Bei Bang

Uses

Bei Bang 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: Bei Bang 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

Bei Bang is also used to associated treatment for these conditions: Invasive Breast Cancer, Osteoporosis, Osteoporosis caused by glucocorticoid

How Bei Bang works

Bei Bang 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

Bei Bang dosage

One tablet (60 mg) once daily orally. It can be taken without regard to meal. High fat meal increases the absorption of Bei Bang.

Side Effects

Bei Bang 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 Bei Bang with systemic estrogens is not recommended.

Lipid Metabolism: Concurrent use of Bei Bang and lipid-lowering agents has not been studied.

Interaction

Co-administered with cholestyramin, ampicillin and amoxicillin may reduce the absorption of Bei Bang.

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.

Bei Bang 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.

Bei Bang 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

Bei Bang 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. Bei Bang is widely distributed in the tissues. It is not known whether raloxifene is excreted in human milk.

Elimination Route

Bei Bang 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

Bei Bang 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: Bei Bang should not be used in women who are or may become pregnant.

Lactation: It is not known whether Bei Bang 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 Bei Bang 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

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