Raloxifene Hydrochloride (Page 3 of 9)

6.2 Postmarketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.Adverse reactions reported very rarely since market introduction include retinal vein occlusion, stroke, and death associated with venous thromboembolism (VTE).

7 DRUG INTERACTIONS

7.1 Cholestyramine

Concomitant administration of cholestyramine with raloxifene hydrochloride is not recommended. Although not specifically studied, it is anticipated that other anion exchange resins would have a similar effect. Raloxifene hydrochloride should not be co-administered with other anion exchange resins [see Clinical Pharmacology (12.3)].

7.2 Warfarin

If raloxifene hydrochloride is given concomitantly with warfarin or other warfarin derivatives, prothrombin time should be monitored more closely when starting or stopping therapy with raloxifene hydrochloride [see Clinical Pharmacology (12.3)].

7.3 Other Highly Protein-Bound Drugs

Raloxifene hydrochloride should be used with caution with certain other highly protein-bound drugs such as diazepam, diazoxide, and lidocaine. Although not examined, raloxifene hydrochloride might affect the protein binding of other drugs. Raloxifene is more than 95% bound to plasma proteins [see Clinical Pharmacology (12.3)].

7.4 Systemic Estrogens

The safety of concomitant use of raloxifene hydrochloride with systemic estrogens has not been established and its use is not recommended.

7.5 Other Concomitant Medications

Raloxifene hydrochloride can be concomitantly administered with ampicillin, amoxicillin, antacids, corticosteroids, and digoxin [see Clinical Pharmacology (12.3)].
The concomitant use of raloxifene hydrochloride and lipid-lowering agents has not been studied.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Raloxifene hydrochloride is contraindicated for use in pregnant women, and is not indicated for use in females of reproductive potential. Based on mechanism of action, raloxifene hydrochloride may block the important functions that estrogen has during all stages of pregnancy [see Clinical Pharmacology (12.1)]. Limited data with raloxifene hydrochloride use in pregnant women are insufficient to inform any drug associated risks for births defects or miscarriage.

In rabbits and rats dosed during organogenesis or during gestation and lactation, raloxifene hydrochloride produced multiple adverse reproductive and developmental effects, including abortion; fetal anomalies; and delayed or disrupted parturition leading to maternal and neonatal mortality, at doses less than or similar to the maximum recommended human dose

(based on human body surface area comparison).

Data

Animal Data

In the developmental and reproductive toxicity studies conducted with raloxifene hydrochloride, numerous adverse effects were observed in multiple animal species. In rabbits dosed during organogenesis, abortion and a low rate of fetal heart anomalies (ventricular septal defects) occurred at doses ≥0.1 mg/kg (≥0.04 times the human dose based on surface area, mg/m2). In rats dosed during organogenesis, retardation of fetal growth and developmental abnormalities (wavy ribs, kidney cavitation) occurred at doses ≥1 mg/kg (≥0.2 times the human dose based on surface area, mg/m2). Treatment of rats during gestation and lactation with doses of 0.1 to 10 mg/kg (0.02 to 1.6 times the human dose based on surface area, mg/m2) 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, the disruption of parturition resulted in maternal and progeny morbidity and death. Effects in adult offspring (4 months of age) included uterine hypoplasia and reduced fertility; however, no ovarian or vaginal pathology was observed.

8.2 Lactation

Risk Summary

Raloxifene hydrochloride is not indicated for use in females of reproductive potential. There is no information on the presence of raloxifene in human milk, the effects on the breastfed child, or the effects on milk production. However, based on mechanism of action, raloxifene hydrochloride may block the important functions that estrogen has in mammary tissue during lactation [see Clinical Pharmacology (12.1)].

8.4 Pediatric Use


Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use


Of the total number of patients in placebo-controlled clinical studies of raloxifene hydrochloride, 61% were 65 and over, while 15.5% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Based on clinical trials, there is no need for dose adjustment for geriatric patients [see Clinical Pharmacology (12.3)].

8.6 Renal Impairment


Raloxifene hydrochloride should be used with caution in patients with moderate or severe renal impairment [see Warnings and Precautions (5.8) and Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment


Raloxifene hydrochloride should be used with caution in patients with hepatic impairment [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)].

10 OVERDOSAGE


In an 8-week study of 63 postmenopausal women, a dose of raloxifene hydrochloride 600 mg/day was safely tolerated. In clinical trials, no raloxifene overdose has been reported.
In postmarketing spontaneous reports, raloxifene overdose has been reported very rarely (less than 1 out of 10,000 [<0.01%] patients treated). The highest overdose has been approximately 1.5 grams. No fatalities associated with raloxifene overdose have been reported. Adverse reactions were reported in approximately half of the adults who took ≥180 mg raloxifene hydrochloride and included leg cramps and dizziness.
Two 18-month-old children each ingested raloxifene hydrochloride 180 mg. In these two children, symptoms reported included ataxia, dizziness, vomiting, rash, diarrhea, tremor, and flushing, as well as elevation in alkaline phosphatase.
There is no specific antidote for raloxifene.
No mortality was seen after a single oral dose in rats or mice at 5000 mg/kg (810 times the human dose for rats and 405 times the human dose for mice based on surface area, mg/m2) or in monkeys at 1000 mg/kg (80 times the AUC in humans).

11 DESCRIPTION

Raloxifene hydrochloride is an estrogen agonist/antagonist, commonly referred to as a selective estrogen receptor modulator (SERM) that belongs to the benzothiophene class of compounds. The chemical structure is:

Chemical Structure

The chemical designation is methanone, [6-hydroxy-2-(4-hydroxyphenyl)benzo[b ]thien-3-yl]-[4-[2-(1-piperidinyl)ethoxy]phenyl]-, hydrochloride. Raloxifene hydrochloride has the molecular formula C28 H27 NO4 S•HCl, which corresponds to a molecular weight of 510.05. Raloxifene hydrochloride USP is almost white to pale yellow powder that is very slightly soluble in water.
Raloxifene hydrochloride USP is supplied in a tablet dosage form for oral administration. Each raloxifene hydrochloride tablet, USP contains 60 mg of raloxifene hydrochloride USP, which is the molar equivalent of 55.71 mg of free base. Inactive ingredients include citric acid monohydrate, crospovidone, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, povidone, and titanium dioxide.USP dissolution test pending.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Raloxifene is an estrogen agonist/antagonist, commonly referred to as a selective estrogen receptor modulator (SERM). The biological actions of raloxifene are largely mediated through binding to estrogen receptors. This binding results in activation of estrogenic pathways in some tissues (agonism) and blockade of estrogenic pathways in others (antagonism). The agonistic or antagonistic action of raloxifene depends on the extent of recruitment of coactivators and corepressors to estrogen receptor (ER) target gene promoters.Raloxifene appears to act as an estrogen agonist in bone. It decreases bone resorption and bone turnover, increases bone mineral density (BMD) and decreases fracture incidence. Preclinical data demonstrate that raloxifene is an estrogen antagonist in uterine and breast tissues. These results are consistent with findings in clinical trials, which suggest that raloxifene hydrochloride lacks estrogen-like effects on the uterus and breast tissue.

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