1. EVISTA HISTORY
How was Evista discovered?

Evista is a distinctive treatment for osteoporosis from the Eli Lilly & Company.

Evista received U.S. Food and Drug Administration (FDA) approval in December 1997. 

Note: World-drugs.net sells generic version of Evista

2.EVISTA FACTS

Eli Lilly and Company has a heritage more than 128 years strong. Eli Lilly and company was founded on May 10, 1876 by Colonel Eli Lilly in Indianapolis , Ind. , in the Midwestern section of the United States.

Eli Lilly and Company has approximately 8,400 employees engaged in research and development. The company has manufacturing plants located in 13 countries and its products marketed in 143 countries. 

3.ABOUT EVISTA MEDICATION

What is Osteporosis?

Osteoporosis, also called porous bone, is a disease characterized by low bone mass and structural deterioration of bone tissue, leading to bone fragility and an increased susceptibility to fractures, especially of the hip, spine, and wrist, although any bone can be affected.

Osteoporosis may result from disease, dietary or hormonal deficiency or advanced age. 

Prevalence of Osteoporosis

Osteoporosis is a major public health threat for an estimated 44 million Americans, or 55 percent of the people 50 years of age or older. In the U.S. today, 10 million individuals are estimated to already have the disease and almost 34 million more are estimated to have low bone mass, placing them at increased risk for osteoporosis.

• Of the 10 million Americans estimated to have osteoporosis, eight million are women and 2 million are men.
• One in two women and one in four men over age 50 will have an osteoporosis-related fracture in her/his remaining lifetime.
• Significant risk has been reported in people of all ethnic backgrounds.
• While osteoporosis is often thought of as an older person's disease, it can strike at any age.

Women

• Eighty percent of those affected by osteoporosis are women.
• Five percent of non-Hispanic black women over age 50 are estimated to have osteoporosis; an estimated additional 35 percent have low bone mass that puts them at risk of developing osteoporosis.
• Ten percent of Hispanic women aged 50 and older are estimated to have osteoporosis, and 49 percent are estimated to have low bone mass.
• Twenty percent of non-Hispanic white and Asian women aged 50 and older are estimated to have osteoporosis, and 52 percent are estimated to have low bone mass.

Men

• Twenty percent of those affected by osteoporosis are men.
• Seven percent of non-Hispanic white and Asian men aged 50 and older are estimated to have osteoporosis, and 35 percent are estimated to have low bone mass.
• Four percent of non-Hispanic black men aged 50 and older are estimated to have osteoporosis, and 19 percent are estimated to have low bone mass.
• Three percent of Hispanic men aged 50 and older are estimated to have osteoporosis, and 23 percent are estimated to have low bone mass.  

Symptoms of Osteoporosis

Osteoporosis is often called the "silent disease" because bone loss occurs without symptoms. People may not know that they have osteoporosis until their bones become so weak that a sudden strain, bump, or fall causes a fracture or a vertebra to collapse. Collapsed vertebrae may initially be felt or seen in the form of severe back pain, loss of height, or spinal deformities such as kyphosis or stooped posture.

Risk Factors for Osteoporosis

Certain people are more likely to develop osteoporosis than others. Factors that increase the likelihood of developing osteoporosis are called "risk factors." These risk factors include:

• Personal history of fracture after age 50
• Current low bone mass
• History of fracture in a 1st degree relative
• Being female
• Being thin and/or having a small frame
• Advanced age
• A family history of osteoporosis
• Estrogen deficiency as a result of menopause, especially early or surgically induced
• Abnormal absence of menstrual periods (amenorrhea)
• Anorexia nervosa
• Low lifetime calcium intake
• Vitamin D deficiency
• Use of certain medications, such as corticosteroids and anticonvulsants
• Presence of certain chronic medical conditions
• Low testosterone levels in men
• An inactive lifestyle
• Current cigarette smoking
• Excessive use of alcohol
• Being Caucasian or Asian, although African Americans and Hispanic Americans are at significant risk as well
• Women can lose up to 20 percent of their bone mass in the five to seven years following menopause, making them more susceptible to osteoporosis.

Detection of Osteoporosis

Specialized tests called bone density tests can measure bone density in various sites of the body.

A bone density scan measures the density of bone in a person. The lower the density of a bone the higher the risk of fractures. A bone scan, along with a patient's medical history, is a useful aid in evaluating the probability of a fracture and whether any preventative treatment is needed. A bone density scan has the advantage of being painless and exposing the patient to only a small amount of radiation.

 

Prevention of Osteoporosis
By about age 20, the average woman has acquired 98 percent of her skeletal mass. Building strong bones during childhood and adolescence can be the best defense against developing osteoporosis later. There are four steps, which together, can optimize bone health and help prevent osteoporosis. They are:

• A balanced diet rich in calcium and vitamin D;
• Weight-bearing exercise;
• A healthy lifestyle with no smoking or excessive alcohol intake; and
• Bone density testing and medication, when appropriate.

How does Evista work?

Evista selectively mimics the effects of oestrogen on bone tissue, but does not affect breast tissue or uterine tissue. This means that long-term use does not carry the increased risk of cancer of the lining of the womb (endometrial cancer) or breast cancer that is associated with long-term use of oestrogen-based hormone replacement therapy (HRT). However, Evista is associated with an increased risk of developing blood clots in the veins (venous thromboembolism). This risk is similar to that associated with hormone replacement therapy (HRT). 

4.EVISTA EFFECTIVENESS
When is Evista best taken?

Absorption

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

Administration of Evista with a standardized, high-fat meal increases the absorption of Evista (C max 28% and AUC 16%), 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 of Evista ranging from 30 to 150 mg, the apparent volume of distribution is 2348 L/kg and is not dose dependent.

Evista and the monoglucuronide conjugates are highly bound to plasma proteins. Evista binds to both albumin and D 1-acid glycoprotein, but not to sex steroid binding globulin. In vitro, raloxifene did not interact with the binding of warfarin, phenytoin, or tamoxifen to plasma proteins.

Metabolism

Biotransformation and disposition of Evista in humans have been determined following oral administration of 14 C-labeled raloxifene. Evista undergoes extensive first-pass 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 Evista is not metabolized by cytochrome P450 pathways. Unconjugated raloxifene comprises less than 1% of the total radiolabeled material in 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.

Following intravenous administration, Evista is cleared at a rate approximating hepatic blood flow. Apparent oral clearance is 44.1 L/kg hr. Evista 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 Evista predict multiple-dose pharmacokinetics. Following chronic dosing, clearance ranges from 40 to 60 L/kg •hr. Increasing doses of Evista (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

Evista is primarily excreted in feces, and less than 0.2% is excreted unchanged in urine. Less than 6% of the Evista dose is eliminated in urine as glucuronide conjugates. In the osteoporosis prevention trials, Evista and metabolite concentrations are similar for women with estimated creatinine clearance as low as 23 mL/min. 

5.EVISTA EFFECTS ON SPECIAL POPULATION
(How do different people react to Evista?

Geriatric :

No differences in Evista pharmacokinetics were detected with regard to age (range 42 to 84 years).

Pediatric:

The pharmacokinetics of Evista has 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 female and male volunteers. 

Race:

Pharmacokinetic differences due to race have been studied on a limited basis in 1053 women consisting of 93.5% Caucasian, 4.3% Hispanic, 1.2% Asian, and 0.5% Black in the osteoporosis prevention trials. There were no discernible differences in Evista plasma concentrations among these groups; however, the influence of race cannot be effectively determined.

Pregnancy

Category X: Evista should not be used in women who are or may become pregnant.

Nursing Mothers:

Lactating women should not use Evista. It is not known whether Evista is excreted in human milk.

6.EVISTA EFFECTS ON MEDICAL CONDITIONS
(How does Evista affect your existing condition/ailment?

Concurrent Estrogen Therapy: The concurrent use of Evista and systemic estrogen or hormone replacement therapy (ERT or HRT) has not been studied in prospective clinical trials and therefore concomitant use of Evista with systemic estrogens is not recommended.

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. 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.

Endometrium: Evista has not been associated with endometrial proliferation. Unexplained uterine bleeding should be investigated as clinically indicated.

Breast: Evista has not been associated with breast enlargement, breast pain, or an increased risk of breast cancer. Any unexplained breast abnormality occurring during Evista therapy should be investigated.

History of Breast Cancer: Evista has not been adequately studied in women with a prior history of breast cancer.

Use in Men: Safety and efficacy have not been evaluated in men.

Renal Insufficiency : Since negligible amounts of Evista are eliminated in urine, a study in patients with renal insufficiency was not conducted.

Hepatic Dysfunction: Evista was studied, as a single dose, in Child-Pugh Class A patients with cirrhosis and total serum bilirubin ranging from 0.6 to 2.0 mg/dL. Plasma Evista 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. 

7.OTHER/ALTERNATE USES OF EVISTA
(What else does Evista treat?

Evista is used for the treatment of Osteoporosis and Paget's disease. 

8.ADVERSE/SIDE EFFECTS of EVISTA
What are the side effects of Evista?

The safety of Evista has been assessed primarily in 12 Phase 2 and Phase 3 studies with placebo, estrogen, and estrogen-progestin replacement therapy (HRT) control groups.

The duration of treatment ranged from 2 to 30 months and 2036 women were exposed to Evista (371 patients received 10 to 50 mg/day, 828 received 60 mg/day, and 837 received from 120 to 600 mg/day).

The majority of adverse events occurring during clinical trials were mild and generally did not require discontinuation of therapy.

Therapy was discontinued due to an adverse event in 11.4% of 581 Evista treated women and 12.2% of 584 placebo-treated women. Common adverse events considered to be drug-related were hot flashes and leg cramps. The first occurrence of hot flashes was most commonly reported during the first 6 months of treatment.

Discontinuation rates due to hot flashes did not differ significantly between Evista and placebo groups (1.7% and 2.2%, respectively).

Adverse Events in Placebo-controlled Clinical Trials

The table below lists adverse events occurring in the placebo-controlled clinical trial database at a frequency 2.0% in either group and in more Evista-treated women than in placebo-treated women. Adverse events are shown without attribution of causality.

Adverse events occurring in placebo-controlled clinical trials at a frequency ³ 2.0% and in more EVISTA-treated (60 mg once daily) women than placebo-treated women
Body System	EVISTA N= 581 %	Placebo N= 584 %
Body as a Whole
Infection	15.1	14.6
Flu Syndrome	14.6	13.5
Leg Cramps	5. 9	1. 9
Chest Pain	4. 0	3. 6
Fever	3. 1	2. 6
Cardiovascular
Hot Flashes	24.6	18.3
Migraine	2. 4	2. 1
Digestive
Nausea	8. 8	8. 6
Dyspepsia	5. 9	5. 8
Vomiting	3. 4	3. 3
Flatulence	3. 1	2. 4
Gastrointestinal Disorder	3. 3	2. 1
Gastroenteritis	2.6	2.1
Metabolic and Nutritional
Weight Gain	8. 8	6. 8
Peripheral Edema	3. 3	1. 9
Musculoskeletal
Arthralgia	10.7	10.1
Myalgia	7. 7	6. 2
Arthritis	4. 0	3. 6
Nervous
Depression	6. 4	6. 0
Insomnia	5. 5	4. 3
Respiratory
Sinusitis	10.3	6.5
Pharyngitis	7. 6	7. 2
Cough Increased	6.0	5.7
Pneumonia	2. 6	1. 5
Laryngitis	2. 2	1. 4
Skin and Appendages
Rash	5. 5	3. 8
Sweating	3. 1	1. 7
Urogenital
Vaginitis	4. 3	3. 6
Urinary Tract Infection	4. 0	3. 9
Cystitis	3. 3	3. 1
Leucorrhoea	3.3	1.7
Endometrial Disorder	3.1	1.9