Professional Drug Information > Keoxifene hydrochloride

Raloxifene (Systemic)

VA CLASSIFICATION
Primary: HS900

Commonly used brand name(s): Evista.

Another commonly used name is
keoxifene hydrochloride ^{02}.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Estrogen receptor modulator, selective—

osteoporosis prophylactic—

Indications

Accepted

Osteoporosis, postmenopausal (prophylaxis)—Raloxifene is indicated for the prevention of osteoporosis in postmenopausal women. The effects on risk of fracture are not known. Also, use of estrogens as ovarian hormone therapy (OHT) with raloxifene has not been studied and their concurrent use is not recommended. Safety and efficacy of raloxifene have not been studied in men. Supplemental calcium and/or vitamin D should be added to the diet if daily intake is inadequate. ^{01}{05}

Osteoporosis, postmenopausal (treatment)—Raloxifene is indicated for the treatment of osteoporosis in postmenopausal women. The effects on risk of fracture are not known. Also, use of estrogens as ovarian hormone therapy (OHT) with raloxifene has not been studied and their concurrent use is not recommended. Safety and efficacy of raloxifene have not been studied in men. Supplemental calcium and/or vitamin D should be added to the diet if daily intake is inadequate.^{01}{05}

Unaccepted
Raloxifene is not effective in reducing the hot flashes or flushes of estrogen deficiency, such as those occurring during the menopause ^{01}.

There is no indication for premenopausal use in women. Safety has not been established and its use is not recommended.^{06}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Note: Raloxifene shows high interindividual variability as seen by an approximate 30% coefficient of variation in most pharmacokinetic parameters ^{01}.


Chemical group—
    Nonsteroidal, benzothiophene derivative ^{01}.
Molecular weight—
    Raloxifene hydrochloride: 510.06 ^{02}

Mechanism of action/Effect:

Selective estrogen receptor modulator—Estrogen receptors regulate gene expression by ligand-, tissue-, or gene-specific pathways or a combination of these. Raloxifene acts as a ligand for the estrogen receptor and, depending on the tissue's subtype of estrogen receptors or available cellular proteins, can cause an estrogenic agonist or antagonist reaction or may not cause any apparent change in a tissue's gene expression. ^{01}

Osteoporosis prophylactic—Raloxifene has estrogen-like effects on bone and increases bone mineral density. It reduces resorption of bone and decreases overall bone turnover, as shown by radiocalcium kinetics studies and by bone turnover markers in the serum and urine. Postmenopausal females who took daily doses of 60 mg raloxifene and 400 to 600 mg of calcium showed a statistically significant increase in bone mineral density (BMD) in the hip, spine, and total body at 12 months that was maintained at 24 months as measured by dual-energy radiography (DXA) compared with women taking a placebo and similar calcium doses. The extent of bone density increase is less with use of raloxifene than with daily doses of 0.625 mg conjugated estrogens. The placebo/calcium females lost 1% of BMD over 24 months. The effects of raloxifene on the forearm have been inconsistent between studies. It is not established whether raloxifene's effect of increasing BMD results in a reduced number of skeletal fractures. ^{01}


Other actions/effects:

Raloxifene has estrogen-like effects for lowering serum total and low-density lipoprotein (LDL) cholesterol, but it does not affect serum concentrations of total high-density lipoprotein (HDL) cholesterol or triglycerides. Raloxifene has not been associated with other estrogen-like effects, such as endometrial proliferation, breast pain, or breast enlargement. ^{01}

Absorption:

Raloxifene is rapidly absorbed after oral administration. Absolute raloxifene bioavailability is 2%, approximately 60% of an oral dose is absorbed, and enterohepatic cycling occurs. Although not considered clinically significant, absorption may increase when raloxifene is given with a high-fat meal, as shown by a 28% increase in peak serum concentration (C _max) and a 16% increase in the area under the plasma concentration–time curve (AUC). ^{01}

Distribution:

For 30 to 150 mg single doses of raloxifene, the apparent volume of distribution (Vol _D) is 2348 L per kg (L/kg) and is not dose-dependent ^{01}.

Protein binding:

Raloxifene and its glucuronide conjugates are highly bound to plasma proteins albumin and alpha-1-acid glycoprotein, but not to sex hormone–binding globulin ^{01}.

Biotransformation:

First-pass metabolism to the glucuronide conjugate is extensive; 1% unconjugated raloxifene appears in the plasma as a result of interconversion between conjugated and unconjugated forms ^{01}.

Half-life:

Elimination—32.5 hours (range 15.8 to 86.6) with multiple dosing ^{01}.

Elimination:
    Primarily fecal, 0.2% renal (unchanged) and 6% renal (glucuronide metabolite) ^{01}.


Precautions to Consider

Carcinogenicity/Tumorigenicity

Raloxifene did not increase the risk of endometrial or breast cancer in patients taking raloxifene for up to 58 months when compared with patients taking placebos ^{07}.

In a 21-month study, there was an increased incidence of benign tumors of granulosal, thecal, or epithelial cell origin in female mice given raloxifene doses of 9 to 242 mg per kg of body weight  (mg/kg) (corresponding to 0.3 to 34 times the systemic exposure of that achieved in postmenopausal women taking a 60-mg daily dose). Malignant tumors of granulosal/thecal origin occurred at the higher doses. There was an increased incidence of testicular interstitial cell tumors, prostatic adenomas, and adenocarcinomas in male mice given 41 mg/kg or 210 mg/kg of raloxifene (corresponding to 4.7 to 24 times the systemic exposure in humans); the higher dose showed incidence of prostatic leiomyoblastomas. ^{01}

In a 2-year study, there was an increased incidence of benign granulosal or thecal cell ovarian tumors in nonovariectomized female rats of reproductive age given doses of 279 mg/kg of raloxifene (corresponding to approximately 400 times the systemic exposure of that achieved in humans). ^{01}

The clinical relevance of the animal data to humans is not known ^{01}.

Mutagenicity

Raloxifene was not found to be mutagenic in the following tests or assays: Ames test, unscheduled DNA synthesis assay in rat hepatocytes, mouse lymphoma assay for mammalian cell mutation, chromosomal aberration assay in Chinese hamster ovary cells, in vivo sister chromatid exchanges assay in Chinese hamsters, and in vivo micronucleus test in mice ^{01}.

Pregnancy/Reproduction

Reproduction studies in rats given raloxifene are consistent with estrogen receptor activity ^{01}.
Fertility—
In rats given at least 5 mg/kg a day of raloxifene (corresponding to 0.8 times or more the human dose based on mg per squared meter [mg/m ²] of body surface area), no pregnancies occurred. In male rats, 100 mg/kg of raloxifene a day for 2 weeks (corresponding to 16 times the human dose based on body surface area) did not affect sperm production or quality or reproductive performance. In female rats, 0.1 to 10 mg/kg a day of raloxifene (corresponding to 0.02 to 1.5 times the human dose based on body surface area) reversibly disrupted estrous cycles, inhibited ovulation, and delayed and disrupted embryo implantation, resulting in prolonged gestation and a small litter size. ^{01}

Pregnancy—
Raloxifene is not recommended during pregnancy.^{01}{08}

Studies in animals have shown that raloxifene decreased neonatal survival, delayed and disrupted parturition, and caused fetal abortion, ventricular septal defects, hydrocephaly, wavy ribs, kidney cavitation, lymphoid compartment size reduction, growth reduction, and pituitary hormone content changes. Although no ovarian or vaginal pathology resulted, effects in adult offspring included uterine hypoplasia and reduced fertility. ^{01}

FDA Pregnancy Category X ^{01}.

Breast-feeding

It is not known whether raloxifene is distributed into breast milk. However, use of raloxifene during breast-feeding is not recommended. ^{01}

Geriatrics


Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of raloxifene in the elderly ^{01}.

Surgical

Raloxifene should be discontinued for at least 72 hours prior to and during prolonged bed rest or immobilization, such as during postsurgical recovery, because of increased risk of venous thromboembolic events. The medication should be resumed only after the patient is fully ambulatory ^{01}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Cholestyramine    (reduces the absorption and enterohepatic recycling of raloxifene by 60%; concomitant use is not recommended ^{01})


» Estrogens, systemic    (raloxifene is not recommended for use with estrogens ^{01})


Highly protein-bound drugs, such as:
Clofibrate
Diazepam
Diazoxide
Ibuprofen
Indomethacin
Lidocaine
Naproxen    (caution is recommended in using concurrently since raloxifene is highly bound to plasma proteins^{01}{06})


» Warfarin    (raloxifene alone does not affect the protein-binding of warfarin, but concurrent use has decreased the prothrombin time by 10% in single-dose studies; when given concurrently, prothrombin time should be monitored and the dose of warfarin may need an initial adjustment ^{01})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Albumin concentration, serum and
Calcium concentration, total, serum and
Phosphate concentration, serum and
Protein concentration, total, serum    (slightly decreased ^{01})


Cholesterol concentrations, total, serum and
Lipoproteins concentrations, low-density (LDL), serum    (compared with the patients' baselines, serum total cholesterol concentrations decreased 5% in 24-month data and 6.6% in a 6-month study; LDL decreased 8% in the 24-month data and 10.9% in a 6-month study ^{01})


Corticosteroid-binding globulin and
Sex steroid-binding globulin and
Thyroid-binding globulin    (may modestly increase serum protein–binding globulins without increasing the free fraction of corresponding hormones ^{01})


Fibrinogen concentration, serum and
Lipoprotein (a) concentration    (in a 6-month study, fibrinogen decreased by a median of 12.2% from patients' baselines and lipoprotein (a) decreased by a median of 4.1% from patients' baselines ^{01})


Lipoproteins concentrations, high-density-3 (HDL-3), serum    (serum HDL-3 concentrations decreased by a median of 2.5% compared with the patients' baselines in a 6-month study; no effect occurred for serum concentrations of triglycerides and serum total high-density lipoprotein [HDL] cholesterol^{01})


Platelet count    (slightly decreased^{01})


Triglycerides, serum^{06}    (values may increase with raloxifene treatment in some women with a history of marked hypertriglyceridemia (>5.6 mmol/L or >500 mg/dL) in response to treatment with oral estrogen plus progestin^{06})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Thromboembolic disorders, active or history of, including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis    (may be exacerbated ^{01})


Risk-benefit should be considered when the following medical problems exist
» Congestive heart failure or
» Neoplasia or
» Other conditions of increased thromboembolic risk    (underlying thromboembolic disorders may be exacerbated ^{01})


Hepatic function impairment    (may increase plasma concentrations of raloxifene. In patients with cirrhosis classified as Child-Pugh Class A, plasma concentrations of raloxifene were 2.5 times greater than expected, correlating with their total bilirubin concentrations; safety and efficacy in patients with severe hepatic function impairment have not been evaluated ^{01})


Sensitivity to raloxifene ^{01}

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Physical examination    (every year or more frequently as determined by physician, with special attention given to breast and pelvic organs^{01})


Triglycerides, serum    (should be monitored during raloxifene treatment; limited clinical data suggests that some women with a history of marked hypertriglyceridemia (>5.6 mmol/L or >500 mg/dL) in response to treatment with oral estrogen plus progestin may develop increased levels of triglycerides when treated with raloxifene^{06})




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Chest pain —4% ^{01}
    
cystitis or urinary tract infection (bloody or cloudy urine; difficult, burning, or painful urination; frequent urge to urinate)—3.3 to 4% ^{01}
    
endometrial disorder ^{01}— 3.1%
    
fever —3.1%
    
infection of the body as a whole
influenza-like syndrome
sinusitis
or pharyngitis (body aches or pain; congestion in throat; cough; dryness or soreness of throat ; fever; loss of voice; runny nose)—7 to 15%
    
leg cramping ^{01}— 5.9%
    
peripheral edema (swelling of hands, ankles, or feet)— 3.3%^{01}
    
skin rash —5.5%
    
vaginitis (vaginal itching)— 4.3%

Incidence less frequent
    
Gastroenteritis (abdominal pain, severe; diarrhea; loss of appetite; nausea; weakness)—2.6% ^{01}
    
laryngitis ( cough; dryness or soreness of throat ; hoarseness; trouble in swallowing)—2.2%
    
migraine headaches —2.4%
    
pneumonia (aching body pains; congestion in lungs; difficulty in breathing; fever; sore throat)—2.6%

Incidence rare
    
Retinal vein occlusion (decreased vision or other changes in vision )^{07}— Observed during clinical practice
    
thromboembolism or thrombus formation ^{01} (coughing blood; headache or migraine headache; loss of or change in speech, coordination, or vision; pain or numbness in chest, arm, or leg; shortness of breath, unexplained)



Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
    
Arthralgia
arthritis
or myalgia (joint or muscle pain; swollen joints)—4 to 10.7%
    
gastrointestinal disturbances (nausea; passing of gas; upset stomach; vomiting)
    
hot flashes (feelings of warmth; sudden sweating)—24.6%, especially common during the first 6 months of treatment ^{01}
    
insomnia (trouble in sleeping)—5.5%
    
leukorrhea (increased white vaginal discharge)—3.3%
    
mental depression —6.4%
    
sweating —3.1%
    
weight gain, unexplained —8.8%





Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Raloxifene (Systemic) .
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to raloxifene or allergies to product"s components

Pregnancy—Not recommended for use during pregnancy. Approved for use in postmenopausal women only. Raloxifene has been associated with fetal abnormalities in animals





Breast-feeding—Not recommended for use during breast-feeding



Surgical
Discontinue use 72 hours before surgery, until patient is fully mobilized
Other medications, especially cholestyramine; estrogens (systemic); or warfarin
Other medical problems, especially congestive heart failure, neoplasia, or other conditions of increased thromboembolic risk; or thromboembolic disorders, active or history of (deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis)

Proper use of this medication
» Reading patient directions that come with medication carefully before using

» Not taking more or less of medication than your physician ordered

» Proper dosing
Missed dose: Skipping missed dose and resuming regular dosing schedule; not doubling dose

» Proper storage

Precautions while using this medication
» Regular visits to physician, keeping appointments even if feeling well

» Discussing continuing medication with physician before having surgery or periods of immobility, including the inactivity of long trips, because of potential increased risk of thromboembolism

» Stopping medication immediately and checking with physician if pregnancy is suspected; present use is for postmenopausal women only

» Reporting occurrences of vaginal bleeding, breast pain, or swelling of hands or feet

» Importance of weight-bearing exercise and calcium and vitamin D supplements for prevention of osteoporosis


Side/adverse effects
Signs of potential side effects, especially chest pain; cystitis or urinary tract infection; endometrial disorder; fever; infection of the body as a whole, influenza-like syndrome, sinusitis, or pharyngitis; leg cramping; peripheral edema; skin rash; vaginitis; gastroenteritis; laryngitis; migraine headaches; pneumonia; retinal vein occlusion; thromboembolism or thrombus formation


General Dosing Information
Because of increased risk of venous thromboembolic events, raloxifene should be discontinued for at least 72 hours prior to surgery and during prolonged bed rest or immobilization, such as in postsurgical recovery or during a long trip when mobility is not possible. To prevent thromboembolic events while taking raloxifene, the patient should understand the importance of mobility during a long trip. The medication may be resumed only after the patient is fully ambulatory. ^{01}

If a pregnancy is possible and is suspected, patient should stop using the medication and contact physician immediately ^{01}. Present use is for postmenopausal women only ^{01}.

Since raloxifene does not act like an estrogen to stimulate the uterus or breast, patients should report any occurrences of vaginal bleeding, breast pain or enlargement, or swelling of hands or feet while on raloxifene ^{01}.

Exercise can be recommended to all patients to prevent development of osteoporosis. Calcium supplementation should be considered as an additional preventive measure if patient's dietary intake is inadequate. ^{01}

Diet/Nutrition
Raloxifene may be given without regard to meals ^{01}.


Oral Dosage Forms

RALOXIFENE HYDROCHLORIDE TABLETS

Note: Formerly known as keoxifene hydrochloride ^{02}.


Usual adult dose
Osteoporosis prophylactic
Oral, 60 mg once a day, without regard to meals ^{01}.

Osteoporosis treatment
Oral, 60 mg once a day, without regard to meals ^{05}.


Usual adult prescribing limits
Efficacy beyond 2 years for prevention of osteoporosis has not been determined ^{{01} {03}}.

Usual geriatric dose
See Usual adult dose .

Strength(s) usually available
U.S.—


60 mg (Rx) [Evista (anhydrous lactose) (lactose monohydrate) (polyethylene glycol) (povidone) (propylene glycol)^{01}]

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), preferably between 20 and 25 °C (68 and 77 °F), unless otherwise specified by manufacturer ^{01}.


Caution:
The previously available product E-Vista, the brand name for hydroxyzine hydrochloride, should not be confused with Evista, raloxifene hydrochloride. They are different products with completely different indications. ^{04}

Note: Include patient information when dispensing ^{01}.

Developed: 3/26/1998
Revised: 02/08/2002

References

1. Raloxifene package insert (Lilly—US), Rev 12/97, Rec 12/97.
   

2. Canada JR, editor. USP dictionary of USAN and international drug names 1998. Rockville, MD: The United States Pharmacopeial Convention, Inc; 1997. p. 627.
   

3. Manufacturer comments, 2/18/98.
   

4. Personal communication, 1/98.
   

5. Raloxifene package insert (Lilly—US), Rev 9/99, Rec 11/99.
   

6. Product Information: Evista®, raloxifene hydrochloride. Eli Lilly and Company, Indianapolis, IN (PI revised 10/2000) PI reviewed 8/2001.
   

7. Product Information: Evista®, raloxifene hydrochloride. Eli Lilly and Company, Indianapolis, IN (PI revised 08/2001) PI reviewed 9/2001.
   

8. USP Expert Committee review comment, 11/2001.
   

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