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

7.2 Warfarin

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

7.3 Other Highly Protein-Bound Drugs

Raloxifene HCl should be used with caution with certain other highly protein-bound drugs such as diazepam, diazoxide and lidocaine. Although not examined, raloxifene HCl 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 HCl with systemic estrogens has not been established and its use is not recommended.

7.5 Other Concomitant Medications

Raloxifene HCl can be concomitantly administered with ampicillin, amoxicillin, antacids, corticosteroids and digoxin [see Clinical Pharmacology (12.3)] .

The concomitant use of raloxifene HCl and lipid-lowering agents has not been studied.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category X. Raloxifene HCl should not be used in women who are or may become pregnant [see Contraindications (4.2)] .

8.3 Nursing Mothers

Raloxifene HCl should not be used by lactating women [see Contraindications (4.2)] . It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when raloxifene is administered to a nursing woman.

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

To report SUSPECTED ADVERSE REACTIONS, contact AvKARE, Inc. at 1-855-361-3993; email drugsafety@avkare.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

10 OVERDOSAGE

In an 8-week study of 63 postmenopausal women, a dose of raloxifene HCl 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 and included leg cramps and dizziness.

Two 18-month-old children each ingested raloxifene 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/m 2) or in monkeys at 1000 mg/kg (80 times the AUC in humans).

11 DESCRIPTION

Raloxifene HCl, USP 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
(click image for full-size original)

The chemical designation is methanone, [6-hydroxy-2-(4-hydroxyphenyl)benzo[ b ]thien-3-yl]-[4-[2-(1-piperidinyl)ethoxy]phenyl]-, hydrochloride. Raloxifene HCl, USP has the molecular formula C 28 H 27 NO 4 S•HCl, which corresponds to a molecular weight of 510.05. Raloxifene HCl, USP is an off-white to pale-yellow solid that is very slightly soluble in water.

Raloxifene HCl, USP is supplied in a tablet dosage form for oral administration. Each raloxifene HCl tablet, USP contains 60 mg of raloxifene HCl, USP, which is the molar equivalent of 55.71 mg of free base. Inactive ingredients include anhydrous lactose, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, povidone, silicon dioxide and titanium dioxide.

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 promotors.

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 HCl lacks estrogen-like effects on the uterus and breast tissue.

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