Evista: Indications, Dosage, Precautions, Adverse Effects
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Evista - Product Information

Manufacture: Eli Lilly and Company
Country: United States
Condition: Breast Cancer, Prevention, Osteoporosis, Prevention of Osteoporosis
Class: Hormones/antineoplastics, Selective estrogen receptor modulators
Form: Tablets
Ingredients: Raloxifene, hydrochloride, lactose

Raloxifene hydrochloride

Summary Product Information

Route of
Administration
Dosage Form / Strength Clinically Relevant Nonmedicinal
Ingredients*
Oral Tablet / 60 mg Lactose

* For a complete listing see Dosage Forms, Composition and Packaging section.

Indications and Clinical Use

EVISTA (raloxifene hydrochloride) is indicated for:

  • The treatment of osteoporosis in postmenopausal women.
  • The prevention of osteoporosis in postmenopausal women.

Women with diagnosed postmenopausal osteoporosis should be considered for pharmacologic therapy, in conjunction with education and appropriate lifestyle modifications.

No single clinical finding or test result can quantify risk of postmenopausal osteoporosis with certainty. However, clinical assessment can help to identify women at increased risk. Widely accepted risk factors include Caucasian or Asian descent, slender body build, early estrogen deficiency, smoking, alcohol consumption, low calcium diet, sedentary lifestyle, personal history of any fracture after age 40 and family history of osteoporosis. The greater the number of clinical risk factors, the greater the probability of developing postmenopausal osteoporosis. These risk factors may be considered in the decision to use EVISTA for prevention of postmenopausal osteoporosis.

For either osteoporosis treatment or prevention, supplemental calcium and/or vitamin D should be added to the diet if daily intake is inadequate.

Geriatrics

Safety and efficacy in older and younger postmenopausal women in the osteoporosis treatment trial appeared to be comparable (see WARNINGS AND PRECAUTIONS).

Pediatrics

The safety and efficacy of EVISTA have not been studied in pediatric populations. EVISTA should not be used in pediatric patients (see WARNINGS AND PRECAUTIONS).

Contraindications

  • Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see DOSAGE FORMS, COMPOSITION and PACKAGING section of the Product Monograph.
  • Women of childbearing potential. EVISTA therapy during pregnancy may be associated with an increased risk of congenital defects in the fetus.
  • Women with active or past history of venous thromboembolic events, including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis.

Warnings and Precautions

General

Concurrent Estrogen Therapy

Safety information regarding the concurrent use of EVISTA and systemic hormone therapy (estrogen with or without progestin) is limited and therefore concomitant use of EVISTA with systemic estrogens is not recommended.

Endometrium

Unexplained uterine bleeding should be investigated as clinically indicated.

Breast

Any unexplained breast abnormality occurring during EVISTA therapy should be investigated.

Other Osteoporosis Treatment and Prevention Measures

Patients should be instructed to take supplemental calcium and/or 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.

Cardiovascular

Vasodilatation

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

Venous Thromboembolic Events (VTE)

The risk-benefit balance should be considered in women at risk of thromboembolic disease for any reason. EVISTA should be discontinued at least 72 hours prior to and during prolonged immobilization (e.g. post-surgical recovery, prolonged bed rest) and EVISTA therapy should be resumed only after the patient is fully ambulatory. In clinical trials, EVISTA-treated women had an increased risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism). VTE events reported in the osteoporosis treatment and prevention trials were infrequent (1.44, 3.32 and 3.63 events per 1,000 person-years for placebo, raloxifene 60 mg/day and raloxifene 120 mg/day, respectively). The incidence rate of VTE reported from the Raloxifene Use for The Heart (RUTH) study was 2.70 and 3.88 events per 1,000 person-years for placebo and raloxifene 60mg/day, respectively.

Other venous thromboembolic events could also occur. A less serious event, superficial thrombophlebitis, also has been reported more frequently with EVISTA. The greatest risk for deep vein thrombosis and pulmonary embolism occurs during the first 4 months of treatment, and the magnitude of risk is similar to that associated with use of hormone replacement therapy.

Stroke

The risk-benefit balance of EVISTA in postmenopausal women with a history of stroke or other significant stroke risk factors, such as transient ischemic attack or atrial fibrillation, should be considered when prescribing EVISTA. The RUTH trial investigated the effects of EVISTA in postmenopausal women (average age = 67 years) with known heart disease or at high risk for a coronary event. The RUTH trial demonstrated an increase in mortality due to stroke for EVISTA compared to placebo. The incidence of stroke mortality was 1.5 per 1,000 women per year for placebo versus 2.2 per 1,000 women per year for EVISTA (p=0.0499). The incidence of stroke, myocardial infarction, hospitalized acute coronary syndrome, cardiovascular mortality, or overall mortality (all causes combined) was comparable for EVISTA and placebo.

Endocrine and Metabolism

Estrogen-Induced Hypertriglyceridemia

Patients with a history of estrogen-induced hypertriglyceridemia can experience an increase in triglyceride levels during treatment with EVISTA. Therefore, triglyceride levels should be followed in such patients and the risk-benefit balance of EVISTA treatment in such cases should be reassessed (see CLINICAL TRIALS, Effects on Lipid Metabolism).

Hepatic Dysfunction

Raloxifene was studied as a single dose in patients with Child-Pugh Class A cirrhosis with total serum bilirubin ranging from 0.6 to 2.0 mg/dL (10.3 to 34.2 mmol/L). Plasma raloxifene concentrations were approximately 2.5 times higher than in controls and correlated with total bilirubin concentrations. Safety and efficacy have not been established in patients with moderate or severe hepatic insufficiency.

Lipid Metabolism

EVISTA lowers serum total and LDL cholesterol by 6% to 11%, but does not affect serum concentrations of total HDL cholesterol or triglycerides. HDL-2 cholesterol subfraction is increased by EVISTA. These effects should be taken into account in therapeutic decisions for patients who may require therapy for hyperlipidemia. Concurrent use of EVISTA and lipid lowering agents has not been studied.

Peri-Operative Considerations

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 EVISTA therapy should be resumed only after the patient is fully ambulatory because of the increased risk of venous thromboembolic events.

Psychiatric

Cognition and Affect

Any change in cognition and affect during EVISTA therapy should be investigated as clinically indicated.

Special Populations

Pregnancy

EVISTA should not be used in women who are or may become pregnant (see CONTRAINDICATIONS).

Nursing Women

EVISTA should not be used by lactating women (see CONTRAINDICATIONS). It is not known whether raloxifene is excreted in human milk.

Premenopausal Use

Safety of EVISTA in premenopausal women has not been established and its use is not indicated.

Pediatrics (< 18 years of age)

EVISTA should not be used in pediatric patients.

Geriatrics

In the osteoporosis treatment trial of 7705 postmenopausal women, 4621 women were considered geriatric (greater than 65 years old). Of these, 845 women were greater than 75 years old. Safety and efficacy in older and younger postmenopausal women in the osteoporosis treatment trial appeared to be comparable.

Use in Men

There is no indication for use of EVISTA in men.

Monitoring and Laboratory Tests

If EVISTA is given concomitantly with warfarin or other coumarin derivatives, the prothrombin time should be monitored when starting or stopping therapy with EVISTA (see DRUG INTERACTIONS section).

Adverse Reactions

The safety of raloxifene has been established in Phase 2 and Phase 3 placebo-controlled, estrogen-controlled, and HRT-controlled studies. Twelve studies comprised the primary safety database for the prevention indication, and the safety of raloxifene in the treatment of osteoporosis was assessed in a large, multinational, placebo-controlled trial. In the osteoporosis prevention trials, the duration of treatment ranged from 2 to 30 months and 2036 women were exposed to raloxifene. In the osteoporosis treatment trial, 5129 women were exposed to raloxifene (2557 received 60 mg/day and 2572 received 120 mg/day) for 36 months. The osteoporosis treatment trial was extended by 12 months to a 4th year during which patients were permitted the concomitant use of bisphosphonates, fluorides and calcitonins.

Adverse Drug Reaction Overview

The most commonly observed treatment-emergent adverse events associated with the use of EVISTA in double-blind, placebo-controlled, osteoporosis treatment and prevention clinical trials were vasodilatation and leg cramps.

Vasodilatation events (hot flashes or flushes) were common in placebo-treated women, and the frequency was modestly increased in EVISTA-treated women. The first occurrence of this event was most commonly reported during the first 6 months of treatment and infrequently was reported de novo after that time.

Venous thromboembolism (VTE) and pulmonary embolism are uncommon but serious adverse events associated with raloxifene therapy. The greatest risk for deep vein thrombosis and pulmonary embolism occurs during the first 4 months of treatment.

An increase in mortality due to stroke for EVISTA compared to placebo was demonstrated in the RUTH trial which investigated the effects of EVISTA in postmenopausal women (average age = 67 years) with known heart disease or at high risk for a coronary event, (see WARNINGS AND PRECAUTIONS).

The majority of adverse events occurring during clinical trials were mild and did not require discontinuation of therapy. Discontinuation of therapy due to any clinical adverse experience occurred in 10.9% of 2557 EVISTA-treated women and 8.8% of 2576 placebo-treated women in the osteoporosis treatment trial, and in 11.4% of 581 EVISTA-treated women and 12.2% of 584 placebo-treated women in the osteoporosis prevention trials.

Clinical Trial Adverse Drug Reactions

   Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Adverse Events in Placebo-Controlled Clinical Trials

Table 1 lists adverse events occurring in either the osteoporosis treatment (up to 3 years) or prevention placebo-controlled clinical trials with EVISTA at a frequency ≥1.0% in EVISTAtreated women and at a significantly greater incidence than in placebo-treated women.

Table 1: Adverse Events Occurring in Placebo-Controlled Osteoporosis Clinical Trials (up to 36 months) at a Frequency ≥1.0% in EVISTA-Treated (60 mg once daily) Women and at a Significantly Greater Incidence Than in Placebo-Treated Women
Body System Osteoporosis Treatment Osteoporosis Prevention
EVISTA
N=2557
%
Placebo
N=2576
%
EVISTA
N=581
%
Placebo
N=584
%
Body as a Whole
   Flu Syndrome 13.5* 11.4 14.6 13.5
   Leg Cramps 7.0* 3.7 5.9* 1.9
Cardiovascular
   Vasodilatation 9.7* 6.4 24.6 18.3
Metabolic and Nutritional
   Diabetes Mellitus 1.2* 0.5 A A

A    Placebo incidence greater than or equal to EVISTA incidence.

*    Significantly (p<0.05) different from placebo.

Glycemic Control

Diabetes mellitus was reported more frequently as an adverse event among EVISTA-treated patients (1.2%) compared with placebo-treated patients (0.5%) in the osteoporosis treatment trial. However, there were no differences between the raloxifene and placebo groups in either fasting glucose or hemoglobin A1c (objective measures of glycemic control) in the osteoporosis treatment trial.

Peripheral Edema in the Treatment and Prevention Trials

A significant dose trend was observed for peripheral edema in the treatment and prevention studies. Cumulative frequency of the event at the 60 mg/day dose was 5.2% for EVISTA-treated patients versus 4.4% for placebo treated patients in the treatment study, and 3.1% for EVISTAtreated patients versus 1.9% for placebo-treated patients in the prevention studies, which was not a statistically significant difference.

48-Month Osteoporosis Treatment Trial Adverse Events

The osteoporosis treatment trial was extended by 12 months to a 4th year during which patients were permitted the concomitant use of bisphosphonates, fluorides and calcitonins. The incidence trend of treatment-emergent adverse events occurring at a frequency ≥1.0% in EVISTA-treated women, and at a significantly greater incidence than in placebo-treated women after year 4 of the osteoporosis treatment trial, were generally similar to the 1 to 3 year results presented in Table 1.

At 48 months in the osteoporosis treatment trial, vasodilatation was reported in 10.6% of patients on EVISTA versus 7.1% of placebo patients (p<0.001), and leg cramps were reported in 9.2% of patients on EVISTA versus 6.0% of placebo patients (p<0.001).

At 48 months in the same osteoporosis treatment trial, flu syndrome (16.2% of EVISTA treated patients versus 14.0% of placebo patients), uterine disorder (endometrial cavity fluid in 12.7% of EVISTA treated patients versus 9.6% of placebo patients), diabetes mellitus (1.5% of EVISTA treated patients versus 0.7% of placebo patients), and peripheral edema (7.1% of EVISTA treated patients versus 6.1% of placebo patients) were also treatment-emergent adverse events which occurred more frequently with patients receiving EVISTA compared to placebo (p≥0.05).

Adverse Reactions in a Placebo-Controlled Trial of Postmenopausal Women at Increased Risk for Major Coronary Events

The safety of EVISTA (60 mg once daily) was assessed in a placebo-controlled multinational trial of 10,101 postmenopausal women (age range 55-92) with documented coronary heart disease (CHD) or multiple CHD risk factors. Median study drug exposure was 5.1 years for both treatment groups (see CLINICAL TRIALS). Therapy was discontinued due to an adverse event in 25% of 5044 EVISTA-treated women and 24% of 5057 placebo-treated women. The incidence per year of all-cause mortality was comparable between the raloxifene (2.07%) and placebo (2.25%) groups.

Adverse reactions reported at a frequency of ≥2.0%, which were considered to be possibly related to EVISTA, and which occurred at a statistically significantly greater rate than placebo, were peripheral edema (14.1% raloxifene versus 11.7% placebo), muscle spasms/leg cramps (12.1% raloxifene versus 8.3% placebo), hot flashes (7.8% raloxifene versus 4.7% placebo), venous thromboembolic events (2.0% raloxifene versus 1.4% placebo), and cholelithiasis (3.3% raloxifene versus 2.6% placebo). Although cholelithiasis was reported more frequently for raloxifene than placebo, reports of cholecystectomy (2.3% raloxifene versus 2.0% placebo) were not significantly different.

Bladder cancer was reported in 0.2% (10/5044) of patients on EVISTA versus 0.1% (4/5057) of placebo patients in the RUTH trial. In an osteoporosis placebo-controlled treatment trial, bladder cancer was reported in 0.1% (3/5129) of patients on EVISTA versus 0.2% (4/2576) of placebo patients.

Comparison of EVISTA and Hormone Replacement Therapy Adverse Events

EVISTA (N=317) was compared with continuous combined (N=96) hormone replacement therapy (HRT) or cyclic estrogen plus progestin HRT in 3 clinical trials for prevention of osteoporosis.

The incidence of breast pain (4.4% for EVISTA-treated patients, 37.5% for continuous combined HRT-treated patients, and 29.7% for cyclic estrogen plus progestin HRT-treated patients), vaginal bleeding (6.2% for EVISTA-treated patients, 64.2% for continuous combined HRTtreated patients and 88.5% for cyclic estrogen plus progestin HRT-treated patients), and abdominal pain (6.6% for EVISTA-treated patients, 10.4% for continuous combined HRTtreated patients, and 18.7% for cyclic estrogen plus progestin HRT-treated patients) were significantly lower in EVISTA-treated patients versus patients treated with either form of HRT (p<0.05).

Conversely, the incidence of vasodilatation (28.7% for EVISTA-treated patients, 3.1% for continuous combined HRT-treated patients, and 5.9% for cyclic estrogen plus progestin HRTtreated patients) was significantly greater in EVISTA-treated patients versus patients treated with either form of HRT (p<0.05).

Laboratory Changes: The following changes in analyte concentrations are commonly observed during EVISTA therapy: increased serum HDL-2 cholesterol subfraction and apolipoprotein A1; and reduced serum total cholesterol, LDL cholesterol, fibrinogen, apolipoprotein B, and lipoprotein (a). EVISTA modestly increases hormone-binding globulin concentrations, including sex steroid binding globulin, thyroxine binding globulin, and corticosteroid binding globulin with corresponding increases in measured total hormone concentrations. There is no evidence that these changes in hormone binding globulin concentrations affect concentrations of the corresponding free hormones.

Drug Interactions

Clinically Significant Drug-Drug Interactions

Cholestyramine

Cholestyramine, an anion exchange resin, significantly reduces the absorption and enterohepatic cycling of raloxifene and should not be coadministered with raloxifene. Although not specifically studied, it is anticipated that other anion exchange resins would have a similar effect.

Warfarin

Coadministration of raloxifene and warfarin does not alter the pharmacokinetics of either compound. However, modest decreases in prothrombin time have been observed in singledose studies. If raloxifene is given concurrently with warfarin or other coumarin derivatives, prothrombin time should be monitored.

Drug-Drug Interactions

Ampicillin and Other Oral Antimicrobials

Peak concentrations of raloxifene are reduced with coadministration of ampicillin. The reduction in peak concentrations is consistent with reduced enterohepatic cycling associated with antibiotic reduction of enteric bacteria. Since the overall extent of absorption and the elimination rate of raloxifene are not affected, raloxifene can be concurrently administered with ampicillin. In the osteoporosis treatment trial, co-administered oral antimicrobial agents (including amoxicillin, cephalexin, ciprofloxacin, macrolide antibiotics, sulfamethoxazole/trimethoprim and tetracycline) had no effect on plasma raloxifene concentrations.

Corticosteroids

The chronic administration of raloxifene in postmenopausal women has no effect on the pharmacokinetics of methylprednisolone given as a single oral dose.

Digoxin

Raloxifene has no effect on the pharmacokinetics of digoxin. In the osteoporosis treatment trial, coadministered digoxin had no effect on plasma raloxifene concentration.

Gastrointestinal Medications

Concurrent administration of calcium carbonate or aluminum and magnesium hydroxide-containing antacids does not affect the systemic exposure of raloxifene. In the osteoporosis treatment trial, coadministered gastrointestinal medications (including bisacodyl, cisapride, docusate, H2-antagonists, laxatives, loperamide, omeprazole and psyllium) had no effect on plasma raloxifene concentration.

Highly Protein-Bound Drugs

Raloxifene is more than 95% bound to plasma proteins. The influence of co-administered highly protein-bound drugs (including diazepam, gemfibrozil, ibuprofen, naproxen and warfarin) on raloxifene plasma concentrations was evaluated in the osteoporosis treatment trial. No clinically significant effects of these agents on raloxifene plasma concentrations were identified. In vitro, raloxifene did not affect the binding of phenytoin, tamoxifen or warfarin.

Highly Glucuronidated Drugs

Raloxifene undergoes extensive first-pass metabolism to glucuronide conjugates. The influence of co-administered highly glucuronidated drugs (including acetaminophen, ketoprofen, morphine and oxazepam) on raloxifene plasma concentrations was evaluated in the osteoporosis treatment trial. No clinically significant effects of these agents on raloxifene plasma concentrations were identified.

Other Medications

The influence of concomitant medications on raloxifene plasma concentrations was evaluated in the osteoporosis treatment clinical trial. The 152 most commonly co-administered medications were grouped by pharmacological class based on their therapeutic use. Frequently co-administered drugs included: ACE inhibitors and angiotensin antagonists, alpha agonists and antagonists, anticholinergics, antidepressants, antimicrobials, antipsychotics, benzodiazepines, beta blockers and agonists, bisphosphonates, calcium channel blockers, diuretics, estrogen preparations, glucocorticoids, guaifenesin, H1-antagonists, H2- antagonists and proton pump inhibitors, hypoglycemics, hypolipidemics, iron preparations, muscle relaxants, nitrates, non-benzodiazepine hypnotics, non-steroidal anti-inflammatory drugs (NSAIDs), opioid analgesics, theophylline and thyroid hormone. No clinically relevant effects of the co-administration of any of these agents on raloxifene plasma concentrations were observed.

Drug-Food Interactions

EVISTA can be administered without regard to meals.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established (see ADVERSE REACTIONS for additional laboratory safety information).

Dosage and Administration

Recommended Dose

The recommended dosage is one 60-mg EVISTA tablet daily which may be administered any time of day without regard to meals.

Missed Dose

If a scheduled daily dose of EVISTA is missed, it should be taken as soon as remembered and one tablet once daily resumed. Do not take two doses at the same time.

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 overdose of raloxifene has been reported.

In postmarketing spontaneous reports, 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 overdose have been reported. In adults, symptoms reported in patients who took more than 120 mg as a single ingestion included leg cramps and dizziness. In some cases, no adverse events were reported as a result of the overdose.

In accidental overdose in children under 2 years of age, the maximum reported dose has been 180 mg. In 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.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Action and Clinical Pharmacology

Mechanism of Action

Raloxifene is a selective estrogen receptor modulator (SERM) that belongs to the benzothiophene class of compounds. The SERM profile of raloxifene includes estrogen agonist effects on bone and lipid metabolism, and estrogen antagonist effects in uterine and breast tissues. Raloxifene’s biological actions, like those of estrogen, are mediated through highaffinity binding to estrogen receptors and regulation of gene expression. This binding results in differential expression of multiple estrogen-regulated genes in different tissues.

Pharmacodynamics

Effects On the Skeleton

During early to middle adult life, bone undergoes continuous remodeling. In this process, local areas of bone resorption are refilled completely by ensuing bone formation; that is, resorption and formation are in balance. The result is that bone mass remains relatively constant. Ovarian estrogen is important for maintenance of this balance in bone turnover. Marked decreases in estrogen availability, such as after oophorectomy or menopause, lead to marked increases in bone resorption, accelerated bone loss and increased risk of fracture. After menopause, bone is initially lost rapidly because the compensatory increase in bone formation is inadequate to offset resorptive losses.

This imbalance between resorption and formation may be related to loss of estrogen, or to agerelated impairment of osteoblasts or their precursors. Estrogen replacement therapy reduces resorption of bone by inhibiting the formation and action of osteoclasts, and decreases overall bone turnover. These effects on bone are manifested as reductions in the serum and urine levels of bone turnover markers, histologic evidence of decreased bone resorption and formation, and increased bone mineral density (BMD). Although EVISTA increases BMD to a lesser extent than estrogen, the effects of EVISTA on bone turnover in postmenopausal women parallel those of estrogen, as shown by studies of bone mineral densitometry, radiocalcium kinetics, bone markers, and bone histomorphometry. EVISTA reduces biochemical markers of bone metabolism into the range seen in premenopausal women.

Pharmacokinetics

The disposition of raloxifene has been evaluated in more than 3000 postmenopausal women in selected raloxifene osteoporosis treatment and prevention clinical trials using a population approach. Pharmacokinetic data were also obtained in conventional clinical pharmacology studies in 292 postmenopausal women. Raloxifene exhibits high within-subject variability (approximately 30%) of most pharmacokinetic parameters. Table 2 summarizes the pharmacokinetic parameters of raloxifene.

Table 2: Summary of Raloxifene Pharmacokinetic Parameters in the Healthy Postmenopausal Woman
Cmaxa
(ng/mL)/
(mg/kg)
t½ (hr) AUC0-∞a
(ng•hr/mL)/
(mg/kg)
CL/F
(L/kg•hr)
V/F
(L/kg)
Single Dose
   Mean 0.5 27.7 27.2 44.1 2348
   CV(%) 52 10.7 to 273b 44 46 52
Multiple Dose
   Mean 1.36 32.5 24.2 47.4 2853
   CV(%) 37 15.8 to 86.6b 36 41 56

Abbreviations: Cmax = maximum plasma concentration, t½ = half-life, AUC = area under the curve, CL = clearance,

V = volume of distribution, F = bioavailability, CV = coefficient of variation.

a    data normalized based on dose in mg and body weight in kg

b    range of observed half-life

Absorption

Raloxifene is absorbed rapidly after oral administration. Approximately 60% of an oral dose is absorbed, but presystemic glucuronide conjugation is extensive. Absolute bioavailability of raloxifene is 2.0%. The time to reach average maximum plasma concentration and bioavailability are functions of systemic interconversion and enterohepatic cycling of raloxifene and its glucuronide metabolites.

Administration of raloxifene HCl with a standardized, high-fat meal increases the absorption of raloxifene slightly, but does not lead to clinically meaningful changes in systemic exposure. EVISTA can be administered without regard to meals.

Distribution

Following oral administration of single doses ranging from 30 to 150 mg of raloxifene HCl, the apparent volume of distribution is 2348 L/kg and is not dose dependent.

Raloxifene and the monoglucuronide conjugates are highly bound to plasma proteins. Raloxifene binds to both albumin and α1-acid glycoprotein, but not to sex steroid binding globulin.

Metabolism

Biotransformation and disposition of raloxifene in humans have been determined following oral administration of14 C-labeled raloxifene. Raloxifene undergoes extensive firstpass 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. Unconjugated raloxifene comprises less than 1% of the total radiolabeled material in plasma. The terminal log-linear portion of the plasma concentration curve for raloxifene and the glucuronides are generally parallel. This is consistent with interconversion of raloxifene and the glucuronide metabolites.

Following intravenous administration, raloxifene is cleared at a rate approximating hepatic blood flow. Apparent oral clearance is 44.1 L/kg•hr. Raloxifene and its glucuronide conjugates are interconverted by reversible systemic metabolism and enterohepatic cycling, thereby prolonging its plasma elimination half-life to 27.7 hours after oral dosing.

Results from single oral doses of raloxifene predict multiple-dose pharmacokinetics. Following chronic dosing, clearance ranges from 40 to 60 L/kg•hr. Increasing doses of raloxifene HCl (ranging from 30 to 150 mg) result in slightly less than a proportional increase in the area under the plasma time concentration curve (AUC).

Excretion

Raloxifene is primarily excreted in feces, and negligible amounts are excreted unchanged in urine. Less than 6% of the raloxifene dose is eliminated in urine as glucuronide conjugates.

Special Populations and Conditions

Geriatrics

The pharmacokinetics of raloxifene are independent of age (42 to 84 years).

Pediatrics

The pharmacokinetics of raloxifene have not been evaluated in a pediatric population.

Gender

Total extent of exposure and oral clearance, normalized for lean body weight, are not significantly different between age-matched male and female volunteers.

Race

Pharmacokinetic differences due to race have been studied in 1712 women including 97.5% Caucasian, 1.0% Asian, 0.7% Hispanic, and 0.5% Black in the osteoporosis treatment trial and in 1053 women including 93.5% Caucasian, 4.3% Hispanic, 1.2% Asian, and 0.5% Black in the osteoporosis prevention trials. There were no discernible differences in raloxifene plasma concentrations among these groups. The influence of race cannot be conclusively determined because of the small numbers of non-Caucasians.

Renal Insufficiency

Since negligible amounts of raloxifene are eliminated in urine, a study in patients with renal insufficiency was not conducted. In the osteoporosis treatment and prevention trials, raloxifene and metabolite concentrations were not affected by renal function in women having estimated creatinine clearance as low as 21 mL/min (0.35 mL/s). EVISTA should be used with caution in patients with moderate or severe renal impairment, Safety and efficacy have not been established in patients with moderate or severe renal impairment.

Hepatic Insufficiency

Raloxifene was studied as a single dose in patients with Child-Pugh Class A cirrhosis with total serum bilirubin ranging from 0.6 to 2.0 mg/dL (10.3 to 34.2 mmol/L). Plasma raloxifene concentrations were approximately 2.5 times higher than in controls and correlated with bilirubin concentrations. Safety and efficacy have not been evaluated further in patients with hepatic insufficiency (see WARNINGS AND PRECAUTIONS).

Storage and Stability

Store at room temperature, 15° to 30°C.

Dosage Forms, Composition and Packaging

EVISTA is supplied in a tablet dosage form for oral administration. Each EVISTA tablet contains 60 mg of raloxifene HCl, which is the molar equivalent of 55.71 mg of free base. Inactive ingredients include anhydrous lactose, crospovidone, FD&C Blue No. 2 aluminum lake, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, polysorbate 80, povidone, macrogol 400 and titanium dioxide E171.

EVISTA 60-mg tablets are white, elliptical and film coated. They are imprinted on one side with the tablet code 4165 in blue ink. Available in blister packages of 28 tablets.