OBESITY STATISTICS

Obesity is considered a disease (defined as being 20% or more over ideal body weight) and is one of the most common and serious health problems in the United States affecting more than 60 million Americans. Morbid obesity (a much more severe form of obesity in which a person is 100 pounds or more overweight) affects approximately 4 million Americans. Over time obesity in the United States has increased to epidemic levels with a resulting 8% increase in obesity in both adults and children over the past decade and these percentages continue to rise. Recent estimations attribute 280,000 deaths per year in the United States to the medical complications of obesity. A recent study reported that the states with the highest rate of obesity (over 30%) are Alabama, Michigan, Mississippi, West Virginia and Wisconsin. The thinnest people were in Hawaii and Colorado.

Health care costs directly attributable to obesity amount to approximately $68 billion per year and an additional $30 billion per year is spent on weight-reduction programs and special foods. According to C. Everett Koop, former Surgeon General of the United States, obesity is the second leading cause of preventable death in America.

OBESITY-RELATED DISEASES

Obesity is recognized by the National Institutes of Health as a disease and medical problems caused by obesity are numerous and can be serious or life threatening and is independently associated with an increased mortality rate.

Some of these obesity-related medical conditions are:

Diabetes (80% of Type II diabetics are obese), stroke, hypertension, heart trouble, shortness of breath, gallbladder disease, elevated blood cholesterol levels, some cancers (including breast cancer, colorectal, prostate, endometrial, cervical, and ovarian), arthritis, other orthopedic problems, reflux esophagitis (heart burn), snoring, sleep apnea, menstrual irregularities, infertility, and others medical conditions that are more common in heavy people than in persons of normal weight. These problems in many cases can be improved with significant permanent weight loss.

SOCIAL DISCRIMINATION OF THE OBESE

Americans have been called the fattest people on earth and recent studies show they are growing even fatter which translates into increased medical and social problems for the American population. In addition to medical problems, obese persons often suffer from social problems, including discrimination in the work place (where the unemployment of persons who are 100 or more pounds overweight approaches 50%) and when they do have jobs they are often overlooked when there are opportunities for promotion.

It is very common for heavy persons to be discriminated against socially, where they are often treated as non-persons for our cultural perceptions are that obesity is caused by slothful living, poor personal eating/exercise habits, limited intelligence, and lack of self-control. This prejudicial thinking is not based in fact, and needs to change.

HOW OBESITY IS DEFINED

Obesity is loosely defined as an excess of fat over that needed to maintain health or another way of explaining it is a greater amount of caloric intake than caloric expenditure.

A convenient clinical and epidemiological measure of adiposity (body fat content) is the Body Mass Index (BMI) which is calculated as follows:

Body Mass Index (BMI) = (Weight in Kilograms)

(Height in Meters)²

OR

Body Mass Index (BMI) = (Weight in Pounds) x 700

(Height in Inches)²

For example: a person who weighs 150 pounds and is 68 inches tall has a BMI of 22.7. A person is considered medically obese with a BMI value of 28 for men and 27 for women that corresponds to a weight that is 20% above ideal body weight.

The accumulation of body fat around the abdomen appears to be a risk factor for insulin resistance, diabetes and heart disease. Body fat distribution is determined by the Waist-to-Hip Ratio as follows:

Waist-to-Hip Ratio = (Waist Size in Inches)

(Hip Size in Inches)

For example: a person with a 29 inch waist and a 39 inch hip would have a ratio of 0.74 and a person with a 44 inch waste and 40 inch hip would have waist-to-hip ratio of 1.1 (The lower the waist-to-hip ratio the better). The risk of heart disease and other obesity linked medical conditions rises sharply for women with ratios above 0.8 and for men with ratios above 1.0.

THE CAUSES OF OBESITY

Obesity is caused by multiple factors, the primary factor being genetics which is the one factor relating to obesity over which individuals have no control. In fact, studies in twins, adoptees, and families indicate that as much as 80 percent of the variance in the body-mass index is attributable to genetic factors. Recently, several genes have been implicated in the development of obesity. An example is the obese gene (the ob gene) and its protein leptin discovered in 1994. Leptin is produced in adipose tissue and effects the appetite and satiety centers of the brain. Another genetic factor linked to obesity is a variation in the beta3-adrenergic receptor located mainly in adipose tissue and involved in the regulation of lipolysis (the hydrolysis of fat) and thermogenesis (production of body heat).

Other important factors involved in obesity are: the mechanisms of fat storage; the balance between energy intake and energy expenditure; an individual’s lifestyle: eating habits and exercise; and psychological, cultural and socioeconomic influences.

American dietary habits have changed dramatically during the 20^th century. In 1910, the proportion of fat in the diet was 27%, by 1984 the dietary fat content had risen to 44%. An increase in dietary fat leads to an increase in the amount of energy converted to triglyceride and stored in adipocytes (fat cells). The enzyme lipoprotein lipase regulates the storage of triglycerides in adipocytes and its activity varies in different parts of the body, being very active in abdominal fat and less active in hip fat. Fat deposits in highly active sites are associated with higher cholesterol levels and other cardiac risk factors. Findings have shown that a waist-to-hip ratio greater than 1.0 for women and 0.8 for men increases the risk of ischemic heart disease, stroke, and death, independent of total body fat.

When triglycerides are deposited in adipocytes (fat cells), the cells initially increase in size, when a maximal size is reached, the cells divide. A (BMI < 40) characterized as moderate obesity is believed to result in an increase in adipocyte (fat cell) size. A (BMI > 40), characterized as extreme or morbid obesity is believed to result in adipocyte (fat cell) division and multiplication.

An interesting finding is that most studies on obesity have NOT demonstrated that obese persons consume more food than those of normal weight. Therefore, the imbalance between energy intake and energy expenditure in most obese persons must be explained by factors other than abnormal energy intake (over eating) especially when the caloric expenditure in moving a greater body mass and the heat loss over a larger body surface area are taken into account.

There are three components to energy expenditure: the resting metabolic rate (RMR), dietary thermogenesis (the heat produced by food digestion, absorption and storage) and facultative thermogenesis (the heat produced by activity). The RMR accounts for about 60% of energy expenditure. The most recent studies have shown that the obese compensate for weight loss by decreasing total energy expenditure to a significantly greater extent than nonobese people. Facultative thermogenesis consumes about 20% of total energy expenditure in the average sedentary individual. Increased voluntary exercise can increase the facultative thermogenesis and the RMR can also be increased for at least 18 hours after increased activity. Dietary thermogenesis is the smallest component of energy expenditure and may be lower in the obese than those of normal weight. Most of the thermogenic mechanisms are controlled by the sympathetic nervous system with epinephrine, norepinephrine, glucagon, and glucocorticoids appearing to be the primary hormones to stimulate these processes.

The obese in relation to the nonobese may: be more metabolically efficient, have lower thermic responses to food and exercise, have lower activity levels.

TREATMENT OF OBESITY

There is no doubt that the loss of weight in the obese is accompanied by health benefits or that the medical risks of obesity increase exponentially as weight increases. However, the treatment of obesity is difficult for it is a chronic medical condition or disease that is rarely cured. It takes a caloric deficit of 3,500 kcal to lose 1 pound of adipose tissue (fat) and a weight loss of no more than 1 to 2 pounds per week is recommended by experts in the field resulting in weight loss that is typically slow. In addition, programs intended to promote the long-term maintenance of weight reduction (especially in the morbidly obese) are mostly ineffective as 90 to 95 percent of persons who lose weight subsequently regain it.

Factors that contribute to obesity today in the United States are: availability of a highly varied diet, a high percentage of fat in the diet, lowered activity levels and in susceptible individuals an excessive metabolic response to dieting (the lowering of thermogenesis and the RMR). Treatment must take these factors into account. In order to lose weight caloric intake must be reduced, the percentage of fat in the diet should be considerably reduced, and activity levels should be increased. These changes may counteract the RMR decrease caused by dieting. Weight loss, especially where health risk is concerned, is a serious undertaking and should be considered by the patient and the health care provider as a long-term commitment.

Weight loss programs usually encompass caloric reduction, behavioral therapy and increased exercise. Studies have shown that this combination is more favorable and cost-efficient than pharmacological treatment for maintenance of weight loss. In many cases, pharmacotherapy produces a more rapid initial weight loss, however, behavior therapy maintains weight loss to a better degree than drug therapy as patients usually regain weight as soon as the drug therapy is terminated.

PHARMACOLOGICAL TREATMENT: ANTI-OBESITY AGENTS

Over the years, starting around 1890, a variety of agents, compounds, drugs and drug combinations have been used to try to induce weight loss with a variety of results (some partially effective, some controversial and some dangerous, even fatal). In 1893 when thyroid extract was thought to be therapeutic, doses up to 1500mg of desiccated thyroid (about 75 mg of synthetic levothyroxine) were used. This treatment remained in use until the 1970’s when it was abandoned because of risks for electrolyte disturbances, metabolic imbalances, cardiac dysrhythmias, and increased bone absorption leading to osteoporosis. On May 15, 1978, the FDA issued a ruling warning against the use of thyroid preparation for the treatment of obesity. Currently, thyroid hormone is not indicated for obesity treatment unless the patient suffers from proven hypothyroidism.

Dinitrophenol (2,4-DNP) was introduced in 1933 for the treatment of obesity via "anit-fat" patent medicines. This drug induced weight loss by markedly increasing metabolic rate and body temperature. However, in 1937 the use of these patent medicines was terminated due to reports of severe intoxications and deaths.

In 1940, digitalis was added to weight loss regimens to induce nausea and anorexia and to counteract the tachycardia caused by the large doses then given of thyroid hormone. The cardiac glycoside strophanthin was combined with thyroxine in a commercial product known by the brand name Neo-Barine that was advertised as "a safe and dependable weight-reducing agent." Even though it was cardiotoxic, Neo-Barine was commonly used for weight reduction until, June 19, 1964 when the medical journal Medical Letter on Drugs and Therapeutics claimed that Neo-Barine was a dangerous drug and recommended its removal from the market.

Two classes of anorectic drugs (appetite suppressants) currently available are the norandrenergic agents which effect the appetite center, and serotonergic agents which effect the satiety center:

Noradrenergic agents include phenylpropanolamine, (Acutrim, Dexatrim), diethylpropion (Tenuate), mazindol (Mazanor, Sanorex), phentermine (Fastin, Ionamin), phendimetrazine (Bontril, Plegine), and benzphetamine (Didrex).

Serotonergic agents include fenfluramine (Pondimin) dexfenfluramine (Redux) and fluoxatine (Prozac).

NORADRENERGIC AGENTS

Noradrenergic agents or appetite suppressant drugs in use today act directly on the central nervous system and appear to lower food intake by activating central beta and/or dopaminergic receptors in the hypothalamus of the brain.

In 1938 amphetamine was prescribed for weight loss because of its appetite suppressant qualities, but it often lead to drug dependency and abuse. Amphetamine is a norandrenergic agent and functions by activating central beta and or dopaminergic receptors in the hypothalamus of the brain. Except for mazindol, the noradrenergic agents are chemically related to amphetamine. Because of its high potential for drug abuse, the molecular structure of amphetamine was altered to make it safer and the results were the adjusted form Phenylpropanolamine.

Phenylpropanolamine, is the only FDA-approved over-the-counter (OTC) weight loss drug. Possible side-effects of phenylpropanolamine include: nervousness, irritability, headache, sweating, dry mouth, nausea, constipation, and it has been known to cause severe high blood pressure and stroke if taken in doses of 75 mg or higher in the immediate-release form. In addition, phenylpropanolamine is contraindicated if the patient is taking any antidepressant in the chemical family called monoamine oxidase inhibitors (MAOI’s). Phenylpropanolamine helps the obese to control their appetites, but this drug tends to loose its appetite suppressant effectiveness over time. Acutrim and Dexatrim are two well-known OTC drugs used to aid in weight loss that contain phenylpropanolamine. Cough medicines and cold remedies are other OTC drugs that often contain phenylpropanolamine.

People must be cautious when using any weight-loss over-the-counter diet pills, and herbal or so-called natural remedies. For example: Ephedrine which is a thermogenic drug is present in the so-called "herbal fen-phen" and is sold as an over-the-counter weight loss remedy. It is derived from the ephedra herb also known as Ma Huang. Studies have reported that even small amounts of this herb can cause severe adverse effects including: rapid heart beat, high blood pressure, psychosis, and seizure. In fact, 18 deaths have been reported with the use of weight loss remedies containing ephedrine since 1994.

Phenteramine, phendimetrazine, phenmetrazine, diethylpropion, benzphetamine, and mazindol are the prescription noradrenergics currently available in the United States.

Diethylpropion (Tenuate) limits appetite because of its effects on the hypothalamus, a control center in the brain. The usual dose is 25mg 3 times

per day 1 hour before meals. Known side effects of Tenuate include: nervousness, irritability, headache, sweating, dry mouth, nausea, and constipation. This drug is also contraindicated if the patient is taking any monamine oxidase inhibitor antidepressants (MAOI’s) because of possible hypertensive crises.

Mazindol (Mazanor or Sanorex) when used in a physician-directed weight-loss program can increase weight loss an additional 10% over a combination diet/exercise/behavioral program alone and it has possible side effects of: nervousness, irritability, headache, sweating, dry mouth, nausea, and constipation. It also is contraindicated if the patient is taking any monamine oxidase inhibitor antidepressants (MAOI’s).

Anorectic agents (appetite suppressants) such as fenfluramine, dexfenfluramine, and phentermine have been shown to be superior to placebos in terms of weight loss in carefully conducted clinical trials. Phentermine is an adrenergic compound; fenfluramine and dexfenfluramine are serotoninergic compounds.

Phentermine (Fastin or Ionamin) when used in a physician directed weight loss program that includes low-fat diet, behavioral modification and exercise, can increase weight loss by about 10%. After these drugs are discontinued, weight loss may cease and weight may be regained.

PHENTERMINE (Fastin or Ionamin) adverse reactions are:

Cardiac:

Palpitations, tachycardia, elevation of blood pressure;

Central Nervous System:

Overstimulation, restlessness, dizziness, insomnia, euphoria, dysphoria, tremors, headache, rare psychotic episodes. Concomitant use of alcohol may also cause adverse reactions.

Gastrointestinal:

Mouth dryness, unpleasant taste, diarrhea, constipation, and other gastrointestinal disturbances.

Allergic:

Urticaria.

Endocrine:

Impotence, and changes in libido.

PHENTERMINE (Fastin or Ionamin) contraindications are:

Advanced arteriosclerosis, symptomatic cardiovascular disease, moderate to severe hypertension, hyperthyroidism, known hypersensitivity or idiosyncrasy to the sympathomimetic amines, glaucoma and during or within 14 days following the administration of monoamine oxidase (MAO) inhibitors hypertensive crises may result.

Precautions listed were:

Caution is to be exercised in prescribing Ionamin for patients with even mild hypertension. Insulin requirements in diabetes may be altered in association with the use of Ionamin and the concomitant dietary regimen. Ionamin may decrease the hypotensive effect of adrenergic neuron blocking drugs.

FENFLURAMINE (Pondimin) adverse reactions are:

Dizziness, dry mouth, drowsiness, diarrhea, rare pulmonary hypertension (which probability is increased when the drug is used for more than 3 months).

FENFLURAMINE (Pondimin) Warnings and Precautions are listed as:

Body as a whole:

abdominal pain, chills, fever, headache, allergic reaction, anaphylaxis, asthenia, face edema, malaise, photosensitivity reaction, suicide attempt, and death.

Cardiovascular System:

Chest pain, hypotension, hypertension, syncope, angina pectoris, arrhythmia, bradycardia, cerebrovascular accident, heart arrest, heart block, heart failure, intracranial hemorrhage, migraine, myocardial infarct, peripheral vascular disorder, postural hypotension, pulmonary embolus, tachycardia, thrombosis, valvular heart disease, vasculitis, and vasodilation.

Digestive System:

Constipation, nausea, dyspepsia, hepatic failure, hepatitis,

Increased appetite, ischemic colitis, jaundice, liver damage, abnormal liver function tests, melena, pancreatitis, peptic ulcer and vomiting.

Endocrine System:

Fertility decreased male.

Hemic and Lymphatic System:

Anemia, aplastic anemia, idiopathic thrombocytopenic purpura, leukopenia, thrombocytopenia, and thrombotic thrombocytopenic purpura.

Metabolic and Nutritional:

Dehydration, and peripheral edema.

Musculoskeletal System:

Myalgia, and arthralgia.

Nervous System:

Dizziness, confusion, incoordination, euphoria, depression, anxiety, nervousness or tension, insomnia, weakness or fatigue, increased or decreased libido, agitation, dysarthria, amnesia, abnormal dreams, ataxia, coma, convulsion, emotional lability, encephalopathy, hallucinations, hemiplegia, hostility, hyperkinesia, hypertonia, hypesthesia, irritability, manic reaction, neuropathy, optic neuritis, panic attach, paranoid reaction, personality disorder, psychosis, somnolence, speech disorder, suicidal ideation, abnormal thinking, tremor and vertigo.

Respiratory System:

Pulmonary hypertension, asthma, increased cough, dyspnea, and lung edema.

Skin and Appendages:

Alopecia, rash, urticaria, burning sensation, sweating, angioedema, pruritus, and toxic epidermal necrolysis.

Special Senses:

Blurred vision, eye irritation, taste perversion, abnormal vision, deafness, dry eyes, and mydriasis.

Urogenital System:

Dysuria, urinary frequency, abnormal ejaculation/orgasm, amenorrhea, breast pain, dysmenorrhea, hematuria, impotence, kidney failure, menstrual disorder, spontaneous abortion, unintended pregnancy, urinary incontinence, and urinary retention.

PHENTERMINE drugs, nicknamed "phen" were often prescribed with FENFLURAMINE (Pondimin) or DEXFENFLURAMINE (Redux) nicknamed "fen" and in combination known as "fen-phen." Both fenfluramine and phentermine were approved separately by the FDA in 1996 for short-term use as an anti-obesity drug and worked adequately separately. However, used together it was believed that they could be administered in lower dosages with fewer incidences of side effects.

The fen-phen combination was not specifically FDA approved for short-term weight control, but once drugs are approved for any purpose, doctors may legally and ethically prescribe them in combination.

In 1996, prescriptions issued in the United States for fenfluramine and phentermine exceeded 18 million costing Americans more than $100 million.

The Mayo Clinic report "Valvular Heart Disease Associated with Fenfluramine-Phentermine." published in the New England Journal of Medicine on August 28, 1997discussed findings that 24 previously healthy women had developed potentially serious mitral valve abnormalities after taking "fen-phen." The Mayo Clinic article concluded: "These cases arouse concern that fenfluramine-phentermine therapy may be associated with valvular heart disease. Candidates for fenfluramine-phentermine therapy should be informed about serious potential adverse effects, including pulmonary hypertension and valvular heart disease."

This report prompted the FDA to request that doctors who prescribe the drugs to submit any information that they had linking them to mitral valve problems. In the two weeks after the Mayo Clinic report, the FDA received reports of heart valve problems in 60 more people. The FDA considered this an alarmingly high number and asked that both Fenfluramine (Pondimin) and Dexfenfluramine (Redux) be recalled by their manufacturers. Recent studies indicate that as many as 30% of the patients taking these recalled drugs might have heart valve abnormalities.

The following is recommended for any patient who took fenfluramine (Pondimin) or dexfenfluramine (Redux), either alone or in combination with other drugs, even for a short period of time.

See a doctor for a detailed medical history and physical examination. If the doctor detects a heart murmur or if symptoms such as shortness of breath are present, further evaluation with an echocardiogram should be done to determine whether there is any heart valve abnormalities.

If neither a heart murmur nor other symptoms are present, there is no immediate need for an echocardiogram. However, one should have an echocardiogram before undergoing dental, medical or surgical procedures.

These recommendations were developed by the Centers for Disease Control (CDC), the Food and Drug Administration (FDA), and the National Institutes of Health (NIH) in consultation with the American Heart Association (AHA), American College of Cardiology (ACC) and American Dental Association (ADA). They were published in the November 17, 1997, edition of the Morbidity and Mortality Weekly Report.

Studies are underway to determine whether these valvular abnormalities will eventually reverse after withdrawal from the drugs. Additionally, persons who have developed heart valve disease are at risk for a bacterial heart infection called endocarditis. Some experts are also concerned that serotonin levels may be depleted for as long as 18 months after these drugs are ceased which could cause severe depression.

THE NEW ANTI-OBESITY DRUG: MERIDIA

Meridia, (sibutramine hydrochloride monohydrate) was FDA approved in December 1997, and is manufactured by Knoll Pharmaceutical Company, Mt. Olive, NJ. It was originally developed and tested in 1984 as an antidepressant. Clinical trials failed to demonstrate antidepressant efficacy, but significant weight loss was observed in both healthy and depressed patients.

Because Meridia is so recently FDA approved and marketed, most of the information in this course about Meridia is taken from material obtained from the Knoll Pharmaceutical Company in Mt. Olive, New Jersey. In addition, because every aspect of Meridia obtained from the Knoll Pharmaceutical Company has not been included in this course, any health care professional planning to administer Meridia (sibutramine hydrochloride monohydrate) to a patient should be sure to read the Meridia Package Insert to familiarize themselves with all the necessary information concerning the administration of Meridia.

Meridia (sibutramine) is a norepinephrine and serotonin reuptake inhibitor that keeps the neurotransmitters serotonin and norepinephrine in balance and increases metabolism. Sibutramine increases both energy levels and the feeling of fullness. In clinical trials 69% of patients treated daily with 15 mg of sibutramine obtained a 5% or greater reduction in weight loss in their baseline weight. Additionally a significant reduction in waist/hip ratio, decreases in plasma triglycerides, total cholesterol and low density lipoprotein (LDL) cholesterol were observed. There were also increases in high-density lipoprotein (HDL).

How Meridia is Supplied:

5 mg (NDC 0048-0605-01) blue/yellow capsules imprinted with "MERIDIA" on the cap and "-5-" on the body, in bottles of 100 capsules.

10 mg (NDC 0048-0610-01) blue/white capsules imprinted with "MERIDA" on the cap and "-10-" on the body, in bottles of 100 capsules.

15 mg (NDC 0048-0615-01) yellow/white capsules imprinted with "MERIDIA" on the cap and "-15-" on the body, in bottles of 100 capsules.

Dosage and Administration:

The recommended starting dose of Meridia is 10 mg administered once daily with or without food. If there is inadequate weight loss, the dose may be titrated after 4 weeks to a total of 15 mg once a day. The 5 mg dose should be used for patients who do not tolerate the 10 mg dose. Dose titration decisions should take into consideration patient blood pressure and pulse fluctuations.

Doses above 15 mg daily are NOT recommended. In most of the clinical trials, Meridia was given in the morning.

Sixty percent of the patients who lost at least 4 pounds in the first 4 weeks of treatment with a given dose of Meridia in combination with a reduced caloric intake lost at least 5% (placebo subtracted) of their initial body weight by the end of 6 months to 1 year of treatment. Approximately 80% of patients who do not lose 4 pounds in the first 4 weeks of treatment with a given dose of Meridia do not lose at least 5% of their initial body weight by the end of 6 months to 1 year of treatment. Therefore, if a patient does NOT lose at least 4 pounds in the first 4 weeks of treatment, the physician should consider reevaluation of therapy that may include increasing the dose or discontinuation of Meridia.

The Knoll Pharmaceutical Company has stated: "THE SAFETY AND EFFECTIVENESS OF MERIDIA, AS DEMONSTRATED IN DOUBLE BLIND, PLACEBO-CONTROLLED TRIALS, HAVE NOT BEEN DETERMINED BEYOND 1 YEAR AT THIS TIME."

Sibutramine is rapidly absorbed from the gastrointestinal tract following oral administration and undergos extensive metabolism in the liver forming four metabolites M₁, M₂, M₅, and M₆. However, the two major pharmacologically active metabolites are M₁ and M₂. Peak plasma concentrations of the sibutramine metabolite (M₁ and M₂) are reached within 3 to 4 hours. At least 77% of a single dose of sibutramine is absorbed. However, the absolute bioavailability of sibutramine has not been determined.

Radiolabeled studies in animals have shown rapid and extensive distribution of sibutramine into tissues with the highest concentration found in the eliminating organs the liver and kidneys. M₁ and M₂ plasma concentrations reached steady state within four days of dosing and were approximately twice as high as the administration of a single dose. The elimination half-lives of M₁ and M₂ is 14 and 16 hours respectively and were unchanged with repeated dosing. Approximately 85% of a single orally administered radiolabeled dose was excreted in urine and feces over a 15 day period with the majority of the dose (77%) excreted in urine. The primary route of excretion for M₁ and M₂ is hepatic and for M₅ and M₆ is renal.

The administration of a single 20 mg dose of sibutramine with a standard breakfast resulted in reduced peak M₁ and M₂ concentrations (by about 27% and 32% respectively) and delayed the time to peak by approximately 3 hours.

In general, dose selection for an elderly person should be cautious and should reflect the greater frequency of decreased hepatic, renal, and cardiac function; and concomitant disease or other drug therapy.

The effect of renal disease has not been studied. However, since sibutramine and its active metabolites are eliminated by hepatic metabolism, renal disease is unlikely to have a significant effect on their disposition. MERIDIA (SIBUTRAMINE HYDROCHLORIDE MONOHYDRATE) SHOULD NOT BE USED IN PATIENTS WITH SEVERE RENAL IMPAIRMENT.

The observed differences in M₁ and M₂ concentrations do not warrant dosage adjustment in patients with mild to moderate hepatic impairment. However, MERIDIA SHOULD NOT BE USED IN PATIENTS WITH SEVERE HEPATIC DYSFUNCTION.

The long-term effects of Meridia on the morbidity and mortality associated with obesity have not been established. Weight was examined in 11 double blind, placebo-controlled obesity trials with durations of 12 to 52 weeks with doses ranging from 1mg to 30mg once daily. Weight was significantly reduced in a dose-related manner in sibutramine-treated patients compared to placebo over the dose range of 5 to 20 mg once daily. In two 12-month studies, maximal weight loss was achieved by 6 months and statistically significant weight loss was maintained over 12 months. The amount of placebo-subtracted weight loss achieved on Meridia was consistent across studies.

Indications and Usage

Meridia (sibutramine hydrochloride monohydrate) is indicated for the management of obesity, including weight loss and maintenance of weight loss, and should be used in conjunction with a reduced calorie diet.

General Precautions, Contraindications, and Warnings:

Meridia is contraindicated in patients receiving monoamine oxidase inhibitors (MAOIs).

Meridia is contraindicated in patients with hypersensitivity to sibutramine or any of the inactive ingredients of Meridia.

Meridia is contraindicated in patients who have anorexia nervosa.

Meridia is contraindicated in patients taking other centrally acting appetite suppressant drugs.

Blood Pressure and Pulse

MERIDIA SUBSTANTIALLY INCREASES BLOOD PRESSURE IN SOME PATIENTS. REGULAR MONITORING OF BLOOD PRESSURE IS REQUIRED WHEN PRESCRIBING MERIDIA. PULSE RATE SHOULD ALSO BE MONIOTORED.

Meridia has been associated with mean increases in systolic and diastolic blood pressure of approximately 1 to 3 mm Hg relative to placebo and with mean increases in pulse rate of approximately 4 to 5 beats per minute. Larger increases were seen in some patients, especially when Meridia therapy was initiated at higher doses.

MERIDA SHOULD NOT BE USED IN PATIENTS WITH A HISTORY OF CORONARY ARTERY DISEASE, CONGESTIVE HEART FAILURE, ARRHYTHMIAS, OR STROKE.

Merida has a FDA Pregnancy Risk Rating of "C" which means that adequate studies have not been done to determine Meridia’s effect on a human fetus. Therefore, Meridia should not be administered to pregnant women or women who are planning to become pregnant.

Meridia also should not be given to nursing mothers or persons under 16 years of age.

Because Meridia can cause mydriasis (dilation of the pupil), it should be used with caution in patients with narrow angle glaucoma.

Adverse Reactions to Meridia:

Body as a Whole:

Headache, back pain, flu syndrome, injury accident, asthenia, abdominal pain, chest pain, neck pain, allergic reaction, fever.

Cardiovascular System:

Tachycardia, vasodilation, Migraine, hypertension/increased blood pressure, palpitation

Digestive System:

Anorexia, constipation, increased appetite, nausea, dyspepsia, gastritis, vomit, rectal disorder, diarrhea, flatulence, gastroenteritis, tooth disorder.

Metabolic and Nutritional:

Thirst, generalized edema, peripheral edema.

Musculoskeletal System:

Arthralgia, myalgia, tenosynovitis, joint disorder, arthritis.

Nervous System:

Dry mouth, insomnia, dizziness, nervousness, anxiety, depression paresthesia, somnolence, CNS stimulation, emotional lability, agitation, leg cramps, hypertonia, thinking abnormal.

Respiratory System:

Rhinitis, pharyngitis, sinusitis, cough increase, laryngitis, bronchitis, dyspnea.

Skin and Appendages:

Rash, herpes simplex, acne, pruritus.

Special Senses:

Taste perversion, ear disorder, ear pain, amblyopia.

Urogenital System:

Dysmenorrhea, urinary tract infection, vaginal monilia, metrorrhagia, menstrual disorder.

Convulsions were reported in three of 4588 (<0.1%) Meridia treated patients.

Altered Laboratory Findings: Abnormal liver function tests, including increases in

AST, ALT, GGT, LDH, alkaline phosphatase, and bilirubin were reported as adverse reactions in 1.6% of Meridia-treated patients.

Meridia (sibutramine hydrochloride monohydrate) is controlled in Schedule IV of the Controlled Substances Act (CSA).

Physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely to check on possible signs of misuse or abuse.

Overdosage of Meridia:

There is very limited experience of overdose of Meridia. Only three cases have been reported.

One 2-year old child who took approximately eight 10 mg. capsules.

No complications were observed during his overnight hospitalization.

A 30-year old depressed male ingested about 100 mg of Meridia in a suicide attempt, was hospitalized overnight, but did not suffer any adverse effects.

A 45-year old husband of a woman in an obese study ingested 400 mg of his wife’s drug. He was hospitalized overnight for observation, a heart rate of 120 bpm was noted. He was discharged the next day with no apparent sequelae.

There is NO specific antidote for Meridia. Treatment should consist of general measures employed in the management of overdosage: establishment of an airway, cardiac and vital signs monitoring, general symptomatic and supportive measures should be instituted.

Patient Information:

MERIDIA SHOULD NOT BE TAKEN BY PEOPLE WHO:

Have uncontrolled or poorly controlled high blood pressure because Meridia substantially increases blood pressure in some patients.

Are taking prescription medicines called monoamine oxidase inhibitors (MAOI’s) for depression, Parkinson’s Disease, or any other disorder (for example: Eldepryl, Parnate, Nardil).

Are taking other weight loss medications of any kind, especially those that act on the brain (for example: phentermine). This includes over-the-counter medications and herbal products.

Have had prior allergic reactions to Meridia or sibutramine.

Have a diagnosis of coronary artery disease and/or angina pectoris (heart-related chest pain).

Have arrhythmias (irregular heart beats).

Have had a prior heart attach.

Have a diagnosis of congestive heart failure.

Have severe liver or kidney disease.

Have had a stroke or symptom of a stroke (transient ischemic attacks

[TIA’s]).

11) Are pregnant or planning to become pregnant.

12) Are breast-feeding their infants.

Are suffering from anorexia nervosa.

Are taking prescription medications for depression.

Have had seizures (epilepsy or convulsions).

Have an eye disorder called narrow angle glaucoma.

Are less than 16 years of age.

Are taking any of the other medications that regulate the neurotransmitter serotonin in the brain (for example: Prozac, Zoloft, Effexor, Luvox, or Paxil).

If any questions concerning this patient advice should arise, be SURE to discuss them with the physician administering/prescribing this medication.

IMPORTANT: It is very important that the person taking Meridia make sure that their primary care doctor and all other health care providers know the following:

What medications in addition to Meridia are being taken including prescription medications, OTC remedies and herbal remedies.

What medical conditions and allergies the patient may have.

That the prescribing doctor know the patient’s entire medical history including: Drugs taken, previous weight loss drugs taken, current medical problems or symptoms.

Any allergies the patient may have to foods, drugs or other substances.

It is mandatory that the doctor be aware of any of the following medical conditions: Heart diseased of any kind, high blood pressure, migraine headaches, glaucoma, seizure, depression, Parkinson’s disease, prior strokes, prior transient ischemic attacks (TIA’s), thyroid disorders, osteoporosis, gallstones, liver disease, kidney disease, or history of major eating disorder (anorexia nervosa or bulimia nervosa).

The patient on Meridia must be sure to have regular physician follow-up visits as directed so that body weight, and other physical factor can be carefully followed during the Meridia weight loss and weight maintenance program.

The patient should be aware that the metabolism of Meridia might be inhibited by ketoconazole (an anti-fungal medicine) and to a lesser degree erythromycin (an antibiotic medicine). Therefore, the patient must make sure that his/her doctor knows if the patient is taking these medicines prior to or concomitantly with Meridia.

Many over-the-counter cough and cold remedies as well as certain allergy products and decongestants, contain substances such as: phenylpropanolamine, ephedrine, or pseudoephedrine that may increase blood pressure or heart rate. Before taking these medications, the patient should check with their doctor to make sure it is safe to take these medications while taking Meridia. The doctor may advise the patient to take a certain type of cough, cold, decongestant or allergy medicine that will not negatively interact with Meridia.

ANTI-OBESITY DRUGS UNDER INVESTIGATION

Drugs with novel mechanisms of action are currently under investigation and development. These newer agents act by mechanisms that are not appetite dependent as the noradrenergic and serotonergic agents are. An example is Tetrahydrolipstatin, (Orlistat) which is a lipase inhibitor and acts by decreasing up to 33% of ingested dietary fat absorbed by the gastrointestinal tract.

Thermogenic agents are also under investigation with effects similar to exercise. These effects enhance cardiovascular fitness, increase potential for fatty acid oxidation by muscle, slows bone loss by strengthening trabecular bone and provides a feedback signal for modulation of food intake and body fat storage.

SURGICAL TREATMENT FOR OBESITY

The National Institutes of Health Consensus Conference in 1992 recommended that obesity surgery is an appropriate treatment for patients with a body mass index (BMI) >40 kg/m² who had failed in attempts at medical treatment and for a body mass index (BMI) >35 kg/m² with severe medical complications due to obesity.

Surgical weight loss programs because of their serious, invasive nature, are reserved for the morbidly obese (those who are at least 100 pounds overweight) and have tried and failed all other methods of weight loss. Surgical weight loss programs for the morbidly obese have been effective and usually have a high long-term success rate.

Surgery should be considered adjuvant therapy and to be successful over time should be part of a multidisciplinary approach. The significant long-term weight control resulting from surgical obesity therapy is associated with improvement of comorbidities, including diabetes, hypertension, hyperlipidemia, and pulmonary insufficiency.

There are three different surgical approaches to obesity: 1) vertical banded gastroplasty, 2) gastric bypass, and 3) biliopancreatic diversion. Because of severe complications (fat malabsorption with steatorrhea (excessive fat in the feces), severe protein deficiency, osteoporosis secondary to calcium and vitamin D malabsorption, and problems due to malabsorption of other fat-soluble vitamins) associated with biliopancreatic diversion, this procedure is considered by most investigators to be unacceptable.

Both gastric bypass and vertical banded gastroplasty are currently used procedures in the United States. One study showed that patients with gastric bypass maintained a loss of over 60% of their excess weight compared with 40% for vertical banded gastroplasty three years after surgery. A five year follow up showed equally satisfactory results.

Complications associated with vertical banded gastroplasty include rupture of the suture line and gastric ulcer with twenty-five percent of the patients complaining of nausea.

Complications associated with gastric bypass include an occasional anastomotic leak (leak where the bypass is connected), stomal stenosis, cholecystitis, the dumping syndrome, and iron-deficiency anemia.

The mortality for such surgical procedures is approximately one percent. In spite of the complications associated with obesity surgery, such surgery may be lifesaving for the high-risk, morbidly obese patient for whom other approaches to weight loss has failed.

A surgical program specializing in the treatment of morbid obesity through gastric stapling that is described on the Internet, describes their data concerning weight loss resulting from their operative procedures for obesity as follows:

1) Banded gastroplasty patients have maintained an average of 60% excess

weight loss at the end of five years.

2) Adjustable gastric band patients have maintained an average of 70%

excess weight loss at the end of five years.

3) Gastric bypass patients have maintained an average of 89% excess weight

loss at the end of five years.

The weight loss results of the surgical program as described are not guaranteed claiming that specific outcomes depend on a variety of clinical factors including how well the patient follows the recommended post-surgical regimen. If reliable, this information gives the reader some idea of the possible weight loss success rates of these surgical procedures for the treatment of morbid obesity.

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