Peringatan Keamanan

LD50 and Overdose

The oral LD50 value in rats is > 5000 mg/kg, which is about 810 times the human dose.MSDS In monkeys, no mortality was seen after a single oral dose of 1000 mg/kg.label 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.A721 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. label

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.label

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.label

Raloxifene

DB00481

small molecule approved investigational

Deskripsi

Raloxifene is a second generation selective estrogen receptor modulator (SERM) that mediates anti-estrogenic effects on breast and uterine tissues, and estrogenic effects on bone, lipid metabolism, and blood coagulation.A4979,T28 Exhibiting tissue-specific effects distinct from estradiol, raloxifene is the first of the benzothiophene group of antiestrogens to be labelled a SERM.A4977 Available in many countries worldwide, raloxifene was initially approved by the FDA in December, 1997 under the market name Evista® for the management and prevention of osteoporosis in postmenopausal women and reduction in risk for invasive breast cancer in postmenopausal women with osteoporosis or those who are at high risk for invasive breast cancer. However, it has a negligible effect on altering the development and progression of breast cancer itself.label The most common causes of osteoporosis include postmenopausal deficiency of estrogen and age-related deterioration in bone homeostasis. Due to the risk of bone fractures that may lead to morbidities and reduced quality of life, the management of osteoporosis in postmenopausal women with the use of therapeutic agents in addition to concurrent therapies is critical. Due to the decline in estrogen levels in postmenopausal osteoporosis, hormone replacement therapy (HRT), such as estradiol, has been used to ameliorate the condition. However, due to the off-target actions by HRT, newer non-hormonal agents such as raloxifene and tamoxifen have been developed to reduce adverse events through selective pharmacological actions on tissue-specific therapeutic targets.T28

The main effects of raloxifene are to preserve the bone mineral density and decrease the risk of breast cancer in postmenopausal women. Compared to estrogen and tamoxifen, raloxifene was not associated with an increased risk of uterine cancer and it does not cause endometrial proliferation.A716 Although rare, there was an increased risk of venous thromboembolism during clinical trials of postmenopausal women receiving raloxifene. In addition, a clinical study consisting of postmenopausal women with documented coronary heart disease or at increased risk for coronary events showed an increased risk for fatal stroke with raloxifene therapy compared to placebo.label It is strongly advised that the risk-benefit ratio is considered before starting raloxifene therapy in women at risk of thromboembolic disease or strokes, such as the prior history of stroke, transient ischemic attack, atrial fibrillation, hypertension, or cigarette smoking.label

Struktur Molekul 2D

Berat 473.583
Wujud solid

Peta Jejaring Molekuler
Legenda: Obat • Target • Gen • Enzim • (Panah → menunjukkan arah efek / relasi) • Transporter • Carrier

Profil Farmakokinetik

Waktu Paruh (Half-Life) The average plasma elimination half-life of raloxifene ranges from 27 to 32 hours.[A4977,T28] The prolonged half-life has been attributed to the drug's reversible systemic metabolism and significant enterohepatic cycling.[A4977]
Volume Distribusi 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.[label]
Klirens (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.[label]

Absorpsi

Raloxifene is well absorbed from the gastrointestinal tract, with approximately 60% fo the drug being absorbed following oral administration.T28 Due to the extensive first-pass hepatic metabolism that involves glucuronide conjugation, the absolute oral bioavailability of raloxifene is about 2%.T28 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.label Although not clinically significant, oral ingestion of raloxifene with high-fat meals is thought to increase the systemic bioavailability of the drugA4977 by increasnig the peak plasma concentrations (Cmax) and AUC by 28% and 16%, respectively.label

Metabolisme

Raloxifene is reported to undergo metabolism in the intestines and liver devoid of cytochrome P450 pathway.A4977 It is extensively metabolized, where less than 1% of the total dose exists as unchanged compound.label It mainly undergoes first-pass metabolism to form glucuronide conjugates, raloxifene-4'-glucuronide (raloxifene-4'-?-glucuronide), raloxifene-6-glucuronide (raloxifene-6-?-glucuronide), and raloxifene-6,4'-diglucuronide. No other metabolites have been detected in human plasma. The terminal log-linear portions of the plasma concentration curves for raloxifene and the glucuronides are generally parallel. This is consistent with interconversion of raloxifene and the glucuronide metabolites.label

Rute Eliminasi

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%.T28

Interaksi Makanan

2 Data
  • 1. Avoid excessive or chronic alcohol consumption. Excessive and chronic alcohol consumption may be associated with vitamin D deficiency.
  • 2. Take with or without food. The absorption is unaffected by food.

Interaksi Obat

478 Data
Eliglustat The metabolism of Eliglustat can be decreased when combined with Raloxifene.
Ibrutinib The metabolism of Ibrutinib can be decreased when combined with Raloxifene.
Cilostazol The metabolism of Cilostazol can be decreased when combined with Raloxifene.
Colchicine The metabolism of Colchicine can be decreased when combined with Raloxifene.
Iloperidone The metabolism of Iloperidone can be decreased when combined with Raloxifene.
Retapamulin The metabolism of Retapamulin can be decreased when combined with Raloxifene.
Tofacitinib The metabolism of Tofacitinib can be decreased when combined with Raloxifene.
Vardenafil The metabolism of Vardenafil can be decreased when combined with Raloxifene.
Eszopiclone The metabolism of Eszopiclone can be decreased when combined with Raloxifene.
Zopiclone The metabolism of Zopiclone can be decreased when combined with Raloxifene.
Lovastatin The metabolism of Lovastatin can be decreased when combined with Raloxifene.
Alfuzosin The metabolism of Alfuzosin can be decreased when combined with Raloxifene.
Colestipol Colestipol can cause a decrease in the absorption of Raloxifene resulting in a reduced serum concentration and potentially a decrease in efficacy.
Sevelamer Sevelamer can cause a decrease in the absorption of Raloxifene resulting in a reduced serum concentration and potentially a decrease in efficacy.
Colesevelam Colesevelam can cause a decrease in the absorption of Raloxifene resulting in a reduced serum concentration and potentially a decrease in efficacy.
Cholestyramine Cholestyramine can cause a decrease in the absorption of Raloxifene resulting in a reduced serum concentration and potentially a decrease in efficacy.
Alprazolam The metabolism of Alprazolam can be decreased when combined with Raloxifene.
Levothyroxine Raloxifene can cause a decrease in the absorption of Levothyroxine resulting in a reduced serum concentration and potentially a decrease in efficacy.
Ospemifene The risk or severity of adverse effects can be increased when Raloxifene is combined with Ospemifene.
Warfarin The serum concentration of Warfarin can be increased when it is combined with Raloxifene.
Acenocoumarol The serum concentration of Acenocoumarol can be increased when it is combined with Raloxifene.
(R)-warfarin The serum concentration of (R)-warfarin can be increased when it is combined with Raloxifene.
R,S-Warfarin alcohol The serum concentration of R,S-Warfarin alcohol can be increased when it is combined with Raloxifene.
S,R-Warfarin alcohol The serum concentration of S,R-Warfarin alcohol can be increased when it is combined with Raloxifene.
(S)-Warfarin The serum concentration of (S)-Warfarin can be increased when it is combined with Raloxifene.
Midazolam The serum concentration of Midazolam can be increased when it is combined with Raloxifene.
Rifampin The metabolism of Raloxifene can be increased when combined with Rifampicin.
Nelfinavir The metabolism of Raloxifene can be increased when combined with Nelfinavir.
Desogestrel The metabolism of Raloxifene can be increased when combined with Desogestrel.
Zidovudine The metabolism of Raloxifene can be increased when combined with Zidovudine.
Lamotrigine The metabolism of Raloxifene can be increased when combined with Lamotrigine.
Primidone The metabolism of Raloxifene can be increased when combined with Primidone.
Ethinylestradiol The metabolism of Raloxifene can be increased when combined with Ethinylestradiol.
Phenobarbital The metabolism of Raloxifene can be increased when combined with Phenobarbital.
Testosterone propionate The metabolism of Raloxifene can be increased when combined with Testosterone propionate.
Tipranavir The metabolism of Raloxifene can be increased when combined with Tipranavir.
Tacrolimus The serum concentration of Tacrolimus can be increased when it is combined with Raloxifene.
Atorvastatin The metabolism of Atorvastatin can be decreased when combined with Raloxifene.
Cholic Acid The excretion of Raloxifene can be increased when combined with Cholic Acid.
Bupropion The serum concentration of Bupropion can be increased when it is combined with Raloxifene.
Pravastatin Pravastatin may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Beclomethasone dipropionate Beclomethasone dipropionate may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Sulfasalazine Sulfasalazine may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Telmisartan Telmisartan may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Novobiocin Novobiocin may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Hesperetin Hesperetin may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Rabeprazole Rabeprazole may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Genistein Genistein may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Topiroxostat Topiroxostat may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Daidzin Daidzin may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Fusidic acid Fusidic acid may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Naringenin Naringenin may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Quercetin Quercetin may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Taurocholic acid Taurocholic acid may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Elacridar Elacridar may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Dovitinib Dovitinib may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Safinamide Safinamide may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Teriflunomide Teriflunomide may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Afatinib Afatinib may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Cannabidiol Cannabidiol may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Letermovir The excretion of Raloxifene can be decreased when combined with Letermovir.
Medical Cannabis The metabolism of Medical Cannabis can be decreased when combined with Raloxifene.
Nabiximols Nabiximols may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Fedratinib Fedratinib may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Caffeine Caffeine may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Pantoprazole Pantoprazole may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Gefitinib Gefitinib may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Progesterone Progesterone may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Lansoprazole Lansoprazole may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Buprenorphine Buprenorphine may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Dexamethasone Dexamethasone may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Simeprevir Simeprevir may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Vismodegib Vismodegib may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Cobicistat Cobicistat may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Daclatasvir Daclatasvir may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Rolapitant Rolapitant may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Glasdegib Glasdegib may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Voxilaprevir Voxilaprevir may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Gilteritinib Gilteritinib may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Ritonavir The metabolism of Raloxifene can be increased when combined with Ritonavir.
Saquinavir Saquinavir may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Rilpivirine Rilpivirine may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Ripretinib Ripretinib may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Fostemsavir Fostemsavir may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Pralsetinib Pralsetinib may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Isavuconazole Isavuconazole may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Clofazimine Clofazimine may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Dexamethasone acetate Dexamethasone acetate may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Avanafil Avanafil may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Tepotinib Tepotinib may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Tivozanib Tivozanib may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Belumosudil Belumosudil may decrease the excretion rate of Raloxifene which could result in a higher serum level.
Aripiprazole The metabolism of Aripiprazole can be decreased when combined with Raloxifene.
Aripiprazole lauroxil The metabolism of Aripiprazole lauroxil can be decreased when combined with Raloxifene.
Valsartan The excretion of Raloxifene can be decreased when combined with Valsartan.
Levocarnitine The excretion of Raloxifene can be decreased when combined with Levocarnitine.
Nystatin The excretion of Raloxifene can be decreased when combined with Nystatin.
Ouabain The excretion of Raloxifene can be decreased when combined with Ouabain.
Hyperforin The excretion of Raloxifene can be decreased when combined with Hyperforin.
Posizolid The excretion of Raloxifene can be decreased when combined with Posizolid.

Target Protein

Estrogen receptor ESR1
Estrogen receptor beta ESR2
Serpin B9 SERPINB9
Trefoil factor 1 TFF1

Referensi & Sumber

Synthesis reference: Massimo Ferrari, Fabrizio Zinetti, Paolo Belotti, "Process for preparing raloxifene hydrochloride." U.S. Patent US20070100147, issued May 03, 2007.
Artikel (PubMed)
  • PMID: 12940590
    Heringa M: Review on raloxifene: profile of a selective estrogen receptor modulator. Int J Clin Pharmacol Ther. 2003 Aug;41(8):331-45.
  • PMID: 10376571
    Cummings SR, Eckert S, Krueger KA, Grady D, Powles TJ, Cauley JA, Norton L, Nickelsen T, Bjarnason NH, Morrow M, Lippman ME, Black D, Glusman JE, Costa A, Jordan VC: The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. JAMA. 1999 Jun 16;281(23):2189-97.
  • PMID: 10418979
    Bryant HU, Glasebrook AL, Yang NN, Sato M: An estrogen receptor basis for raloxifene action in bone. J Steroid Biochem Mol Biol. 1999 Apr-Jun;69(1-6):37-44.
  • PMID: 9571395
    Balfour JA, Goa KL: Raloxifene. Drugs Aging. 1998 Apr;12(4):335-41; discussion 342.
  • PMID: 10983739
    Clemett D, Spencer CM: Raloxifene: a review of its use in postmenopausal osteoporosis. Drugs. 2000 Aug;60(2):379-411.
  • PMID: 18778124
    Moen MD, Keating GM: Raloxifene: a review of its use in the prevention of invasive breast cancer. Drugs. 2008;68(14):2059-83.
  • PMID: 10507743
    Scott JA, Da Camara CC, Early JE: Raloxifene: a selective estrogen receptor modulator. Am Fam Physician. 1999 Sep 15;60(4):1131-9.
  • PMID: 8703055
    Yang NN, Venugopalan M, Hardikar S, Glasebrook A: Identification of an estrogen response element activated by metabolites of 17beta-estradiol and raloxifene. Science. 1996 Aug 30;273(5279):1222-5.
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Textbook
  • ISBN: 978-0-7020-3471-8
    35. (2012). In Rang and Dale's Pharmacology (7th ed., pp. 438-439). Edinburgh: Elsevier/Churchill Livingstone.

Contoh Produk & Brand

Produk: 70 • International brands: 1
Produk
  • Act Raloxifene
    Tablet • 60 mg • Oral • Canada • Approved
  • Apo-raloxifene
    Tablet • 60 mg • Oral • Canada • Generic • Approved
  • Evista
    Tablet • 60 mg/1 • Oral • US • Approved
  • Evista
    Tablet • 60 mg/1 • Oral • US • Approved
  • Evista
    Tablet • 60 mg/1 • Oral • US • Approved
  • Evista
    Tablet • 60 mg/1 • Oral • US • Approved
  • Evista
    Tablet • 60 mg/1 • Oral • US • Approved
  • Evista
    Tablet • 60 mg • Oral • Canada • Approved
Menampilkan 8 dari 70 produk.
International Brands
  • Keoxifene

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