Keoxifene

Keoxifene - General Information

A second generation selective estrogen receptor modulator (SERM) used to prevent osteoporosis in postmenopausal women. It has estrogen agonist effects on bone and cholesterol metabolism but behaves as a complete estrogen antagonist on mammary gland and uterine tissue. [PubChem]

Pharmacology of Keoxifene

Keoxifene, a selective estrogen receptor modulator (SERM) of the benzothiophene class, is similar to tamoxifen in that it produces estrogen-like effects on bone and lipid metabolism, while antagonizing the effects of estrogen on mammary tissue. Keoxifene decreases bone resorption, increases bone mineral density (BMD) and decreases incidence of fractures. Keoxifene is used in the prevention of postmenopausal osteoporosis and breast cancer.

Keoxifene for patients

For safe and effective use of EVISTA, the physician should inform patients about the following:

Patient Immobilization: EVISTA should be discontinued at least 72 hours prior to and during prolonged immobilization
(e.g., post-surgical recovery, prolonged bed rest), and patients should be advised to avoid prolonged restrictions of
movement during travel because of the increased risk of venous thromboembolic events.

Hot flashes or flushes: EVISTA is not effective in reducing hot flashes or flushes associated with estrogen deficiency.
In some asymptomatic patients, hot flashes may occur upon beginning EVISTA therapy.

Other Preventive Measures: Patients should be instructed to take supplemental calcium and vitamin D, if daily dietary
intake is inadequate. Weight-bearing exercise should be considered along with the modification of certain behavioral
factors, such as cigarette smoking, and/or alcohol consumption, if these factors exist.

Physicians should instruct their patients to read the patient package insert before starting therapy with EVISTA and to
re-read it each time the prescription is renewed.

Keoxifene Interactions

Cholestyramine: Cholestyramine causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene and should not be coadministered with EVISTA.

Warfarin: The coadministration of EVISTA and warfarin has not been assessed under chronic conditions. However, 10% decreases in prothrombin time have been observed in single-dose studies. If EVISTA is given concurrently with warfarin, prothrombin time should be monitored.

Other Highly Protein-Bound Drugs: Raloxifene is more than 95% bound to plasma proteins. In vitro, raloxifene did not affect the binding of warfarin, phenytoin, or tamoxifen. Caution should be used when EVISTA is coadministered with other highly protein-bound drugs, such as clofibrate, indomethacin, naproxen, ibuprofen, diazepam, and diazoxide.

See also CLINICAL PHARMACOLOGY, Drug-Drug Interactions

Keoxifene Contraindications

EVISTA is contraindicated in women who are or may become pregnant. EVISTA may cause fetal harm when administered to a pregnant woman. In rabbit studies, abortion and a low rate of fetal heart anomalies (ventricular septal defects) occurred in rabbits at doses ³ 0.1 mg/kg (³ 0.04 times the human dose based on surface area, mg/m²), and hydrocephaly was observed in fetuses at doses ³10 mg/kg (³ 4 times the human dose based on surface area, mg/m²). In rat studies, retardation of fetal development and developmental abnormalities (wavy ribs, kidney cavitation) occurred at doses ³ 1mg/kg (³0.2 times the human dose based on surface area, mg/m²). Treatment of rats at doses of 0.1 to 10 mg/kg (0.02 to 1.6 times the human dose based on surface area, mg/m²) during gestation and lactation produced effects that included delayed and disrupted parturition; decreased neonatal survival and altered physical development; sex-and age-specific reductions in growth and changes in pituitary hormone content; and decreased lymphoid compartment size in offspring. At 10 mg/kg, raloxifene disrupted parturition which resulted in maternal and progeny death and morbidity. Effects in adult offspring (4 months of age) included uterine hypoplasia and reduced fertility; however, no ovarian or vaginal pathology was observed. The patient should be apprised of the potential hazard to the fetus if this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug.

EVISTA is contraindicated in women with active or past history of venous thromboembolic events, including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis.

EVISTA is contraindicated in women known to be hypersensitive to raloxifene or other constituents of the tablets.

Additional information about Keoxifene

Keoxifene Indication: For the prevention of osteoporosis in post-menopausal women
Mechanism Of Action: Keoxifene binds to estrogen receptors, resulting in differential expression of multiple estrogen-regulated genes in different tissues. Keoxifene produces estrogen-like effects on bone, reducing resorption of bone and increasing bone mineral density in postmenopausal women. Keoxifene also antagonizes the effects of estrogen on mammary tissue and blocks uterotrophic responses to estrogen.
Drug Interactions: Chlorotrianisene Association not recommended
Clomifene Association not recommended
Diethylstilbestrol Association not recommended
Estradiol Association not recommended
Estriol Association not recommended
Conjugated Estrogens Association not recommended
Estropipate Association not recommended
Ethinyl Estradiol Association not recommended
Mestranol Association not recommended
Levothyroxine Keoxifene decreases absorption of levothyroxine
Cholestyramine The resin decreases the effect of raloxifene
Colestipol The resin decreases the effect of raloxifene
Food Interactions: Avoid alcohol.
Generic Name: Raloxifene
Synonyms: RAL; Raloxifene Hcl; Raloxifene Hydrochloride; Raloxifeno [Spanish]; Raloxifenum [Latin]; LY-139481
Drug Category: Antihypocalcemic Agents; Osteoporosis Prophylactic; Selective Estrogen Receptor Modulators; Estrogen Antagonists
Drug Type: Small Molecule; Approved; Investigational

Other Brand Names containing Raloxifene: Evista; Keoxifene;
Absorption: Approximately 60% of an oral dose is absorbed, but presystemic glucuronide conjugation is extensive. Absolute bioavailability of raloxifene is 2.0%
Toxicity (Overdose): Not Available
Protein Binding: 95%
Biotransformation: Hepatic, 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, providing strong evidence that raloxifene is not metabolized by cytochrome P450 pathways
Half Life: 27.7
Dosage Forms of Keoxifene: Tablet Oral
Chemical IUPAC Name: [6-hydroxy-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl]-[4-(2-piperidin-1-ylethoxy)phenyl]methanone
Chemical Formula: C28H27NO4S
Raloxifene on Wikipedia: https://en.wikipedia.org/wiki/Raloxifene
Organisms Affected: Humans and other mammals