With a jangle of bracelets, Patricia Shelton slid her chair in front of the air-conditioner in her daughter's apartment and fluttered her hands to cool her face.

"I swear, some days it's the menopause that gets me, not the H.I.V.," she said.

At 51, what she calls "being H.I.V." never really gets her. She has known she was infected since 1990, "the same time Magic Johnson announced to the world."

She is still on the two-drug regimen she started on, and her viral load is too low to be detected. But she leads workshops for older infected adults, and "I know I am very blessed," she said. "Some of them are on their fourth regimens, get bouts of PCP pneumonia, rashes, herpes, diarrhea."

In her 20's and 30's, she was a "closet heroin addict," keeping a Wall Street secretarial job, raising her children, not losing control. "A lot of us who had a past are happy housewives now, are mothers and grandmothers, are productive members of society," she said.

The infection lingers, but she has proved wrong the doctor who told her in 1990 that she had two years to live.

Although AIDS is thought of as a disease of the young, in the United States it is rapidly becoming one of the middle-aged and even the old. The number of Americans over age 50 infected with the virus that causes AIDS quintupled during the 1990's, "and a conservative estimate would be that there are more than 100,000 now," said Dr. Marcia G. Ory, a professor of public health at Texas A & M University and co-author of a 2003 report for the Centers for Disease Control and Prevention on AIDS in older Americans. Unless there is a new explosion of the disease among teenagers, demographers estimate, the majority of cases by the end of the decade will be in people over 50.

In New York City, the curve has moved even further. About 64 percent of the city's cases are over 40 right now, the New York City Department of Health said, and about 25 percent are over 50.

The medical and social ramifications of this shift are already becoming evident, particularly as the cost of care escalates.

"There will be some reality checking very soon," said Dr. Stephen Karpiak, research director at the AIDS Community Research Initiative of America, or Acria, a nonprofit group based in New York that does surveys and clinical trials. "People are already being assigned to nursing homes at age 55. That gets very expensive."

In large part, the changing demographic of the disease is a testament to medical progress. Thanks to a growing armory of antiretroviral drugs and advances in the way secondary infections are fought, the infected live longer. Many have heard from their doctors words that are strangely gratifying: You're getting old, and you'll die of something, but it won't be AIDS.

The increase is also, in part, statistical. Very few newborns now get the virus from their mothers, and very few hemophiliac children get it from blood products, so the average age of the infected has climbed. But there is a countervailing pressure; blood transfusions were once a major cause of AIDS among those over 50, and that risk has all but vanished.

There is also a new pool of cases, those who contract the infection later in life. In a 1999 C.D.C. survey, 44 percent of infected people aged 60 or over did not know how they encountered the virus. Only 30 percent of those under 50 did not.

Dr. Karpiak's team has interviewed 160 infected people over the age of 50 and plans to interview 1,000 more to assess the challenges of treating older patients. The preliminary results uncovered some problems.

For example, 71 percent lived alone. "That really struck me," Dr. Karpiak said. "That's the antithesis of the regular population, where 30 percent live alone."

More than half said they were not dating. Although most had living children, siblings or parents, only 23 percent said they looked to them first for emotional support or for help with chores like going to the store or changing a light bulb. More asked friends, and 26 percent said they relied on themselves or no one.

In Dr. Karpiak's survey, 79 percent said they needed more help with daily tasks like cooking, cleaning and transportation. Depression, inability to get out and forgetfulness about pill-taking may speed their declines.

Gay elderly people often have no children, and former addicts may be estranged from their families. In both groups, many may have already buried most of their old friends.

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"That's me," Dr. Karpiak said. "I'm a 57-year-old gay male. My peers are gone. My social network was zapped."

Poverty is another problem. About 60 percent in Dr. Karpiak's survey said they had "just enough money to get by," while another 9 percent said they could not make ends meet.

The city health department said 72 percent of New York's infected over 50 were on Medicaid. While less generous states have waiting lists for people needing help with paying for antiretrovirals, any infected resident of New York City is eligible for a raft of services. The homeless get apartments without having to stay in shelters. Nine centers run by the Momentum Project offer two meals a day, free groceries and subway fare, counseling, job training, and medical and dental care.

For those earning less than $30,000, a diagnosis leads to hospital care under Medicaid and antiretroviral drugs subsidized by the Ryan White Act. Social Security disability payments provide some income. That makes some AIDS patients complain that some of the uninfected are jealous. "People say, 'You've got it made, girl,' " said Helen Hernandez, who lives in the West Farms section of the Bronx. "They say they'd do better if they were infected, and they ask if they can buy your M11Q," she added, naming the city form that confirms the diagnosis.

There are medical challenges in treating this population. Older people take more medications, and drug interactions are magnified by toxic antiretrovirals. Older patients are also more likely to have heart disease or diabetes, and some antiretroviral drugs tend to drive up cholesterol or interfere with the way insulin is metabolized.

Some antiretrovirals strain the liver, and many older people have livers damaged by alcohol and the hepatitis that comes with drug use. And antiretroviral drugs may also exacerbate problems with the peripheral nerves needed for walking or opening jars.

Also, a recent study at the University of California, San Francisco, indicates that aging AIDS patients may have an increased risk of dementia as the virus allows the plaques associated with Alzheimer's disease to accumulate.

Older patients tend to be more forgetful anyway, which is dangerous because each lapse in taking pills on time increases the chances of developing a drug-resistant strain.

Meanwhile, efforts at prevention are complicated. Ms. Shelton said that in the discussions she leads, ignorance about sexual activity was common. Once when she led a group, she said, "People were asking me, 'Do people over 50 have sex?' and I said I gave somebody's dad condoms, and he was 83!"

Public health advertisements promoting condoms are usually aimed at the young, and as Kathleen M. Nokes, a nursing professor at Hunter College and chairwoman of the New York Association on H.I.V. over Fifty has pointed out, a postmenopausal woman cannot use fear of pregnancy to ask a man to use a condom, but "the virus doesn't care how old you are."

To some women, the news that they are infected comes as a shock because they have been faithful to husbands they thought were too.

Also, experts say, older people are less likely to admit to doctors or survey-takers that they engage in homosexual sex or extramarital sex. And doctors are less likely to ask older patients about their sex lives.

Doctors are also more likely to misdiagnose AIDS symptoms in the elderly. Shingles, for example, may be seen as a disease of aging. Night sweats may be written off as a symptom of menopause. AIDS dementia looks like Alzheimer's disease. Pneumocystis pneumonia can be mistaken for congestive heart failure.

Several studies have found that people over 50 are more likely to discover they are infected later than average, when they are severely immuno-compromised. Also, their survival after diagnosis is usually shorter.

A study done in 1992, before antiretroviral drugs were widespread, found that older people typically died within six months of diagnosis, compared with 16 months for younger people. As with flu, deterioration seemed to be faster in the old; specifically, they lose CD-4 immune-system cells faster.

Yet a survey done for the National Institutes of Health in 1997 found that many older patients felt that their arthritis, heart disease and diabetes were greater burdens than their H.I.V. infections. Dr. Karpiak's survey found similar results. Many in it had hepatitis C, nerve damage, arthritis, high blood pressure, diabetes, and vision and hearing problems.

"For a lot of the people we see, AIDS is not the most important thing in their lives," said J. Daniel Stricker, executive director of Acria. "A grandmother in the South Bronx may be taking care of her kids' kids, and be more worried about food and shelter and just getting through the day."

Despite facing serious problems, many older AIDS patients say they are relatively optimistic. In the Acria survey, about two-thirds reported some symptoms of depression, and most had sought treatment for it. Nonetheless, 78 percent said that, over all, they were somewhat or very satisfied with their lives.

Ms. Shelton said she hoped to live as long as one of her aunts. "She was 100-and-something," she said, "and still walking to the store."

New York Times

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back to:   Gender Community Homepage ~ Depression and Gender ToC

In an era of ever-expanding gay rights, gay awareness and gay pride, New Jersey Gov. James McGreevey's lifestyle seems antiquated: a gay man twice married to women and the father of two children.

But, say experts and formerly married gay men, pressures to live straight still override sexual orientation. Churches, the corporate world and family relationships continue to push gay men and lesbians into the closet, with a straight spouse as the perfect cover.

"There's an inordinate pressure for people to fit a certain mold," said Mark Shields, spokesman for the Human Rights Campaign in Washington, D.C., the country's largest gay and lesbian organization. Gays "stand against so many things you've been taught implicitly and explicitly from the moment you were born in this culture."

The number of gays or lesbians married to straight spouses is difficult to determine. Currently there are 6,000 to 7,000 active members of the national Straight Spouse Network, said Executive Director Amity Pierce Buxton in El Cerrito.

Buxton has been researching gay/straight marriages and speaking with some 9,000 spouses since the mid-1980s, when her husband came out as gay.

"He led a perfectly straight life, and it nearly killed him," said Buxton, who has two children with him. "He became physically depressed and withdrawn."

Many face similar lifelong struggles in these marriages, which are often based on true affection and respect. Information networks now exist for gay married men, married lesbians, straight partners and their children -- who each face different, painful issues.

"There is still a huge, negative wedge that says being gay or lesbian is sinful," said Bob, a 71-year-old formerly married gay man who asked that his last name not be used. He organized a chapter of the GAMMA (Gay Married Men Association) support group in Grand Rapids, Mich., where about 14 members of the national organization meet twice monthly.

In speaking with hundreds of gay married men through the years, Bob said, he most often hears of two pressures: church and family.

"Their families say, 'When are you going to marry and give me grandchildren?' And their churches look down on being gay" -- some even ask gays to renounce their sexuality or leave the congregation, Bob said.

Others are in professions that don't allow them to be themselves.

"I have clients who are teachers in Catholic schools and physicians very worried about being pegged as gay," said Joanne Fleisher, a licensed clinical social worker in Philadelphia who counsels married women attracted to other women. She's author of the upcoming book "Living Two Lives: A Married Woman's Guide to Coming Out."

The gay rights movement, especially active in recent years, isn't much inspiration to these men and women.

Tom Fronczak, a Providence, R.I., psychotherapist who has counseled gay married men for 17 years, said they generally don't identify with the increased visibility and acceptance of gays.

"They'll say, 'That's not me,' with all the (gay) pride celebrations" and other public pictures of gays, Fronczak said.

He runs the Gay Fathers of Rhode Island support group. During twice- monthly gatherings, men discuss the pull between marriage and fatherhood, and their identity as a gay or bisexual. "They're very conflicted about who they are, versus who they need to be for others," Fronczak said.

He added that he has never met a gay married man who has not been depressed or considered suicide: "These guys are so isolated. ... They feel there is no way out. They feel they are trapped between two worlds."

That's because despite more openness about being gay, it continues to be difficult.

"It is important to remember that only 14 states prohibit discrimination based on sexual orientation," said Karen Krahulik, director of the Center for Lesbian, Gay, Bisexual and Transgender Life at Duke University. "So far this year, 99 marriage-related bills have been introduced in 37 states, 91 of them to restrict gay marriage."

Some who work with married gays are cautiously optimistic that the younger generation of gays won't have to marry into the straight world.

"Hopefully it's dying out with old duffers like me," said Bob of Grand Rapids.

Shields, with the Human Rights Campaign, added, "One of the best ways gay people can help that is by living their lives out and open and honestly, so gay kids growing up today can see those happy role models. That is how change happens."

Dru Sefton, Michele M. Melendez, Newhouse News Service

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Community Health Survey Reveals Top Concern of Gay Men and Lesbians

A health survey conducted by K-Y Brand® Liquid at the Millennium March on Washington revealed that and mental health are among the most serious health concerns for gay men and lesbians. depression

Depression and mental health topped a list of health concerns that included, among other things, HIV/AIDS, , heart disease, aging and eating disorders. In fact, the issue of depression and mental health was the number one concern for lesbians and the number one concern for gay men after HIV/AIDS. drug use

"Depression and mental health are serious issues for the gay and lesbian community," said Dr. Stephen Goldstone, a physician who operates a predominantly gay practice in New York City. "This survey helps shed light on a problem that has long existed, but has received little attention."

Almost 75 percent of the respondents to the survey believe that depression is more common among gay men and lesbians than in the general population. Goldstone noted that it's no surprise that gay men and lesbians identified depression and mental health as a major concern, given the daily challenges that they face. Living openly or closeted each bring their own pressures that can affect a person's health and it can stem from a sense of isolation that so many feel, he said.

The problem of depression may also be heightened or caused by an individual's behavior, added Goldstone. For example, the degree to which someone uses illegal drugs or consumes alcohol can affect his or her mental health. Interestingly, these issues also ranked high as health concerns among gay and lesbian respondents.

A significant finding from the survey was the common use of "party drugs" among gay male respondents. Nearly 40 percent of gay men surveyed at the Millennium March said that "party drugs," such as cocaine, special K, crystal, ecstasy and GHB, are used at least once a month or more among their close circle of friends. On a positive note, an almost equal number, more than 38 percent, said that "party drugs" are never used among their close circle of friends.

Also significant was the finding that lesbians ranked alcohol abuse as their second highest health concern for the community after depression and mental health. More than 30 percent of gay men reported the same concern.

"What we are seeing is that mental and behavioral health are among the most pressing concerns for gay men and lesbians," said Goldstone. "Medical professionals need to recognize that these issues should be an integral part of any patient evaluation and they should treat patients accordingly. Gay and lesbian health is more than just sexual practices."

Other findings of the survey include:

· More than 70 percent of lesbians and more than 60 percent of gay men have sought or are actively considering mental health counseling.

· When asked where LGBT health organizations should focus their attention in the year 2000 and beyond, respondents identified depression as their #1 choice after HIV/AIDS.

· Seventy-five percent of those surveyed believe that drug, alcohol and tobacco addiction are greater in the gay community than in the general public.

· Almost 90 percent of gay men believe that "party drugs" are a threat to the health of the community.

· Almost 40 percent of gay men surveyed said that a partner has pressured them to have unprotected or unsafe sex.

· Nearly one in four respondents reported having been struck or hit by a boyfriend or girlfriend. (In many instances, gay and lesbian victims of domestic violence receive fewer protections than heterosexuals under various state laws and have fewer support services available to them, according to the American Bar Association. The fear of being "outed," or perceived law enforcement bias, may also limit reporting.)

· More than 83 percent of gay men and lesbians surveyed feel it is important or very important to have a gay or gay-friendly physician.

The vast majority of gay men and lesbians who completed the survey were out to family and close friends 97.6 percent and 86.3 percent, respectively. And more than 72 percent reported that their doctor knows they are gay.

"In light of the findings on depression and mental health, it's very encouraging to see such a large number of people living openly and honestly," said Goldstone. "Events such as the Millennium March and gay pride celebrations can play a crucial role in the development of a positive self-image. Gay men and lesbians need to know that they are not alone."

The K-Y Brand® Liquid Community Health Survey was conducted over a two-day period at the Millennium March in Washington, DC and asked respondents for their opinions on a wide range of health-related issues, including their personal health concerns, concerns for the health of the community and the future direction of gay and lesbian health care.

More than 1,200 gay men and lesbians were surveyed for the K-Y Brand® Liquid Community Health Survey. It is the third in a series of surveys targeting the gay and lesbian community conducted by K-Y Brand® Liquid. The first survey dealt with HIV/AIDS. The second explored the community's knowledge, attitudes and opinions about sexually transmitted diseases.

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back to:   Gender Community Homepage ~ Depression and Gender ToC

In the process of discovering your sexual orientation, there are many feelings you may experience as you develop self- acceptance. Because the world is still relatively hostile and prejudice towards gays and lesbians, it is not uncommon to feel confused, isolated, lonely, guilty or depressed. Unfortunately, many societies make people hide their homosexuality and as a result they end up living double lives and denying who they really are. Experiencing these feelings is normal. However, some feelings like depression, low self-esteem and suicidal thoughts indicate you need some professional help learning to accept your homosexuality.

Millions of Americans, both gay and straight, transgender and non-transgender, have emotional or psychological problems of some sort during their lives. While we know that homosexuality, bisexuality, and transgender identity are not mental illnesses, the stresses caused by society's negative messages, condemnation, and violence can sometimes result in depression and other types of emotional difficulties for GLBT persons.

Depression and GLBT Issues

• Depression and Mental Health Emerge as Major Concerns for the Gay/Lesbian Community
• Some Gays Feel Pushed to Marry Straights
• Facing Middle Age and AIDS
• Homophobia Causes Real Emotional Damage
• The Fallout: When a Spouse Comes Out

Depression Treatment

The treatment of mood disorders is not a simple matter. It is not so simple as diagnosing depression and writing a prescription for Zoloft or Effexor. The individual causes of depression are diverse and poorly understood. The antidepressant medications used to treat it are just as diverse and matching a drug with an individual is not a clear cut decision. Individual symptoms, co-existing illness, tolerance of side-effects, and other medications previously tried are just a few factors that must be considered.

In this section on abuse and depression, you'll find a few articles on treatment.

• Is Clinical Depression Treatable?
• Can Caviar Cure Depression?
• Cognitive Therapy for Depression
• Self Help for Depression

For the most comprehensive information about Depression and Treatment, visit our Depression Community Center at HealthyPlace.com.

 

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Contents

• Gay Is OK! Homepage
• About Me
• Coming Out - For Gay Teenagers
• Coming Out and Staying Out
• Coming Out Stories

Articles Table of Contents

• Searching for a Way Out
• Youth Suicide: What A Parent Needs To Know
• Suicide Myths and Facts
• Which Gay Teens Attempt Suicide?
• Suicide and Gay, Lesbian, Bisexual, and Transgender Youth
• Gay, Lesbian, Bisexual, Transgender Youth Suicide
• Gay Youth Suicide Prevention May Be Missing The Mark
• Stories of Gay Teen Suicide
• A Suicide Note From Bruce David Ciniello
• A Price Too High
• Who Pays The Price Of Hatred?
• Why Did Robbie Kirkland Have To Die?
• Stories about "Paying the Price of Being Gay
• Darren's Boyfriend's Gay
• About Joey
• Dreams

From Those Left Behind

• About Joey
• A Mother's Letter To Her Gay Son Bruce

Resources

• Emergency Numbers
• Teen Hotlines

Introduction

• Inside Intersexuality Homepage
• About Me

Frequently Asked Questions

• Intersexuality Frequently Asked Questions
  • What is intersexuality (or hermaphroditism)?
  • What is androgen insensitivity syndrome?
  • Is there a test for androgen insensitivity syndrome?
  • What is partial androgen insensitivity syndrome?
  • What is Progestin Induced Virilization?
  • What is Adrenal Hyperplasia?
  • What is Klinefelter syndrome?
  • What is hypospadias?
  • What are the frequencies of intersex conditions?
  • Is there a risk of gonadal tumors?
  • Hormone replacement therapy and osteoporosis
  • Where can I read some of the earliest first person writings of medicalized intersexuals?
  • Where can I read some of the earliest deconstructions of the medical viewpoint?
• Parents of Intersexed Children FAQ
  • The truth and reality about having an intersexual child
  • Q A about your intersex child
  • What is intersexuality?
  • What do you mean by "ambiguous genitalia"?
  • What is the traditional medical treatment for a child with ambiguous genitalia?
  • What do I do if I have a child with ambiguous genitals?
  • What sex should I raise my baby as?
  • What should I tell my child about his/her condition?
  • Can an intersexual live a happy, fulfilled life?
  • Recommendable Literature
  • Recommendable Family Support Groups
  • Addendum: A note on follow-ups
• Frequently Asked Questions from Non-Intersexed People
• Sexual Development - Glossary of Terms

Articles

• Hermaphrodite Porn is Faked
• Sexpolice
• The True Story of John / Joan
• Intersex Survivors of Domestic Violence
• A Native American Perspective on the Theory of Gender Continuum by DRK
• Berdache Tradition
• Multi-Dimensionality of Gender
• Marriage Between Close Relations Increases Risk Of Hermaphroditism
• Intersexuality - A Plea for Honesty and Emotional Support
• Syndromes of Abnormal Sex Differentiation
• A Single Word: Stop!
• Report on Treatment of Newborns With Genital Abnormalities
• The Medical Management of Intersexed Children: An Analogue for Childhood Sexual Abuse
• Management of Intersexuality
• Sexual Scientists Question Medical Treatment of Hermaphroditism
• Genital Surgery On Intersexed Children
• Trauma
• Sexual Differentiation
• Multi-Dimensionality of Gender
• First-Person Stories By Intersexuals About Their Lives
• Guide to Medical Intersexuality Vocabulary

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~ all articles on gender

Pain And Sorrow This life is filled with pain and sorrow, I always wonder if I'll make it through tomorrow. I don't know what I'm going to do, I'm always missing missing and missing you. I think about the joy, laughter, and tears, and try not to have any fears. I close my eyes and take a deep breath, But once again I start thinking about your death. You know you will always be in my heart, But it is slowly cracking and breaking apart. I always loved having you near, and now I wish you were still here. Why couldn't god give me one more day with my Bub my Hero my guardian angel that's now up above. I love and miss my Bub... Truly, Your Bub

1. Alternative Sexual Practices
   Guest: Randy Chelsey, MFT

2. Reclaiming Your Sexuality
   Guest: Sex Therapist, Linda Savage, Ph.D.

3. Sexual Addiction
   Guest: Dr. Phillip Sharp

4. Sexual Issues and Sex Questions
   Guest: Dr. Marlene Shiple

 

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back to: Sex Community Homepage ~ Other Conference Transcripts on Mental Health

1. Coming Out and other GLBT Issues
   Guest: Joe Kort, MSW

2. Coping With Feelings and Thoughts of Suicide
   Guest: Dr. Alan Lewis

3. Gay and Lesbian Relationships
   Guest: Roy Young, MSW

4. Gay Teen Issues
   Guest: Greg Cason, Ph.D.

 

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back to: Gender LGBT Community Homepage ~ Other Conference Transcripts on Mental Health

Brand Name: Starlix
Generic Name: nateglinide tablets

Contents:

Description
Clinical Pharmacology
Clinical Studies
Indications and Usage
Contraindications
Precautions
Adverse Reactions
Overdosage
Dosage and Administration
How Supplied

Starlix, nateglinide, full patient information (in plain English)

Description

Starlix® (nateglinide) is an oral antidiabetic agent used in the management of Type 2 diabetes mellitus [also known as non-insulin dependent diabetes mellitus (NIDDM) or adult-onset diabetes]. Starlix, (-)-N-[(trans-4-isopropylcyclohexane)carbonyl]-D-phenylalanine, is structurally unrelated to the oral sulfonylurea insulin secretagogues.

The structural formula is as shown

Nateglinide is a white powder with a molecular weight of 317.43. It is freely soluble in methanol, ethanol, and chloroform, soluble in ether, sparingly soluble in acetonitrile and octanol, and practically insoluble in water. Starlix biconvex tablets contain 60 mg, or 120 mg, of nateglinide for oral administration.

Inactive Ingredients: colloidal silicon dioxide, croscarmellose sodium, hydroxypropyl methylcellulose, iron oxides (red or yellow), lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, talc, and titanium dioxide.

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Clinical Pharmacology

Mechanism of Action

Nateglinide is an amino-acid derivative that lowers blood glucose levels by stimulating insulin secretion from the pancreas. This action is dependent upon functioning beta-cells in the pancreatic islets. Nateglinide interacts with the ATP-sensitive potassium (K+ATP) channel on pancreatic beta-cells. The subsequent depolarization of the beta cell opens the calcium channel, producing calcium influx and insulin secretion. The extent of insulin release is glucose dependent and diminishes at low glucose levels. Nateglinide is highly tissue selective with low affinity for heart and skeletal muscle.

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Pharmacokinetics

Absorption

Following oral administration immediately prior to a meal, nateglinide is rapidly absorbed with mean peak plasma drug concentrations (Cmax) generally occurring within 1 hour (Tmax) after dosing. When administered to patients with Type 2 diabetes over the dosage range 60 mg to 240 mg three times a day for one week, nateglinide demonstrated linear pharmacokinetics for both AUC (area under the time/plasma concentration curve) and Cmax. Tmax was also found to be independent of dose in this patient population. Absolute bioavailability is estimated to be approximately 73%. When given with or after meals, the extent of nateglinide absorption (AUC) remains unaffected. However, there is a delay in the rate of absorption characterized by a decrease in Cmax and a delay in time to peak plasma concentration (Tmax). Plasma profiles are characterized by multiple plasma concentration peaks when nateglinide is administered under fasting conditions. This effect is diminished when nateglinide is taken prior to a meal.

Distribution

Based on data following intravenous (IV) administration of nateglinide, the steady-state volume of distribution of nateglinide is estimated to be approximately 10 liters in healthy subjects. Nateglinide is extensively bound (98%) to serum proteins, primarily serum albumin, and to a lesser extent α1 acid glycoprotein. The extent of serum protein binding is independent of drug concentration over the test range of 0.1-10 µg/mL.

Metabolism

Nateglinide is metabolized by the mixed-function oxidase system prior to elimination. The major routes of metabolism are hydroxylation followed by glucuronide conjugation. The major metabolites are less potent antidiabetic agents than nateglinide. The isoprene minor metabolite possesses potency similar to that of the parent compound nateglinide.

In vitro data demonstrate that nateglinide is predominantly metabolized by cytochrome P450 isoenzymes CYP2C9 (70%) and CYP3A4 (30%).

Excretion

Nateglinide and its metabolites are rapidly and completely eliminated following oral administration. Within 6 hours after dosing, approximately 75% of the administered 14C-nateglinide was recovered in the urine. Eighty-three percent of the 14C-nateglinide was excreted in the urine with an additional 10% eliminated in the feces. Approximately 16% of the 14C-nateglinide was excreted in the urine as parent compound. In all studies of healthy volunteers and patients with Type 2 diabetes, nateglinide plasma concentrations declined rapidly with an average elimination half-life of approximately 1.5 hours. Consistent with this short elimination half-life, there was no apparent accumulation of nateglinide upon multiple dosing of up to 240 mg three times daily for 7 days.

Drug Interactions

In vitro drug metabolism studies indicate that Starlix is predominantly metabolized by the cytochrome P450 isozyme CYP2C9 (70%) and to a lesser extent CYP3A4 (30%). Starlix is a potential inhibitor of the CYP2C9 isoenzyme in vivo as indicated by its ability to inhibit the in vitro metabolism of tolbutamide. Inhibition of CYP3A4 metabolic reactions was not detected in in vitro experiments.

Glyburide: In a randomized, multiple-dose crossover study, patients with Type 2 diabetes were administered 120 mg Starlix three times a day before meals for 1 day in combination with glyburide 10 mg daily. There were no clinically relevant alterations in the pharmacokinetics of either agent.

Metformin: When Starlix 120 mg three times daily before meals was administered in combination with metformin 500 mg three times daily to patients with Type 2 diabetes, there were no clinically relevant changes in the pharmacokinetics of either agent.

Digoxin: When Starlix 120 mg before meals was administered in combination with a single 1-mg dose of digoxin to healthy volunteers, there were no clinically relevant changes in the pharmacokinetics of either agent.

Warfarin: When healthy subjects were administered Starlix 120 mg three times daily before meals for four days in combination with a single dose of warfarin 30 mg on day 2, there were no alterations in the pharmacokinetics of either agent. Prothrombin time was not affected.

Diclofenac: Administration of morning and lunch doses of Starlix 120 mg in combination with a single 75-mg dose of diclofenac in healthy volunteers resulted in no significant changes to the pharmacokinetics of either agent.

Special Populations

Geriatric: Age did not influence the pharmacokinetic properties of nateglinide. Therefore, no dose adjustments are necessary for elderly patients.

Gender: No clinically significant differences in nateglinide pharmacokinetics were observed between men and women. Therefore, no dose adjustment based on gender is necessary.

Race: Results of a population pharmacokinetic analysis including subjects of Caucasian, Black, and other ethnic origins suggest that race has little influence on the pharmacokinetics of nateglinide.

Renal Impairment: Compared to healthy matched subjects, patients with Type 2 diabetes and moderate-to-severe renal insufficiency (CrCl 15-50 mL/min) not on dialysis displayed similar apparent clearance, AUC, and Cmax. Patients with Type 2 diabetes and renal failure on dialysis exhibited reduced overall drug exposure. However, hemodialysis patients also experienced reductions in plasma protein binding compared to the matched healthy volunteers.

Hepatic Impairment: The peak and total exposure of nateglinide in non-diabetic subjects with mild hepatic insufficiency were increased by 30% compared to matched healthy subjects. Starlix® (nateglinide) should be used with caution in patients with chronic liver disease. (See PRECAUTIONS, Hepatic Impairment.)

Pharmacodynamics

Starlix is rapidly absorbed and stimulates pancreatic insulin secretion within 20 minutes of oral administration. When Starlix is dosed three times daily before meals there is a rapid rise in plasma insulin, with peak levels approximately 1 hour after dosing and a fall to baseline by 4 hours after dosing.

In a double-blind, controlled clinical trial in which Starlix was administered before each of three meals, plasma glucose levels were determined over a 12-hour, daytime period after 7 weeks of treatment. Starlix was administered 10 minutes before meals. The meals were based on standard diabetic weight maintenance menus with the total caloric content based on each subject's height. Starlix produced statistically significant decreases in fasting and postprandial glycemia compared to placebo.

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Clinical Studies

A total of 3,566 patients were randomized in nine double-blind, placebo- or active-controlled studies 8 to 24 weeks in duration to evaluate the safety and efficacy of Starlix® (nateglinide). 3,513 patients had efficacy values beyond baseline. In these studies Starlix was administered up to 30 minutes before each of three main meals daily.

Starlix® Monotherapy Compared to Placebo

In a randomized, double-blind, placebo-controlled, 24-week study, patients with Type 2 diabetes with HbA1C ≥ 6.8% on diet alone were randomized to receive either Starlix (60 mg or 120 mg three times daily before meals) or placebo. Baseline HbA1C ranged from 7.9% to 8.1% and 77.8% of patients were previously untreated with oral antidiabetic therapy. Patients previously treated with antidiabetic medications were required to discontinue that medication for at least 2 months before randomization. The addition of Starlix before meals resulted in statistically significant reductions in mean HbA1C and mean fasting plasma glucose (FPG) compared to placebo (see Table 1). The reductions in HbA1C and FPG were similar for patients naïve to, and those previously exposed to, antidiabetic medications.

In this study, one episode of severe hypoglycemia (plasma glucose < 36 mg/dL) was reported in a patient treated with Starlix 120 mg three times daily before meals. No patients experienced hypoglycemia that required third party assistance. Patients treated with Starlix had statistically significant mean increases in weight compared to placebo (see Table 1).

In another randomized, double-blind, 24-week, active- and placebo-controlled study, patients with Type 2 diabetes were randomized to receive Starlix (120 mg three times daily before meals), metformin 500 mg (three times daily), a combination of Starlix 120 mg (three times daily before meals) and metformin 500 mg (three times daily), or placebo. Baseline HbA1C ranged from 8.3% to 8.4%. Fifty-seven percent of patients were previously untreated with oral antidiabetic therapy. Starlix monotherapy resulted in significant reductions in mean HbA1C and mean FPG compared to placebo that were similar to the results of the study reported above (see Table 2).

Table 1: Endpoint results for a 24-week, fixed dose study of Starlix® monotherapy

	Placebo	Starlix® 60 mg three times daily before meals	Starlix® 120 mg three times daily before meals
HbA1C (%)	N=168	N=167	N=168
Baseline (mean)	8.0	7.9	8.1
Change from baseline (mean)	+0.2	-0.3	-0.5
Difference from placebo (mean)		-0.5 a	-0.7 a
FPG (mg/dL)	N=172	N=171	N=169
Baseline (mean)	167.9	161.0	166.5
Change from baseline (mean)	+9.1	+0.4	-4.5
Difference from placebo (mean)		-8.7 a	-13.6 a
Weight (kg)	N=170	N=169	N=166
Baseline (mean)	85.8	83.7	86.3
Change from baseline (mean)	-0.7	+0.3	+0.9
Difference from placebo (mean)		+1.0 a	+1.6 a

a p-value ≤ 0.004

Starlix® Monotherapy Compared to Other Oral Antidiabetic Agents

Glyburide

In a 24-week, double-blind, active-controlled trial, patients with Type 2 diabetes who had been on a sulfonylurea for ≥ 3 months and who had a baseline HbA1C ≥ 6.5% were randomized to receive Starlix (60 mg or 120 mg three times daily before meals) or glyburide 10 mg once daily. Patients randomized to Starlix had significant increases in mean HbA1C and mean FPG at endpoint compared to patients randomized to glyburide.

Metformin

In another randomized, double-blind, 24-week, active- and placebo-controlled study, patients with Type 2 diabetes were randomized to receive Starlix (120 mg three times daily before meals), metformin 500 mg (three times daily), a combination of Starlix 120 mg (three times daily before meals) and metformin 500 mg (three times daily), or placebo. Baseline HbA1C ranged from 8.3% to 8.4%. Fifty-seven percent of patients were previously untreated with oral antidiabetic therapy. The reductions in mean HbA1C and mean FPG at endpoint with metformin monotherapy were significantly greater than the reductions in these variables with Starlix monotherapy (see Table 2). Relative to placebo, Starlix monotherapy was associated with significant increases in mean weight whereas metformin monotherapy was associated with significant decreases in mean weight. Among the subset of patients naïve to antidiabetic therapy, the reductions in mean HbA1C and mean FPG for Starlix monotherapy were similar to those for metformin monotherapy (see Table 2). Among the subset of patients previously treated with other antidiabetic agents, primarily glyburide, HbA1C in the Starlix monotherapy group increased slightly from baseline, whereas HbA1C was reduced in the metformin monotherapy group (see Table 2).

Starlix® Combination Therapy

Metformin

In another randomized, double-blind, 24-week, active- and placebo-controlled study, patients with Type 2 diabetes were randomized to receive Starlix (120 mg three times daily before meals), metformin 500 mg (three times daily), a combination of Starlix 120 mg (three times daily before meals) and metformin 500 mg (three times daily), or placebo. Baseline HbA1C ranged from 8.3% to 8.4%. Fifty-seven percent of patients were previously untreated with oral antidiabetic therapy. Patients previously treated with antidiabetic medications were required to discontinue medication for at least 2 months before randomization. The combination of Starlix and metformin resulted in statistically significantly greater reductions in HbA1C and FPG compared to either Starlix or metformin monotherapy (see Table 2). Starlix, alone or in combination with metformin, significantly reduced the prandial glucose elevation from pre-meal to 2-hours post-meal compared to placebo and metformin alone.

In this study, one episode of severe hypoglycemia (plasma glucose ≤ 36 mg/dL) was reported in a patient receiving the combination of Starlix and metformin and four episodes of severe hypoglycemia were reported in a single patient in the metformin treatment arm. No patient experienced an episode of hypoglycemia that required third party assistance. Compared to placebo, Starlix monotherapy was associated with a statistically significant increase in weight, while no significant change in weight was observed with combined Starlix and metformin therapy (see Table 2).

In another 24-week, double-blind, placebo-controlled trial, patients with Type 2 diabetes with HbA1C ≥ 6.8% after treatment with metformin (≥ 1500 mg daily for ≥ 1 month) were first entered into a four week run-in period of metformin monotherapy (2000 mg daily) and then randomized to receive Starlix (60 mg or 120 mg three times daily before meals) or placebo in addition to metformin. Combination therapy with Starlix and metformin was associated with statistically significantly greater reductions in HbA1C compared to metformin monotherapy (-0.4% and -0.6% for Starlix 60 mg and Starlix 120 mg plus metformin, respectively).

Table 2: Endpoint results for a 24-week study of Starlix®monotherapy and combination with metformin

	Placebo	Starlix® 120 mg three times daily before meals	Metformin 500 mg three times daily	Starlix® 120 mg before meals plus Metformin*
HbA1C (%)
All	N=160	N=171	N=172	N=162
Baseline (mean)	8.3	8.3	8.4	8.4
Change from baseline (mean)	+0.4	-0.4 bc	-0.8 c	-1.5
Difference from placebo		-0.8 a	-1.2 a	-1.9 a
NaÑ—ve	N=98	N=99	N=98	N=81
Baseline (mean)	8.2	8.1	8.3	8.2
Change from baseline (mean)	+0.3	-0.7 c	-0.8 c	-1.6
Difference from placebo		-1.0 a	-1.1 a	-1.9 a
Non-NaÑ—ve	N=62	N=72	N=74	N=81
Baseline (mean)	8.3	8.5	8.7	8.7
Change from baseline (mean)	+0.6	+0.004 bc	-0.8 c	-1.4
Difference from placebo		-0.6 a	-1.4 a	-2.0 a
FPG (mg/dL)
All	N=166	N=173	N=174	N=167
Baseline (mean)	194.0	196.5	196.0	197.7
Change from baseline (mean)	+8.0	-13.1 bc	-30.0 c	-44.9
Difference from placebo		-21.1 a	-38.0 a	-52.9 a
Weight (kg)
All	N=160	N=169	N=169	N=160
Baseline (mean)	85.0	85.0	86.0	87.4
Change from baseline (mean)	-0.4	+0.9 bc	-0.1	+0.2
Difference from placebo		+1.3 a	+0.3	+0.6

a p-value ≤ 0.05 vs. placebo

b p-value ≤ 0.03 vs. metformin

c p-value ≤ 0.05 vs. combination

* Metformin was administered three times daily

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Rosiglitazone

A 24-week, double blind multicenter, placebo-controlled trial was performed in patients with Type 2 diabetes not adequately controlled after a therapeutic response to rosiglitazone monotherapy 8 mg daily. The addition of Starlix (120 mg three times per day with meals) was associated with statistically significantly greater reductions in HbA1C compared to rosiglitazone monotherapy. The difference was -0.77% at 24 weeks. The mean change in weight from baseline was about +3 kg for patients treated with Starlix plus rosiglitazone vs about +1 kg for patients treated with placebo plus rosiglitazone.

Glyburide

In a 12-week study of patients with Type 2 diabetes inadequately controlled on glyburide 10 mg once daily, the addition of Starlix (60 mg or 120 mg three times daily before meals) did not produce any additional benefit.

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Indications and Usage

Starlix® (nateglinide) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

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Contraindications

Starlix® (nateglinide) is contraindicated in patients with:

1. Known hypersensitivity to the drug or its inactive ingredients.

2. Type 1 diabetes.

3. Diabetic ketoacidosis. This condition should be treated with insulin.

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Precautions

Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Starlix or any other antidiabetic drug.

Hypoglycemia: All oral blood glucose lowering drugs that are absorbed systemically are capable of producing hypoglycemia. The frequency of hypoglycemia is related to the severity of the diabetes, the level of glycemic control, and other patient characteristics. Geriatric patients, malnourished patients, and those with adrenal or pituitary insufficiency or severe renal impairment are more susceptible to the glucose lowering effect of these treatments. The risk of hypoglycemia may be increased by strenuous physical exercise, ingestion of alcohol, insufficient caloric intake on an acute or chronic basis, or combinations with other oral antidiabetic agents. Hypoglycemia may be difficult to recognize in patients with autonomic neuropathy and/or those who use beta-blockers. Starlix® (nateglinide) should be administered prior to meals to reduce the risk of hypoglycemia. Patients who skip meals should also skip their scheduled dose of Starlix to reduce the risk of hypoglycemia.

Hepatic Impairment: Starlix should be used with caution in patients with moderate-to-severe liver disease because such patients have not been studied.

Loss of Glycemic Control

Transient loss of glycemic control may occur with fever, infection, trauma, or surgery. Insulin therapy may be needed instead of Starlix therapy at such times. Secondary failure, or reduced effectiveness of Starlix over a period of time, may occur.

Information for Patients

Patients should be informed of the potential risks and benefits of Starlix and of alternative modes of therapy. The risks and management of hypoglycemia should be explained. Patients should be instructed to take Starlix 1 to 30 minutes before ingesting a meal, but to skip their scheduled dose if they skip the meal so that the risk of hypoglycemia will be reduced. Drug interactions should be discussed with patients. Patients should be informed of potential drug-drug interactions with Starlix.

Laboratory Tests

Response to therapies should be periodically assessed with glucose values and HbA1C levels.

Drug Interactions

Nateglinide is highly bound to plasma proteins (98%), mainly albumin. In vitro displacement studies with highly protein-bound drugs such as furosemide, propranolol, captopril, nicardipine, pravastatin, glyburide, warfarin, phenytoin, acetylsalicylic acid, tolbutamide, and metformin showed no influence on the extent of nateglinide protein binding. Similarly, nateglinide had no influence on the serum protein binding of propranolol, glyburide, nicardipine, warfarin, phenytoin, acetylsalicylic acid, and tolbutamide in vitro. However, prudent evaluation of individual cases is warranted in the clinical setting.

Certain drugs, including nonsteroidal anti-inflammatory agents (NSAIDs), salicylates, monoamine oxidase inhibitors, and non-selective beta-adrenergic-blocking agents may potentiate the hypoglycemic action of Starlix and other oral antidiabetic drugs.

Certain drugs including thiazides, corticosteroids, thyroid products, and sympathomimetics may reduce the hypoglycemic action of Starlix and other oral antidiabetic drugs.

When these drugs are administered to or withdrawn from patients receiving Starlix, the patient should be observed closely for changes in glycemic control.

Drug/Food Interactions

The pharmacokinetics of nateglinide were not affected by the composition of a meal (high protein, fat, or carbohydrate). However, peak plasma levels were significantly reduced when Starlix was administered 10 minutes prior to a liquid meal. Starlix did not have any effect on gastric emptying in healthy subjects as assessed by acetaminophen testing.

Carcinogenesis/Mutagenesis/Impairment of Fertility

Carcinogenicity: A two-year carcinogenicity study in Sprague-Dawley rats was performed with oral doses of nateglinide up to 900 mg/kg/day, which produced AUC exposures in male and female rats approximately 30 and 40 times the human therapeutic exposure respectively with a recommended Starlix dose of 120 mg, three times daily before meals. A two-year carcinogenicity study in B6C3F1 mice was performed with oral doses of nateglinide up to 400 mg/kg/day, which produced AUC exposures in male and female mice approximately 10 and 30 times the human therapeutic exposure with a recommended Starlix dose of 120 mg, three times daily before meals. No evidence of a tumorigenic response was found in either rats or mice.

Mutagenesis: Nateglinide was not genotoxic in the in vitro Ames test, mouse lymphoma assay, chromosome aberration assay in Chinese hamster lung cells, or in the in vivo mouse micronucleus test.

Impairment of Fertility: Fertility was unaffected by administration of nateglinide to rats at doses up to 600 mg/kg (approximately 16 times the human therapeutic exposure with a recommended Starlix dose of 120 mg three times daily before meals).

Pregnancy

Pregnancy Category C

Nateglinide was not teratogenic in rats at doses up to 1000 mg/kg (approximately 60 times the human therapeutic exposure with a recommended Starlix dose of 120 mg, three times daily before meals). In the rabbit, embryonic development was adversely affected and the incidence of gallbladder agenesis or small gallbladder was increased at a dose of 500 mg/kg (approximately 40 times the human therapeutic exposure with a recommended Starlix dose of 120 mg, three times daily before meals). There are no adequate and well-controlled studies in pregnant women. Starlix should not be used during pregnancy.

Labor and Delivery

The effect of Starlix on labor and delivery in humans is not known.

Nursing Mothers

Studies in lactating rats showed that nateglinide is excreted in the milk; the AUC0-48h ratio in milk to plasma was approximately 1:4. During the peri- and postnatal period body weights were lower in offspring of rats administered nateglinide at 1000 mg/kg (approximately 60 times the human therapeutic exposure with a recommended Starlix dose of 120 mg, three times daily before meals). It is not known whether Starlix is excreted in human milk. Because many drugs are excreted in human milk, Starlix should not be administered to a nursing woman.

Pediatric Use

The safety and effectiveness of Starlix in pediatric patients have not been established.

Geriatric Use

No differences were observed in safety or efficacy of Starlix between patients age 65 and over, and those under age 65. However, greater sensitivity of some older individuals to Starlix therapy cannot be ruled out.

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Adverse Reactions

In clinical trials, approximately 2,600 patients with Type 2 diabetes were treated with Starlix® (nateglinide). Of these, approximately 1,335 patients were treated for 6 months or longer and approximately 190 patients for one year or longer.

Hypoglycemia was relatively uncommon in all treatment arms of the clinical trials. Only 0.3% of Starlix patients discontinued due to hypoglycemia. Gastrointestinal symptoms, especially diarrhea and nausea, were no more common in patients using the combination of Starlix and metformin than in patients receiving metformin alone. Likewise, peripheral edema was no more common in patients using the combination of Starlix and rosiglitazone than in patients receiving rosiglitazone alone. The following table lists events that occurred more frequently in Starlix patients than placebo patients in controlled clinical trials.

Common Adverse Events (≥ 2% in Starlix® patients) in Starlix® Monotherapy Trials (% of patients)

	Placebo	Starlix®
	N=458	N=1441
Preferred Term
Upper Respiratory Infection	8.1	10.5
Back Pain	3.7	4.0
Flu Symptoms	2.6	3.6
Dizziness	2.2	3.6
Arthropathy	2.2	3.3
Diarrhea	3.1	3.2
Accidental Trauma	1.7	2.9
Bronchitis	2.6	2.7
Coughing	2.2	2.4
Hypoglycemia	0.4	2.4

During post-marketing experience, rare cases of hypersensitivity reactions such as rash, itching and urticaria have been reported. Similarly, cases of jaundice, cholestatic hepatitis and elevated liver enzymes have been reported.

Laboratory Abnormalities

Uric Acid: There were increases in mean uric acid levels for patients treated with Starlix alone, Starlix in combination with metformin, metformin alone, and glyburide alone. The respective differences from placebo were 0.29 mg/dL, 0.45 mg/dL, 0.28 mg/dL, and 0.19 mg/dL. The clinical significance of these findings is unknown.

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Overdosage

In a clinical study in patients with Type 2 diabetes, Starlix® (nateglinide) was administered in increasing doses up to 720 mg a day for 7 days and there were no clinically significant adverse events reported. There have been no instances of overdose with Starlix in clinical trials. However, an overdose may result in an exaggerated glucose-lowering effect with the development of hypoglycemic symptoms. Hypoglycemic symptoms without loss of consciousness or neurological findings should be treated with oral glucose and adjustments in dosage and/or meal patterns. Severe hypoglycemic reactions with coma, seizure, or other neurological symptoms should be treated with intravenous glucose. As nateglinide is highly protein bound, dialysis is not an efficient means of removing it from the blood.

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Dosage and Administration

Starlix® (nateglinide) should be taken 1 to 30 minutes prior to meals.

Monotherapy and Combination with Metformin or a Thiazolidinedione

The recommended starting and maintenance dose of Starlix, alone or in combination with metformin or a thiazolidinedione, is 120 mg three times daily before meals.

The 60-mg dose of Starlix, either alone or in combination with metformin or a thiazolidinedione, may be used in patients who are near goal HbA1C when treatment is initiated.

Dosage in Geriatric Patients

No special dose adjustments are usually necessary. However, greater sensitivity of some individuals to Starlix therapy cannot be ruled out.

Dosage in Renal and Hepatic Impairment

No dosage adjustment is necessary in patients with mild-to-severe renal insufficiency or in patients with mild hepatic insufficiency. Dosing of patients with moderate-to-severe hepatic dysfunction has not been studied. Therefore, Starlix should be used with caution in patients with moderate-to-severe liver disease (see PRECAUTIONS, Hepatic Impairment).

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How Supplied

Starlix® (nateglinide) tablets

60 mg

Pink, round, beveled edge tablet with "Starlix" debossed on one side and "60" on the other.

Bottles of 100.......................................................NDC 0078-0351-05

120 mg

Yellow, ovaloid tablet with "Starlix" debossed on one side and "120" on the other.

Bottles of 100.......................................................NDC 0078-0352-05

Storage

Store at 25 ºC (77 ºF); excursions permitted to 15 ºC-30 ºC (59 ºF-86 ºF).

Dispense in a tight container, USP.

T2008-01

REV: JULY 2008

Manufactured by:

Novartis Pharma Stein AG
Stein, Switzerland

Distributed by:

Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936

©Novartis

Last Updated 07/2008

Starlix, nateglinide, full patient information (in plain English)

Detailed Info on Signs, Symptoms, Causes, Treatments of Diabetes

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The information in this monograph is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects. This information is generalized and is not intended as specific medical advice. If you have questions about the medicines you are taking or would like more information, check with your doctor, pharmacist, or nurse.

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