens typically maintain the bone integrity by inhibiting the cytokines that recruit osteoclasts and oppose the bone-resorbing, Ca2+-mobilizing action of parathyroid hormone. In contrast, estrogens promote osteoblast proliferation, augment the production of TGF-β3 and bone morphogenic proteins, and inhibit apoptosis. Mimicking the action of endogenous estrogen in bone tissues, raloxifene binds to the estrogen receptor to influence gene transcription through interactions with the estrogen response element (ERE) and a distinct DNA target, the raloxifene response element (RRE). It occupies the same ER ligand binding site as estrogen. Upon binding, raloxifene induces a conformational change of the receptor, allowing mediation of direct binding to transcriptional elements by accessory proteins. Increased expression of bone matrix proteins, such as alkaline phosphatase, osteonectin, osteocalcin and collagen may be seen. The agonistic or antagonistic action of raloxifene depends on the extent of recruitment of coactivators and corepressors to estrogen receptor (ER) target gene promotors. In breast tissues, raloxifene acts as an estrogen receptor antagonist to attenuate the estrogen-dependent proliferative effects of epithelial cell expansion. In addition to the antiproliferative effects, raloxifene prevents the production of cytokines and recruitment of macrophages and lymphocytes into tumor mass.
Dosage
Raloxifene dosage
One tablet (60 mg) once daily orally. It can be taken without regard to meal. High fat meal increases the absorption of Raloxifene.
Side Effects
Raloxifene is generally well tolerated. However, a few side effects like hot flushes, leg cramps, and influenza like symptoms, gastro-intestinal disturbances etc may be seen usually during first 6 months of treatment and were not different from placebo.
Toxicity
LD50 and Overdose
The oral LD50 value in rats is > 5000 mg/kg, which is about 810 times the human dose. In monkeys, no mortality was seen after a single oral dose of 1000 mg/kg. No cases of raloxifene overdose have been reported during clinical trials. A rare postmarketing report of a non-fatal overdose after oral ingestion of 1.5 g has been reported. Common adverse events of leg cramps, hot flushes, and dizziness have been reported with the use of raloxifene at doses of greater than 180 mg. More serious adverse event of venous thromboembolic events were observed with raloxifene. Two 18-month-old children accidentally ingested 180 mg of raloxifene and symptoms of ataxia, dizziness, vomiting, rash, diarrhea, tremor, flushing, and elevated alkaline phosphatase levels were reported. There is no known antidote for raloxifene.
Nonclinical Toxicology
In a two-year mouse carcinogenicity study at raloxifene doses that are higher than the human therapeutic doses, there was an increased incidence of benign and malignant ovarian tumors of granulosa or theca cell origin. Another study showed an increased incidence of testicular interstitial cell tumors, prostatic adenomas, adenocarcinomas, and prostatic leiomyoblastoma in male mice receiving doses higher than human therapeutic doses. There was no evidence of the genotoxic potential of raloxifene in bacterial mutagenicity assays, in vitro rat DNA assays, or other in vitro rodent cell line assays. When assessing effects on the reproductive system of male and female rats, raloxifene caused lack of pregnancy and disruptions in estrous cycles and inhibited ovulation at dose of 0.1 to 10 mg/kg/day. Administration of raloxifene during the preimplantation period at doses greater than 0.1 mg/kg resulted in delayed and disrupted embryo implantation, further leading to prolonged gestation and reduced litter size. There were no effects on sperm production or quality or reproductive performance in male rats. The effects on the fertility by raloxifene were reversible.
Use in special populations
The use of raloxifene in pregnant or nursing women is not advised. Although there are no specific dosing adjustment guidelines, caution should be undertaken when administering raloxifene in geriatric patients or patients with renal or hepatic impairment.
Precaution
Concurrent Estrogen Therapy: Concomitant use of Raloxifene with systemic estrogens is not recommended.
Lipid Metabolism: Concurrent use of Raloxifene and lipid-lowering agents has not been studied.
Interaction
Co-administered with cholestyramin, ampicillin and amoxicillin may reduce the absorption of Raloxifene.
Food Interaction
- Avoid excessive or chronic alcohol consumption. Excessive and chronic alcohol consumption may be associated with vitamin D deficiency.
- Take with or without food. The absorption is unaffected by food.
Raloxifene Cholesterol interaction
[Moderate] In studies of women with a history of marked hypertriglyceridemia (>5.6 mmol Women with this medical history should have serum triglycerides monitored when taking raloxifene.
Raloxifene Drug Interaction
Moderate: estradiol topical, levothyroxineUnknown: aspirin, aspirin, calcium / vitamin d, calcium / vitamin d, ubiquinone, omega-3 polyunsaturated fatty acids, metoprolol, metoprolol, polyethylene glycol 3350, albuterol, bifidobacterium infantis / lactobacillus acidophilus, acetaminophen, cyanocobalamin, pyridoxine, ascorbic acid, ergocalciferol, cholecalciferol, cetirizine
Raloxifene Disease Interaction
Major: thromboembolismModerate: heart disease, hypertriglyceridemia, liver disease, renal impairment
Volume of Distribution
Following oral administration of single doses randing from 30 to 150 mg in postmenopausal women, the volume of distribution was about 2348 L/kg. Following oral administration of multiple doses, the value increased to 2853 L/kg. Raloxifene is widely distributed in the tissues. It is not known whether raloxifene is excreted in human milk.
Elimination Route
Raloxifene is well absorbed from the gastrointestinal tract, with approximately 60% fo the drug being absorbed following oral administration. Due to the extensive first-pass hepatic metabolism that involves glucuronide conjugation, the absolute oral bioavailability of raloxifene is about 2%. Following oral ingestion of a single dose or multiple dose of raloxifen in healthy postmenopausal women, the mean peak plasma concentrations (Cmax) were 0.50 and 1.36 ng/mL, respectively, and the AUC values were 27.2 and 24.2 ngxhr/mL, respectively. The time to reach Cmax following a single or multiple oral doses were 27.7 and 32.5 hours, respectively. Although not clinically significant, oral ingestion of raloxifene with high-fat meals is thought to increase the systemic bioavailability of the drug by increasnig the peak plasma concentrations (Cmax) and AUC by 28% and 16%, respectively.
Half Life
The average plasma elimination half-life of raloxifene ranges from 27 to 32 hours. The prolonged half-life has been attributed to the drug's reversible systemic metabolism and significant enterohepatic cycling.
Clearance
Following intravenous administration, raloxifene was shown to be cleared at a rate approximating hepatic blood flow. The apparent oral clearance is reported to be 44.1 L/kgxhr. The clearance can range from 40 to 60L/kgxhr following chronic dosing. In healthy postmenopausal women receiving multiple oral dose, the mean clearance was 47.4 L/kgxhr. Apparent clearance can be reduced by 56% in patients with hepatic impairment.
Elimination Route
Raloxifene predominantly undergoes fecal excretion, with less than 0.2% of the dose being excreted in the urine as unchanged form of the compound and less than 6% of the dose being excreted as glucuronide conjugates. Co-administration with cholestyramine, a bile acid sequestrant, was shown to reduce the enterohepatic recycling of raloxifene by 60%.
Pregnancy & Breastfeeding use
Pregnancy Category X: Raloxifene should not be used in women who are or may become pregnant.
Lactation: It is not known whether Raloxifene is excreted in breast milk. Lactating mother should not use Raloxifne.
Contraindication
Hepatic & renal impairment. In active or past history of venous thromboembolic events, including deep vein thrombosis, pulmonary embolism and retinal vein thrombosis. Hypersensitivity to Raloxifene or any other constituents of the tablet.
Special Warning
Severe Renal Impairment: Contraindicated.
Hepatic Impairment: Contraindicated.
Acute Overdose
Incidents of overdose in humans have not been reported.
Innovators Monograph
You find simplified version here Raloxifene
Raloxifene contains Raloxifene see full prescribing information from innovator Raloxifene Monograph, Raloxifene MSDS, Raloxifene FDA label
FAQ
What is Raloxifene used for?
Raloxifene is used to prevent and treat osteoporosis (condition in which the bones become thin and weak and break easily) in postmenopausal women.
How safe is Raloxifene?
Raloxifene is associated with an increased risk of deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis. An increased risk of death due to stroke was observed in a trial in postmenopausal women with documented coronary heart disease or at increased risk for major coronary events.
How does Raloxifene work?
Raloxifene prevents and treats osteoporosis by mimicking the effects of estrogen to increase the density (thickness) of bone.
What side effects can Raloxifene cause?
The common side effects of Raloxifene are include:
- hot flashes (more common in the first 6 months of raloxifene therapy)
- leg cramps.
- swelling of the hands, feet, ankles, or lower legs.
- flu-like syndrome.
- joint pain.
- sweating.
- difficulty falling asleep or staying asleep.
Is Raloxifene safe during pregnancy?
Raloxifene must not be given to a pregnant woman or a woman who intends to become pregnant. If a woman becomes pregnant while taking Raloxifene, the medication must be stopped immediately and the woman given appropriate counseling.
Is Raloxifene safe during breastfeeding?
It is not known if Raloxifene passes into breast milk. This medication should not be used by women who are breast-feeding.
Can I drink alcohol with Raloxifene?
Alcohol is unlikely to interact with Raloxifene. However, heavy drinking is a risk factor for osteoporosis and for having falls so it's recommended that you drink alcohol only in moderation.
Can I drive after taking Raloxifene?
This medicine has no or negligible effects on driving or using machines.
When Is the best taken of Raloxifene?
You can take Raloxifene at whatever time of day you find easiest to remember but try to take your doses at the same time of day, each day.
How long does Raloxifene take to work?
Research has shown that Raloxifene significantly and consistently suppressed bone turnover within three months and this persisted for the duration of the trial (24 or 36 months).
Can I take Raloxifene for a long time?
Due to the chronic nature of osteoporosis and the risk of invasive breast cancer, Raloxifene is intended to be used for long-term treatment.
Is Raloxifene a hormone?
Raloxifene is not an estrogen hormone.
Does Raloxifene increase estrogen?
In postmenopausal women, Raloxifene (60 mg/d) did not increase serum estrogen levels.
Does Raloxifene lower prolactin?
Raloxifene had no significant effect on prolactin levels but did increase estradiol and SHBG measurements.
Does Raloxifene suppress immune system?
Raloxifene may decrease the strength of immune responses in vivo through modulation of DC differentiation and activation.
Can I take Raloxifene every other day?
Raloxifene Raloxifene every other day during 2 months before increasing to standard dose of 60 mg/day) was suggested to reduce the incidence of hot flushes.
Is Raloxifene liver toxic?
Clinically apparent liver injury with jaundice has been reported with Raloxifene therapy, it is very rare.
Can Raloxifene cause weight loss?
Raloxifene did not increase abdominal fat loss during weight loss, but did improve some cardiometabolic outcomes.
Who should not take Raloxifene?
Raloxifene may increase your risk of a blood clot in your leg, your lung, or your eye. You should not take Raloxifene if you have ever had this type of blood clot.
What should I avoid while taking Raloxifene?
If you take calcium supplements, do not take more than your doctor has prescribed. Taking more calcium than recommended will not provide extra protection for your bones, and may cause serious side effects including kidney stones.
Avoid sitting still for long periods of time during travel while you are taking Raloxifene.
What happens if I miss a dose?
Take the medicine as soon as you can, but skip the missed dose if it is almost time for your next dose. Do not take two doses at one time.
Can Raloxifene cause stroke?
Raloxifene can also increase your risk of a stroke, which can be fatal.
Can I overdose of Raloxifene?
If you take too much Raloxifene , call your doctor or local Poison Control Center right away.
