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Appetite suppressants are the most popular and reliable treatments when it comes to losing extra pounds from your body. Appetite suppressants promote satiety by altering the chemicals in the brain that control your hunger.The most popular appetite suppressant is Reductil, which is available only on prescription from a doctor. It contains sibutramine as its main ...
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Lose weight with raw foods. Guidance and resources for vibrant health. Angela Stokes lost 160lbs with a raw lifestyle and reversed morbid obesity - she shows you how.
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Rapid Weight Loss - Effects and problems of losing weight fast

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Generally speaking rapid weight loss is associated with extreme dieting. Though there are circumstances under which medically supervised rapid weight loss can be administered, it is generally . . .
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New Research Reveals Cutting Carbohydrates May Be Better Than Low-Fat Dieting.

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As a chiropractor in San Diego, nutrition and diet is an important element in consulting with patients. Eating fat is bad many will say. But no wait; it's carbohydrates that are evil. One expert says one thing, and then another doctor says something else. Back and forth this goes. Maybe that new infomercial selling the latest miracle weight loss product is the way to go? Who knows? In the meantime, you're confused and not losing any weight. Well, get ready for some possible answers and even a few more questions.
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Review on the Zone Diet

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The Zone diet was thought of by Barry Sears, a US Biochemist. This weight loss program is classified as a high protein, low carb diet. This diet program can be a little complicated because of the calculations that you have to follow exactly. According to Sears, for you to ...
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Quick and easy tips to help you lose weight

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Weight problems are a result of poor choices in food and compounded with a bad lifestyle. Do not lose heart because with concerted effort, good practices and a sensible approach to food, you can lose a considerable amount of weight.Fruits are a must in any program when losing weight. These foods are natural and are ...
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Review on Xerisan ASA

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Who does not want to get rid of those extra pounds? There are a lot of pills on the market that promise us that we will lose weight. But which of these diet pills actually are effective for weight loss?Xerisan ASA is a diet pill that came out in 2006. Xerisan has four main ...
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Some Dieters Are Set Up to Regain Weight

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Title: Some Dieters Are Set Up to Regain WeightCategory: Health NewsCreated: 9/10/2010 11:10:00 AMLast Editorial Review: 9/10/2010 11:10:53 AM Related Blogs Celebrity Body on a Budget ? A Weight Loss Solution Designed to … Health Net mobile app aims for improved customer service – Mobile … Diet Loss Plan Weight: Invite Your Family To Support ...
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Slim-Fast offers a range of meal replacement diet products and claims that you can lose 10% of your body weight in six months by following their weight loss plan. According to the official Slim-Fast website all Slim-Fast products are formulated with a special blend of protein, fiber and good fats to keep away the food ...

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Calculation of the Bureau shall inform the number of Hispanic-owned businesses grow by 40% in Texas

Texas Hispanic-owned enterprises rose 447,486, 40,1% growth in 2007, THE U.S. Census Bureau announced today. These companies during the same period, sales increased by almost 47,2% 62.1 billion dollars. Texas ranked, inter alia, the top three States the number of Hispanic-owned enterprises.

Hispanic-owned business in Texas, was the land of five State 254 56.7% — Harris, Bexar, Hidalgo, El Paso and Dallas. (See table 1.[Excel])Harris County ranked third nation in the number of Hispanic-owned enterprises and on the other hand, the business owners of Mexican origin.

Business owners of Mexican origin accounted for 79.7% of all Hispanic-owned business in Texas.

This information comes from the Business owners research: Hispanic-Owned businesses: 2007 and the business, sales volume and revenue, paid employees and an annual payroll. The data is presented in the municipality and the city, industry, and transactions and detailed Hispanic origin.

Three regions that border Dallas County saw large% increase from 2002 to 2007 the number of Hispanic-owned enterprises — Denton (93.9%), Collin (81.3%) and Tarrant (67.7%).

Texas cities, Arlington (51.8%) in Fort Worth (49.8%) and Austin (49.4%) saw a large increase in the number of Hispanic-owned enterprises. (See table 2. [Excel])

Texas metropolitan areas that saw large% of Hispanic-owned enterprises the number of Dallas Fort Worth-Arlington (54.1%), San Antonio (50,0%) and Houston-Sugarland-Bayton (38.1%).

Other highlights:

41,321 Hispanic-owned companies Were in Texas in 2007 20,1% by the year 2002 compared with the growth of paid employees.These companies employed 398,152 person 42.1%.Recalculation is these companies increased by 61.3% 10.0 billion dollars, and revenue rose 39,3% 45,9 billion dollar companies without. Hispanic paid employees increased by 42.5%, the number of 406,165.These undertakings the sum of 16 nonemployer. 2 billion dollars, 75.1% increase in 2007, Hispanic-owned enterprises had 8,161 Texas receipts of more than 1 million dollars.Texas was 69 Hispanic-owned enterprises employ more than 500 employees. Construction, wholesale trade and retail trade 49,1% Texas. Texas income Hispanic-owned enterprises accounted for 356,706 companies which were owned by the people of Mexican origin.These companies employed 327,338 person and their revenue totaled 49.1 billion dollars.

Business owners Survey defines the Hispanic-owned enterprises, with Hispanics owns 51% or more of the equity, interest rates or stock business in the United States for firms.

Note: as the "Mexican-owned," "Puerto Rican owned" References "Cuban-owned" and "other Hispanic Latino companies, business refer to only the 50 States and the District of Columbia, that the self identified 51% or more ownership in 2007, is the Mexican, Puerto Rican, Cuban or other Hispanic or Latino origin to private firms. Survey of Business owners (SBO) does not distinguish between Us residents and nonresidents. undertakings in the public or other foreign Governments, foreign or domestic companies are included in the category" Publicly owned and other companies is not classified as sex, race and ethnicity, veteran status. "

Business owners survey will be carried out every five years as part of the economic calculation. 2007 survey data collected up to 2.3 million companies in the sample. Sample information collected during the investigation, as well as the sampling variance nonsampling errors as errors. sources of nonsampling errors are the answer, and coverage information about nonreporting. concerning the structure of the SBO survey methodology and data limitations, can be found in the .

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The Erotic Goddess: Women Pole Dancing for Weight Loss

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Pole dancing for weight loss is a popular activity among women. Learn how to become an erotic goddess with female empowerment through pole dance.
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Stop Dieting - Renew Your Mind And See Your Body Transformed Forever!

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Some Proven Fast Weight Loss Strategies

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Losing weight in a swift succession is a new trend but you would hardly like to go for some of them after you get acquainted with the hardships you have to undertake. As an option, right here are some methodologies that would match your hectic schedule wi
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Speed Dieting - Speed Dieting Teleseminar Course Information

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La Oficina del Censo Revela que el Número de Empresas Cuyos Propietarios son Aumenta Hispanos un 40 Por Ciento en Texas

La Censo del Oficina de los EE. UU. aunció hoy que el número de empresas en Texas cuyos propietarios son hispanos aumentó a 447,486 un crecimiento de 40,1 por ciento entre 2002 y 2007. Las ventas de estas empresas aumentaron casi 47.2 por ciento $ 62.2 mil millones durante el mismo período. Texas estuvo entre los tres estados con el mayor número de empresas hispanas.

Cinco de los 254 condados en Texas representaron el 56.7 por ciento de las empresas cuyos propietarios son hispanos — Harris, Bexar, Hidalgo, El Paso y Dallas. (Véase la Tabla 1.[Excel])El condado Harris estuvo clasificado tercero en la nación, con el mayor número de empresas cuyos propietarios y son hispanos estuvo clasificado segundo entre los condados con el mayor número de empresas cuyos propietarios son de origen mexicano.

Las empresas cuyos propietarios, Pero Sin de origen mexicano representaron el 79.7 por ciento de todas las empresas en Texas cuyos propietarios hispanos son.

Estos datos provienen de la Encuesta de Empresarios: Empresas Cuyos Propietarios son Hispanos: 2007 y presenta el número de empresas, ventas e ingresos, número de empleados y nómina anual remunerados. Los datos it categorizan según el área geográfica (incluyendo condado, ciudad, industria y tamaño de la empresa, al igual que el origen hispano detallado.

El porcentaje de empresas cuyos propietarios son hispanos aumentó entre 2002 y 2007 en tres condados que bordean Dallas-Denton (93.9 por ciento), Collin (81.3 por ciento), y Tarrant (67.7 por ciento).

Entre las ciudades de Texas, Arlington (51.8 por ciento), Fort Worth (49.8 por ciento), y Austin (49.4 por ciento) tuvieron en los grandes aumentos porcentajes del número de empresas cuyos propietarios hispanos son. (Véase la Tabla 2. [Excel])

Las áreas metropolitanas fi Texas que tuvieron en los grandes aumentos porcentajes del número de empresas cuyos propietarios son hispanos, Pero Sin Dallas Fort Worth-Arlington (54.1 por ciento), San Antonio (50.0 por ciento), y Houston-Sugarland-Bayton (38.1 por ciento).

Otros hallazgos de interés:

Hubo 41,321 empresas cuyos propietarios son hispanos con empleados remunerados fi Texas en 2007, un aumento de 20.1 por ciento desde 2002.Dichas empresas emplearon 398,152 personas, un aumento de 42.1 por ciento. Las nóminas anuales de estas empresas aumentaron 62.1 por ciento, con $ 10.0 mil millones y sus ingresos 39,3 crecieron por ciento, con $ 45.9 mil millones.El número de empresas empleados remunerados cuyos propietarios son hispanos aumentó un 42.5 por ciento sin, con 406,165 empresas.Los ingresos de estas Ultimate Maqui Berry empresas sin empleados remunerados alcanzaron un total de $ 16.2 mil millones, un aumento de 75.1 por ciento. En el 2007, hubo 8,161 empresas en Texas cuyos propietarios son hispanos con más de ingresos de $ 1 millón. Texas tuvo 69 empresas cuyos propietarios emplearon hispanos que son más de 500 personas. La industria de construcción y el comercio al por Mayor y al por menor constituyeron el 49.1 por ciento de los ingresos de empresas hispanas fi Texas. Texas tuvo 356,706 empresas cuyos dueños son de origen mexicano.Empresas Dichas personas y sus emplearon 327,338 ingresos alcanzaron un total de $ 49.1 mil millones.

La Encuesta de Empresarios set las empresas cuyos propietarios son hispanos como empresas localizadas en los Estados Unidos en las cuales son los hispanos propietarios del 51 por ciento o más de las acciones, interés o ganancias de la empresa.

Note: Las referencias empresas cuyos propietarios son mexicanos "", "puertorriqueños", "cubanos" u "otros hispanos o latinos" son para negocios que operan en los 50 estados y el Distrito de Columbia, y que su vez se autodenominan con el 51 por ciento o más de la propiedad en el 2007 como individuos independence party de origen mexicano, u otro grupo hispano o cubano latino. La Encuesta de Empresarios no hace distinción entre residentes y no residentes de los Estados Unidos. Las compañías que son propiedad de gobiernos extranjeros o son propiedad de otras compañías extranjeras o domésticas, están incluidas en la categoría controlada por el público y otras firmas que no se pueden clasificar según el género, origen étnico, breed Raza y estado como veterano de guerra.

La Encuesta de Empresarios se lleva cabo cada 5 años como parte del censo económico. La encuesta de 2007 recopila datos de una muestra de más de 2.3 millones de empresas. Los datos recopilados en la muestra de una encuesta están sujetos a la variabilidad de la muestra y muestreo ajenos al-errores. Los errores ajenos al muestreo it deben errores en las respuestas, falta de respuestas o más información cobertura paragraph acerca del diseño, limitaciones y metodología de los datos de la Encuesta de Empresarios, consulte http://www.census.gov/econ/sbo/methodology.html.

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Do you think you might need a personal trainer to help you lose weight? Read today’s guest post by Andrew Cavanaugh:Losing Weight Is a Battle Best Not Fought Alone - Here’s Why?? by Andrew CavanaughExtra weight can creep up on us simply through the rigors of everyday life. Work, school, and stress can add pounds ...
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ZENAPAX (Daclizumab) Injection, Solution, Concentrate [Genentech, Inc.]

Translate Request has too much data Parameter name: request Translate Request has too much data Parameter name: request ZENAPAX (daclizumab) injection, solution, concentrate
[Genentech, Inc.]

Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe ZENAPAX® (daclizumab). The physician responsible for ZENAPAX administration should have complete information requisite for the follow-up of the patient. ZENAPAX should only be administered by healthcare personnel trained in the administration of the drug who have available adequate laboratory and supportive medical resources.

ZENAPAX® (daclizumab) is an immunosuppressive, humanized IgG1 monoclonal antibody produced by recombinant DNA technology that binds specifically to the alpha subunit (p55 alpha, CD25, or Tac subunit) of the human high-affinity interleukin-2 (IL-2) receptor that is expressed on the surface of activated lymphocytes.

Daclizumab is a composite of human (90%) and murine (10%) antibody sequences. The human sequences were derived from the constant domains of human IgG1 and the variable framework regions of the Eu myeloma antibody. The murine sequences were derived from the complementarity-determining regions of a murine anti-Tac antibody. The molecular weight predicted from the DNA sequence is 144 kilodaltons.

ZENAPAX 25 mg/5 mL is supplied as a clear, sterile, colorless Maqui Berries concentrate for further dilution and intravenous administration. Each milliliter of ZENAPAX contains 5 mg of daclizumab and 3.6 mg sodium phosphate monobasic monohydrate, 11 mg sodium phosphate dibasic heptahydrate, 4.6 mg sodium chloride, 0.2 mg polysorbate 80, and may contain hydrochloric acid or sodium hydroxide to adjust the pH to 6.9. No preservatives are added.

Daclizumab functions as an IL-2 receptor antagonist that binds with high-affinity to the Tac subunit of the high-affinity IL-2 receptor complex and inhibits IL-2 binding. Daclizumab binding is highly specific for Tac, which is expressed on activated but not resting lymphocytes. Administration of ZENAPAX inhibits IL-2-mediated activation of lymphocytes, a critical pathway in the cellular immune response involved in allograft rejection.

While in the circulation, ZENAPAX impairs the response of the immune system to antigenic challenges. Whether the ability to respond to repeated or ongoing challenges with those antigens returns to normal after ZENAPAX is cleared is unknown (see PRECAUTIONS).

In clinical trials involving renal allograft patients treated with a 1 mg/kg IV dose of ZENAPAX every 14 days for a total of five doses, peak serum concentration (mean ± SD) rose between the first dose (21 ± 14 µg/mL) and fifth dose (32 ± 22 µg/mL). The mean trough serum concentration before the fifth dose was 7.6 ± 4.0 µg/mL. Population pharmacokinetic analysis of the data using a two-compartment open model gave the following values for a reference patient (45-year-old male Caucasian patient with a body weight of 80 kg and no proteinuria): systemic clearance = 15 mL/hour, volume of central compartment = 2.5 liter, volume of peripheral compartment = 3.4 liter. The estimated terminal elimination half-life for the reference patient was 20 days (480 hours), which is similar to the terminal elimination half-life for human IgG (18 to 23 days). Bayesian estimates of terminal elimination half-life ranged from 11 to 38 days for the 123 patients included in the population analysis. The influence of body weight on systemic clearance supports the dosing of ZENAPAX on a milligram per kilogram (mg/kg) basis. For patients studied, this dosing maintained drug exposure within 30% of the reference exposure. Covariate analyses showed that no dosage adjustments based on age, race, gender or degree of proteinuria, are required for renal allograft patients. The estimated interpatient variability (percent coefficient of variation) in systemic clearance and central volume of distribution were 15% and 27%, respectively.

Pharmacokinetic parameters were evaluated in 61 pediatric patients treated with a 1 mg/kg IV dose of ZENAPAX every 14 days for a total of five doses. Peak serum concentration (mean ± SD) rose between the first dose (16 ± 12 µg/mL) and fifth dose (21 ± 14 µg/mL). The mean trough serum concentration before the fifth dose was 5.0 ± 2.7 µg/mL. Population pharmacokinetic analysis of the data using a two-compartment open model gave the following values for a reference patient (Caucasian patient with a body weight of 29.7 kg): systemic clearance = 10 mL/hour, volume of central compartment = 2.0 liter, volume of peripheral compartment = 1.4 liter. The estimated terminal elimination half-life for the reference patient was 13 days (317 hours). For the patients studied, this dosing maintained drug exposure within 50% of the reference exposure. Covariate analyses suggested that disposition parameters were not influenced to a clinically relevant extent by race, gender or degree of proteinuria. The estimated interpatient variability (percent coefficient of variation) in systemic clearance and central volume of distribution were 30% and 40%, respectively.

In vitro and in vivo data suggest that serum levels of 5 to 10 µg/mL are necessary for saturation of the Tac subunit of the IL-2 receptors to block the responses of activated T lymphocytes. At the recommended dosage regimen, daclizumab saturates the Tac subunit of the IL-2 receptor for approximately 90 and 120 days posttransplant, respectively in pediatric and adult patients. The duration of clinically significant IL-2 receptor blockade after the recommended course of ZENAPAX is not known. No significant changes to circulating lymphocyte numbers or cell phenotypes were observed by flow cytometry. Cytokine release syndrome has not been observed after ZENAPAX administration.

The safety and efficacy of ZENAPAX for the prophylaxis of acute organ rejection in adult patients receiving their first cadaveric kidney transplant were assessed in two randomized, double-blind, placebo-controlled, multicenter trials. These trials compared a dose of 1.0 mg/kg of ZENAPAX with placebo when each was administered as part of standard immunosuppressive regimens containing either cyclosporine and corticosteroids (double-therapy trial, no US sites) or cyclosporine, corticosteroids, and azathioprine (triple-therapy trial, predominantly US sites) to prevent acute renal allograft rejection. ZENAPAX dosing was initiated within 24 hours pretransplant, with subsequent doses given every 14 days for a total of five doses.

The primary efficacy endpoint of both trials was the proportion of patients who developed a biopsy-proven acute rejection episode within the first 6 months following transplantation. As shown in Table 1, this incidence was significantly lower in the group treated with ZENAPAX in both the double-therapy and triple-therapy trials.

Table 1 Efficacy ParametersTriple-therapy Regimen
(cyclosporine, corticosteroids, and azathioprine)Double-therapy Regimen
(cyclosporine and corticosteroids)(N=134)(N=126)p-value(N=134)(N=141)p-valueIncidence of biopsy-proven acute rejection at 6 monthsIncidence of biopsy-proven acute rejection at 1 yearGraft survival at 3 years posttransplantNo. of patients with functioning graftPatient survival at 3 years posttransplant

Treatment with ZENAPAX was associated with better patient survival up to 3 years posttransplant in the double-therapy study. No difference in patient survival was observed in the triple-therapy study between patients treated with ZENAPAX or placebo up to 3 years posttransplant. No difference was observed for graft survival between treatment groups in both studies at 3 years posttransplant.

The incidence of delayed graft function was not different between patients treated with placebo or ZENAPAX in either study. No difference in graft function was observed 1 year and 3 years posttransplant in either study between patients treated with placebo or ZENAPAX.

In a randomized, double-blind study to assess tolerability, pharmacokinetics, and drug interactions in renal allograft recipients, ZENAPAX (50 patients) or placebo (25 patients) was added to an immunosuppressive regimen of cyclosporine, mycophenolate mofetil, and corticosteroids. In this study, the addition of ZENAPAX did not result in an increased incidence of adverse events or a change in the types of adverse events reported. The incidence of the combined endpoint of biopsy-proven or clinically presumptive acute rejection was 20% (5 of 25 patients) in the placebo group and 12% (6 of 50 patients) in the ZENAPAX group. Although numerically lower, the difference in acute rejection was not significant. However, in a randomized, double-blind, placebo-controlled trial of ZENAPAX in cardiac transplant recipients (n=434) receiving concomitant cyclosporine, mycophenolate mofetil, and corticosteroids, mortality was increased in patients randomized to receive ZENAPAX compared with those randomized to receive placebo (see WARNINGS and ADVERSE REACTIONS).

ZENAPAX is indicated for the prophylaxis of acute organ rejection in patients receiving renal transplants. It is used as part of an immunosuppressive regimen that includes cyclosporine and corticosteroids.

The efficacy of ZENAPAX for the prophylaxis of acute rejection in recipients of other solid organ allografts has not been demonstrated.

ZENAPAX is contraindicated in patients with known hypersensitivity to daclizumab or to any components of this product.

The use of ZENAPAX as part of an immunosuppressive regimen including cyclosporine, mycophenolate mofetil, and corticosteroids may be associated with an increase in mortality. In a randomized, double-blind, placebo-controlled trial of ZENAPAX for the prevention of allograft rejection in 434 cardiac transplant recipients receiving concomitant cyclosporine, mycophenolate mofetil, and corticosteroids, mortality at 6 and 12 months was increased in those patients receiving ZENAPAX compared to those receiving placebo (7% vs 5%, respectively at 6 months; 10% vs 6% respectively at 12 months). Some, but not all, of the increase in mortality appeared related to a higher incidence of severe infections. Concomitant use of anti-lymphocyte antibody therapy may also be a factor in some of the fatal infections.

ZENAPAX should be administered under qualified medical supervision. Patients should be informed of the potential benefits of therapy and the risks associated with administration of immunosuppressive therapy.

While the incidence of lymphoproliferative disorders and opportunistic infections in the limited clinical trial experience was no higher in patients treated with ZENAPAX compared with placebo-treated patients, patients on immunosuppressive therapy are at increased risk for developing lymphoproliferative disorders and opportunistic infections and should be monitored accordingly.

Severe, acute (onset within 24 hours) hypersensitivity reactions including anaphylaxis have been observed both on initial exposure to ZENAPAX and following re-exposure. These reactions may include hypotension, bronchospasm, wheezing, laryngeal edema, pulmonary edema, cyanosis, hypoxia, respiratory arrest, cardiac arrhythmia, cardiac arrest, peripheral edema, loss of consciousness, fever, rash, urticaria, diaphoresis, pruritus, and/or injection site reactions. If a severe hypersensitivity reaction occurs, therapy with ZENAPAX should be permanently discontinued. Medications for the treatment of severe hypersensitivity reactions including anaphylaxis should be available for immediate use. Patients previously administered ZENAPAX should only be re-exposed to a subsequent course of therapy with caution. The potential risks of such re-administration, specifically those associated with immunosuppression, are not known.

It is not known whether ZENAPAX use will have a long-term effect on the ability of the immune system to respond to antigens first encountered during ZENAPAX-induced immunosuppression.

Re-administration of ZENAPAX after an initial course of therapy has not been studied in humans. The potential risks of such re-administration, specifically those associated with immunosuppression and/or the occurrence of anaphylaxis/anaphylactoid reactions, are not known.

The following medications have been administered with ZENAPAX in clinical trials in renal allograft patients with no incremental increase in adverse reactions: cyclosporine, mycophenolate mofetil, ganciclovir, acyclovir, azathioprine, and corticosteroids. Very limited experience exists in these patients with the use of ZENAPAX concomitantly with tacrolimus, muromonab-CD3, antithymocyte globulin, and anti-lymphocyte globulin.

In renal allograft recipients (n=50) treated with ZENAPAX and mycophenolate mofetil, no pharmacokinetic interaction between ZENAPAX and mycophenolic acid, the active metabolite of mycophenolate mofetil, was observed.

However, in a large clinical study in cardiac transplant recipients (n=434), the use of ZENAPAX as part of an immunosuppression regimen including cyclosporine, mycophenolate mofetil, and corticosteroids was associated with an increase in mortality, particularly in patients receiving concomitant anti-lymphocyte antibody therapy and in patients who developed severe infections (see WARNINGS and ADVERSE REACTIONS: Incidence of Infectious Episodes).

Long-term studies to evaluate the carcinogenic potential of ZENAPAX have not been performed. ZENAPAX was not genotoxic in the Ames or the V79 chromosomal aberration assays, with or without metabolic activation. The effect of ZENAPAX on fertility is not known, because animal reproduction studies have not been conducted with ZENAPAX (see WARNINGS and ADVERSE REACTIONS).

Pregnancy Category C: A preclinical developmental toxicity study with ZENAPAX has shown an increased risk of early prenatal loss in cynomolgus monkeys compared to placebo. However, the clinical experience of ZENAPAX exposed pregnancies is still limited. In general, IgG molecules are known to cross the placental barrier. ZENAPAX should not be used in pregnant women unless the potential benefit justifies the potential risk to the fetus. Women of childbearing potential should use effective contraception before beginning ZENAPAX therapy, during therapy, and for 4 months after completion of ZENAPAX therapy.

It is not known whether ZENAPAX is excreted in human milk. However, in preclinical developmental toxicity studies with ZENAPAX, four out of seven lactating cynomolgus monkeys given a 5-10 fold multiple (10mg/kg) of the normal human dose were found to secrete very low levels of ZENAPAX (0.17 – 0.28% of maternal serum levels) in breast milk. Because many drugs are excreted in human milk, including human antibodies, and because of the potential for adverse reactions, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

The safety and effectiveness of ZENAPAX have been established in pediatric patients from 11 months to 17 years of age. Use of ZENAPAX in this age group is supported by evidence from adequate and well-controlled studies of ZENAPAX in adults with additional pediatric pharmacokinetic data (see CLINICAL PHARMACOLOGY). Data from the pediatric pharmacokinetic study were also analyzed for efficacy, immunogenicity and safety. In an open-label study, 60 pediatric renal transplant recipients [median age of 10 years] received standard immunosuppressive agents in addition to a regimen of ZENAPAX administered at a dose of 1.0 mg/kg at intervals of 14 days for a total of 5 doses, starting immediately before transplantation. In this study, the combined incidence of biopsy-proven and clinically presumptive acute rejection at 1 year posttransplant was 17% (10/60). Patient and graft survival at 1 year posttransplant were 100% and 96.7%, respectively. The incidence of anti-daclizumab antibodies (34%) observed in the first 3 months posttransplant was higher than the incidence previously observed in adult patients (14%) (see ADVERSE REACTIONS: Immunogenicity).

The safety profile of ZENAPAX in pediatric transplant patients was shown to be comparable with that in adult transplant patients with the exception of the following adverse events, which occurred more frequently in pediatric patients (>15% difference in incidence): diarrhea, post-operative pain, fever, vomiting, aggravated hypertension, pruritus, and infections of the upper respiratory tract and urinary tract.

It is not known whether the immune response to vaccines, infection, and other antigenic stimuli administered or encountered during ZENAPAX therapy is impaired or whether such response will remain impaired after ZENAPAX therapy.

Also see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.

Clinical studies of ZENAPAX did not include sufficient numbers of subjects age 65 and older to determine whether they respond differently from younger subjects. Caution must be used in giving immunosuppressive drugs to elderly patients.

Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug. Rates observed in clinical studies may not reflect those observed in clinical practice. Adverse reaction information obtained in clinical trials does, however, provide a basis for identifying adverse events that appear to be related to drug use and for approximating the rate of occurrence.

The safety of ZENAPAX was determined in four clinical studies of renal allograft rejection, three of which were randomized controlled clinical trials, in 629 patients receiving renal allografts of whom 336 received ZENAPAX and 293 received placebo. All patients received concomitant cyclosporine and corticosteroids. In these clinical trials, ZENAPAX did not appear to alter the pattern, frequency or severity of known major toxicities associated with the use of immunosuppressive drugs.

The use of ZENAPAX was associated with a higher incidence of mortality when compared to placebo in a large (n=434) randomized controlled study of patients receiving cardiac transplants (see WARNINGS and Incidence of Infectious Episodes).

Adverse events were reported by 95% of the patients in the placebo-treated group and 96% of the patients in the group treated with ZENAPAX. The proportion of patients prematurely withdrawn from the combined studies because of adverse events was 8.5% in the placebo-treated group and 8.6% in the group treated with ZENAPAX.

ZENAPAX did not increase the number of serious adverse events observed compared with placebo. The most frequently reported adverse events were gastrointestinal disorders, which were reported with equal frequency in ZENAPAX- (67%) and placebo-treated (68%) patient groups.

The incidence and types of adverse events were similar in both placebo-treated patients and patients treated with ZENAPAX. The following adverse events occurred in =5% of patients treated with ZENAPAX. These events included: Gastrointestinal System: constipation, nausea, diarrhea, vomiting, abdominal pain, pyrosis, dyspepsia, abdominal distention, epigastric pain not food-related; Metabolic and Nutritional: edema extremities, edema; Central and Peripheral Nervous System: tremor, headache, dizziness; Urinary System: oliguria, dysuria, renal tubular necrosis; Body as a Whole - General: posttraumatic pain, chest pain, fever, pain, fatigue; Autonomic Nervous System: hypertension, hypotension, aggravated hypertension; Respiratory System: dyspnea, pulmonary edema, coughing; Skin and Appendages: impaired wound healing without infection, acne; Psychiatric: insomnia; Musculoskeletal System: musculoskeletal pain, back pain; Heart Rate and Rhythm: tachycardia; Vascular Extracardiac: thrombosis; Platelet, Bleeding and Clotting Disorders: bleeding; Hemic and Lymphatic: lymphocele.

The following adverse events occurred in <5% and =2% of patients treated with ZENAPAX. These included: Gastrointestinal System: flatulence, gastritis, hemorrhoids; Metabolic and Nutritional: fluid overload, diabetes mellitus, dehydration; Urinary System: renal damage, hydronephrosis, urinary tract bleeding, urinary tract disorder, renal insufficiency; Body as a Whole - General: shivering, generalized weakness; Central and Peripheral Nervous System: urinary retention, leg cramps, prickly sensation; Respiratory System: atelectasis, congestion, pharyngitis, rhinitis, hypoxia, rales, abnormal breath sounds, pleural effusion; Skin and Appendages: pruritus, hirsutism, rash, night sweats, increased sweating; Psychiatric: depression, anxiety; Musculoskeletal System: arthralgia, myalgia; Vision: vision blurred; Application Site: application site reaction.

One and 3 years posttransplant, the incidence of malignancies was 2.7% and 7.8%, respectively, in the placebo group compared with 1.5% and 6.4%, respectively, in the ZENAPAX group. Addition of ZENAPAX did not increase the number of posttransplant lymphomas up to 3 years posttransplant. Lymphomas occurred at a frequency of =1.5% in both placebo-treated and ZENAPAX-treated groups.

No differences in abnormal hematologic or chemical laboratory test results were seen between groups treated with placebo or ZENAPAX with the exception of fasting blood glucose. Fasting blood glucose was measured in a small number of patients treated with placebo or ZENAPAX. A total of 16% (10 of 64 patients) of placebo-treated and 32% (28 of 88 patients) of patients treated with ZENAPAX had high fasting blood glucose values. Most of these high values occurred either on the first day posttransplant when patients received high doses of corticosteroids or in patients with diabetes.

The overall incidence of infectious episodes, including viral infections, fungal infections, bacteremia and septicemia, and pneumonia, was not higher in patients treated with ZENAPAX than in placebo-treated patients in trials of renal transplantation. In a large randomized study of ZENAPAX used for the prevention of allograft rejection in patients receiving cardiac allografts, more patients receiving ZENAPAX experienced severe or fatal infections after 12 months of therapy when compared to those receiving placebo (10% vs 7%, respectively). The risks of infection or death may be increased in patients receiving concomitant anti-lymphocyte antibody therapy (see WARNINGS).

The types of infections reported in trials of renal transplantation were similar in both the ZENAPAX-treated and the placebo-treated groups. Cytomegalovirus infection was reported in 16% of the patients in the placebo group and 13% of the patients in the ZENAPAX group. One exception was cellulitis and wound infections, which occurred in 4.1% of placebo-treated patients and 8.4% of patients treated with ZENAPAX. At 1 year posttransplant, 7 placebo patients and 1 patient treated with ZENAPAX had died of an infection. At 3 years posttransplant, 8 placebo patients and 4 patients treated with ZENAPAX had died of infection.

Low titers of anti-idiotype antibodies to daclizumab were detected in the adult patients treated with ZENAPAX with an overall incidence of 14%. The incidence of anti-daclizumab antibodies observed in the pediatric patients was 34%. No antibodies that affected efficacy, safety, serum daclizumab levels or any other clinically relevant parameter examined were detected. The data reflect the percentage of patients whose test results were considered positive for antibodies to daclizumab in an ELISA assay and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in the assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies to daclizumab with the incidence of antibodies to other products may be misleading.

The following adverse reactions have been identified and reported during post-approval use of ZENAPAX (daclizumab). Because the reports of these reactions are voluntary and the population is of uncertain size, it is not always possible to reliably estimate the frequency of the reaction or establish a causal relationship to drug exposure.

Severe acute hypersensitivity reactions including anaphylaxis characterized by hypotension, bronchospasm, wheezing, laryngeal edema, pulmonary edema, cyanosis, hypoxia, respiratory arrest, cardiac arrhythmia, cardiac arrest, peripheral edema, loss of consciousness, fever, rash, urticaria, diaphoresis, pruritus, and/or injection site reactions, as well as cytokine release syndrome, have been reported during post-marketing experience with ZENAPAX. The relationship between these reactions and the development of antibodies to ZENAPAX is unknown.

There have not been any reports of overdoses with ZENAPAX. A maximum tolerated dose has not been determined in patients. A dose of 1.5 mg/kg has been administered to bone marrow transplant recipients without any associated adverse events.

ZENAPAX is used as part of an immunosuppressive regimen that includes cyclosporine and corticosteroids. The recommended dose for ZENAPAX in adult and pediatric patients is 1.0 mg/kg (see PRECAUTIONS: Pediatric Use). The calculated volume of ZENAPAX should be mixed with 50 mL of sterile 0.9% sodium chloride solution and administered via a peripheral or central vein over a 15-minute period.

Based on the clinical trials, the standard course of ZENAPAX therapy is five doses. The first dose should be given no more than 24 hours before transplantation. The four remaining doses should be given at intervals of 14 days.

No dosage adjustment is necessary for patients with severe renal impairment. No dosage adjustments based on other identified covariates (age, gender, proteinuria, race) are required for renal allograft patients. No data are available for administration in patients with severe hepatic impairment.

ZENAPAX IS NOT FOR DIRECT INJECTION. The calculated volume should be diluted in 50 mL of sterile 0.9% sodium chloride solution before intravenous administration to patients. When mixing the solution, gently invert the bag in order to avoid foaming; DO NOT SHAKE.Parenteral drug products should be inspected visually for particulate matter and discoloration before administration. If particulate matter is present or the solution colored, do not use.Care must be taken to assure sterility of the prepared solution, since the drug product does not contain any antimicrobial preservative or bacteriostatic agents.ZENAPAX is a colorless solution provided as a single-use vial; any unused portion of the drug should be discarded.Once the infusion is prepared, it should be administered intravenously within 4 hours. If it must be held longer, it should be refrigerated between 2° to 8°C (36° to 46°F) for up to 24 hours. After 24 hours, the prepared solution should be discarded.No incompatibility between ZENAPAX and polyvinyl chloride or polyethylene bags or infusion sets has been observed. No data are available concerning the incompatibility of ZENAPAX with other drug substances. Other drug substances should not be added or infused simultaneously through the same intravenous line.ZENAPAX should only be administered by healthcare personnel trained in the administration of the drug who have available adequate laboratory and supportive medical resources.ZENAPAX is supplied in single-use glass vials. Each vial contains 25 mg of daclizumab in 5 mL of solution (NDC 0004-0501-09). Vials should be stored between the temperatures of 2° to 8°C (36° to 46°F); do not shake or freeze. Protect undiluted solution against direct light. Diluted medication is stable for 24 hours at 4°C or for 4 hours at room temperature.

Roche Pharmaceuticals

Hoffmann-La Roche Inc.
340 Kingsland Street
Nutley, NJ07110–1199

US Govt. Lic. No. 0136

3609650 USA
27899043

Revised: September 2005

Copyright © 1999-2005 by Hoffmann-La Roche Inc. All rights reserved.

Representative sample of labeling (see the HOW SUPPLIED section for complete listing):

NDC 0004-0501-09

Zenapax®
(daclizumab)

Sterile
Concentrate for
Injection

25 mg/5 mL
(5 mg/mL)

Rx only
1 Vial
(5 mL Size)

Roche

ZENAPAX 
daclizumab   injection, solution, concentrateActive Ingredient/Active Moietysodium phosphate, monobasic, monohydratesodium phosphate, dibasic, heptahydrate
Application Number or Monograph Citation
Labeler - Genentech, Inc. (080129000) Revised: 05/2010Genentech, Inc.

ZOLPIDEM TARTRATEtablet, Film Coated [Qualitest Pharmaceuticals]

ZOLPIDEM TARTRATE tablet, film coated
[Qualitest Pharmaceuticals]

These highlights do not include all the information needed to use zolpidem tartrate tablets safely and effectively. See full prescribing information for zolpidem tartrate tablets

Zolpidem tartrate tablets      

CIV

Initial U.S. Approval: 1992

Indications and Usage (1)  03/2007

Warnings and Precautions
Severe anaphylactic and anaphylactoid reactions (5.2)  03/2007
Abnormal thinking and behavioral changes (5.3)  03/2007
Special populations (5.6)  03/2007

Zolpidem tartrate tablets are indicated for the short-term treatment of insomnia characterized by difficulties with sleep initiation. Zolpidem tartrate tablets have been shown to decrease sleep latency for up to 35 days in controlled clinical studies (1)

Adult dose: 10 mg once daily immediately before bedtime (2.1)Elderly/debilitated patients/hepatically impaired: 5 mg once daily immediately before bedtime (2.2)Downward dosage adjustment may be necessary when used with CNS depressants (2.3)Should not be taken with or immediately after a meal (2.4)
5 mg and 10 mg tablets. Tablets not scored (3)

Known hypersensitivity to zolpidem tartrate or to any of the inactive ingredients in the formulation (4)

Need to evaluate for co-morbid diagnosis: Reevaluate if insomnia persists after 7 to 10 days of use (5.1)Severe anaphylactic/anaphylactoid reactions: Angioedema and anaphylaxis have been reported. Do not rechallenge if such reactions occur (5.2)Abnormal thinking, behavioral changes and complex behaviors: May include "sleep-driving" and hallucinations. Immediately evaluate any new onset behavioral changes (5.3)Depression: Worsening of depression or, suicidal thinking may occur. Prescribe the least amount feasible to avoid intentional overdose (5.3, 5.6)Withdrawal effects: Symptoms may occur with rapid dose reduction or discontinuation (5.4, 9.3)CNS depressant effects: Use can impair alertness and motor coordination. If used in combination with other CNS depressants, dose reductions may be needed due to additive effects. Do not use with alcohol (2.3, 5.5)Elderly/debilitated patients: Use lower dose due to impaired motor, cognitive performance and increased sensitivity (2.2, 5.6)Patients with hepatic impairment, mild to moderate COPD, impaired drug metabolism or hemodynamic responses, mild to moderate sleep apnea: Use with caution and monitor closely (5.6)
Most commonly observed adverse reactions were:
Short-term (<10 nights): Drowsiness, dizziness, and diarrhea
Long-term (28 – 35 nights): Dizziness and drugged feelings (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Vintage Pharmaceuticals, LLC at 1-800-444-4011 or FDA at 1-800-FDA-1088, or http://www.fda.gov/medwatch

CNS depressants: Enhanced CNS-depressant effects with combination use. Use with alcohol causes additive psychomotor impairment (7.1) Imipramine: Decreased alertness observed with combination use (7.1)Chlorpromazine: Impaired alertness and psychomotor performance observed with combination use (7.1)Rifampin: Combination use decreases exposure to and effects of zolpidem (7.2)Ketoconazole: Combination use increases exposure to and effects of zolpidem (7.2)
Pregnancy: Based on animal data, zolpidem may cause fetal harm (8.1)

Nursing mothers: Zolpidem is excreted in human milk (8.3)

Pediatric use: Safety and effectiveness not established. Hallucinations (incidence rate 7.4%) and other psychiatric and/or nervous system adverse reactions were observed frequently in a study of pediatric patients with Attention-Deficit/Hyperactivity Disorder (5.6, 8.4)

See 17 for PATIENT COUNSELING INFORMATION and the FDA-approved Medication Guide FULL PRESCRIBING INFORMATION  Zolpidem tartrate tablets are indicated for the short-term treatment of insomnia characterized by difficulties with sleep initiation. Zolpidem tartrate tablets have been shown to decrease sleep latency for up to 35 days in controlled clinical studies [see Clinical Studies (14)].

The clinical trials performed in support of efficacy were 4–5 weeks in duration with the final formal assessments of sleep latency performed at the end of treatment.

The dose of zolpidem tartrate tablets should be individualized.

The recommended dose for adults is 10 mg once daily immediately before bedtime. The total zolpidem tartrate tablet dose should not exceed 10 mg per day.

Elderly or debilitated patients may be especially sensitive to the effects of zolpidem tartrate. Patients with hepatic insufficiency do not clear the drug as rapidly as normal subjects. The recommended dose of zolpidem tartrate in both of these patient populations is 5 mg once daily immediately before bedtime [see Warnings and Precautions (5.6)].

Dosage adjustment may be necessary when zolpidem tartrate tablets are combined with other CNS depressant drugs because of the potentially additive effects [see Warnings and Precautions (5.5)].

The effect of zolpidem tartrate tablets may be slowed by ingestion with or immediately after a meal.

Zolpidem tartrate tablets are available in 5 mg and 10 mg strength tablets for oral administration. Tablets are not scored.

Zolpidem tartrate tablets 5 mg are pink, film-coated, capsule-shaped, unscored, upper debossed "6468" and lower debossed "V". The 10 mg tablets are white, film-coated, capsule-shaped, unscored, upper debossed "6469" and lower debossed "V".

Zolpidem tartrate tablets are contraindicated in patients with known hypersensitivity to zolpidem tartrate or to any of the inactive ingredients in the formulation. Observed reactions include anaphylaxis and angioedema [see Warnings and Precautions (5.2)].

Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. Worsening of insomnia or the emergence of new thinking or behavior abnormalities may be the consequence of an unrecognized psychiatric or physical disorder. Such findings have emerged during the course of treatment with sedative/hypnotic drugs, including zolpidem.

 Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of sedative-hypnotics, including zolpidem. Some patients have had additional symptoms such as dyspnea, throat closing or nausea and vomiting that suggest anaphylaxis. Some patients have required medical therapy in the emergency department. If angioedema involves the throat, glottis or larynx, airway obstruction may occur and be fatal. Patients who develop angioedema after treatment with zolpidem should not be rechallenged with the drug.

 A variety of abnormal thinking and behavior changes have been reported to occur in association with the use of sedative/hypnotics. Some of these changes may be characterized by decreased inhibition (e.g., aggressiveness and extroversion that seemed out of character), similar to effects produced by alcohol and other CNS depressants. Visual and auditory hallucinations have been reported as well as behavioral changes such as bizarre behavior, agitation and depersonalization. In controlled trials, <1% of adults with insomnia who received zolpidem reported hallucinations. In a clinical trial, 7.4% of pediatric patients with insomnia associated with attention-deficit/hyperactivity disorder (ADHD), who received zolpidem reported hallucinations [see Use in Specific Populations (8.4)].

 Complex behaviors such as "sleep-driving" (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported with sedative hypnotics, including zolpidem. These events can occur in sedative-hypnotic-naive as well as in sedative-hypnotic-experienced persons. Although behaviors such as "sleep-driving" may occur with zolpidem tartrate tablets alone at therapeutic doses, the use of alcohol and other CNS depressants with zolpidem tartrate tablets appears to increase the risk of such behaviors, as does the use of zolpidem tartrate tablets at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of zolpidem tartrate tablets should be strongly considered for patients who report a "sleep-driving" episode. Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative-hypnotic. As with "sleep-driving", patients usually do not remember these events. Amnesia, anxiety and other neuro-psychiatric symptoms may occur unpredictably.

In primarily depressed patients, worsening of depression, including suicidal thoughts and actions (including completed suicides), has been reported in association with the use of sedative/hypnotics.

It can rarely be determined with certainty whether a particular instance of the abnormal behaviors listed above is drug induced, spontaneous in origin, or a result of an underlying psychiatric or physical disorder. Nonetheless, the emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.

Following the rapid dose decrease or abrupt discontinuation of sedative/hypnotics, there have been reports of signs and symptoms similar to those associated with withdrawal from other CNS-depressant drugs [see Drug Abuse and Dependence (9)].

Zolpidem tartrate tablets, like other sedative/hypnotic drugs, have CNS-depressant effects. Due to the rapid onset of action, zolpidem tartrate tablets should only be taken immediately prior to going to bed. Patients should be cautioned against engaging in hazardous occupations requiring complete mental alertness or motor coordination such as operating machinery or driving a motor vehicle after ingesting the drug, including potential impairment of the performance of such activities that may occur the day following ingestion of zolpidem tartrate tablets. Zolpidem tartrate tablets showed additive effects when combined with alcohol and should not be taken with alcohol. Patients should also be cautioned about possible combined effects with other CNS-depressant drugs. Dosage adjustments may be necessary when zolpidem tartrate tablets are administered with such agents because of the potentially additive effects.

Use in the elderly and/or debilitated patients: Impaired motor and/or cognitive performance after repeated exposure or unusual sensitivity to sedative/hypnotic drugs is a concern in the treatment of elderly and/or debilitated patients. Therefore, the recommended zolpidem tartrate tablets dosage is 5 mg in such patients to decrease the possibility of side effects [see Dosage and Administration (2.2)].  These patients should be closely monitored.

Use in patients with concomitant illness: Clinical experience with zolpidem tartrate tablets in patients with concomitant systemic illness is limited. Caution is advisable in using zolpidem tartrate tablets in patients with diseases or conditions that could affect metabolism or hemodynamic responses.

Although studies did not reveal respiratory depressant effects at hypnotic doses of zolpidem in normal subjects or in patients with mild to moderate chronic obstructive pulmonary disease (COPD), a reduction in the Total Arousal Index together with a reduction in lowest oxygen saturation and increase in the times of oxygen desaturation below 80% and 90% was observed in patients with mild-to-moderate sleep apnea when treated with zolpidem tartrate tablets (10 mg) when compared to placebo. Since sedative/hypnotics have the capacity to depress respiratory drive, precautions should be taken if zolpidem tartrate tablets are prescribed to patients with compromised respiratory function. Postmarketing reports of respiratory insufficiency, most of which involved patients with pre-existing respiratory impairment, have been received. Zolpidem tartrate tablets should be used with caution in patients with sleep apnea syndrome or myasthenia gravis.

Data in end-stage renal failure patients repeatedly treated with zolpidem tartrate tablets did not demonstrate drug accumulation or alterations in pharmacokinetic parameters. No dosage adjustment in renally impaired patients is required; however, these patients should be closely monitored [see Clinical Pharmacology (12.3)].

A study in subjects with hepatic impairment did reveal prolonged elimination in this group; therefore, treatment should be initiated with 5 mg in patients with hepatic compromise, and they should be closely monitored [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

Use in patients with depression: As with other sedative/hypnotic drugs, zolpidem tartrate tablets should be administered with caution to patients exhibiting signs or symptoms of depression. Suicidal tendencies may be present in such patients and protective measures may be required. Intentional overdosage is more common in this group of patients; therefore, the least amount of drug that is feasible should be prescribed for the patient at any one time.

Use in pediatric patients:  Safety and effectiveness of zolpidem has not been established in pediatric patients. In an 8-week study in pediatric patients (aged 6–17 years) with insomnia associated with ADHD, zolpidem did not decrease sleep latency compared to placebo. Hallucinations were reported in 7.4% of the pediatric patients who received zolpidem; none of the pediatric patients who received placebo reported hallucinations [see Use in Specific Populations (8.4)].

The following serious adverse reactions are discussed in greater detail in other sections of the labeling:

Associated with discontinuation of treatment: Approximately 4% of 1,701 patients who received zolpidem at all doses (1.25 to 90 mg) in U.S. premarketing clinical trials discontinued treatment because of an adverse reaction. Reactions most commonly associated with discontinuation from U.S. trials were daytime drowsiness (0.5%), dizziness (0.4%), headache (0.5%), nausea (0.6%), and vomiting (0.5%).

Approximately 4% of 1,959 patients who received zolpidem at all doses (1 to 50 mg) in similar foreign trials discontinued treatment because of an adverse reaction. Reactions most commonly associated with discontinuation from these trials were daytime drowsiness (1.1%), dizziness/vertigo (0.8%), amnesia (0.5%), nausea (0.5%), headache (0.4%), and falls (0.4%).

Data from a clinical study in which selective serotonin reuptake inhibitor (SSRI)-treated patients were given zolpidem revealed that four of the seven discontinuations during double-blind treatment with zolpidem (n=95) were associated with impaired concentration, continuing or aggravated depression, and manic reaction; one patient treated with placebo (n=97) was discontinued after an attempted suicide.

Most commonly observed adverse reactions in controlled trials: During short-term treatment (up to 10 nights) with zolpidem tartrate tablets at doses up to 10 mg, the most commonly observed adverse reactions associated with the use of zolpidem and seen at statistically significant differences from placebo-treated patients were drowsiness (reported by 2% of zolpidem patients), dizziness (1%), and diarrhea (1%). During longer-term treatment (28 to 35 nights) with zolpidem at doses up to 10 mg, the most commonly observed adverse reactions associated with the use of zolpidem and seen at statistically significant differences from placebo-treated patients were dizziness (5%) and drugged feelings (3%).

Adverse reactions observed at an incidence of =1% in controlled trials: The following tables enumerate treatment-emergent adverse reaction frequencies that were observed at an incidence equal to 1% or greater among patients with insomnia who received zolpidem tartrate and at a greater incidence than placebo in U.S. placebo-controlled trials. Events reported by investigators were classified utilizing a modified World Health Organization (WHO) dictionary of preferred terms for the purpose of establishing event frequencies. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice, in which patient characteristics and other factors differ from those that prevailed in these clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigators involving related drug products and uses, since each group of drug trials is conducted under a different set of conditions. However, the cited figures provide the physician with a basis for estimating the relative contribution of drug and nondrug factors to the incidence of side effects in the population studied.

The following table was derived from results of 11 placebo-controlled short-term U.S. efficacy trials involving zolpidem in doses ranging from 1.25 to 20 mg. The table is limited to data from doses up to and including 10 mg, the highest dose recommended for use.

Incidence of Treatment-Emergent Adverse Experiences in Placebo-Controlled Clinical Trials Lasting up to 10 Nights  (Percentage of patients reporting)Central and Peripheral Nervous System

The following table was derived from results of three placebo-controlled long-term efficacy trials involving zolpidem tartrate tablets. These trials involved patients with chronic insomnia who were treated for 28 to 35 nights with zolpidem at doses of 5, 10, or 15 mg. The table is limited to data from doses up to and including 10 mg, the highest dose recommended for use. The table includes only adverse events occurring at an incidence of at least 1% for zolpidem patients.

Incidence of Treatment-Emergent Adverse Experiences in Placebo-Controlled Clinical Trials Lasting up to 35 Nights (Percentage of patients reporting)Central and Peripheral Nervous System

Dose relationship for adverse reactions:  There is evidence from dose comparison trials suggesting a dose relationship for many of the adverse reactions associated with zolpidem use, particularly for certain CNS and gastrointestinal adverse events.

Adverse event incidence across the entire preapproval database:  Zolpidem tartrate tablets were administered to 3,660 subjects in clinical trials throughout the U.S., Canada, and Europe. Treatment-emergent adverse events associated with clinical trial participation were recorded by clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals experiencing treatment-emergent adverse events, similar types of untoward events were grouped into a smaller number of standardized event categories and classified utilizing a modified World Health Organization (WHO) dictionary of preferred terms.

The frequencies presented, therefore, represent the proportions of the 3,660 individuals exposed to zolpidem, at all doses, who experienced an event of the type cited on at least one occasion while receiving zolpidem. All reported treatment-emergent adverse events are included, except those already listed in the table above of adverse events in placebo-controlled studies, those coding terms that are so general as to be uninformative, and those events where a drug cause was remote. It is important to emphasize that, although the events reported did occur during treatment with zolpidem tartrate tablets, they were not necessarily caused by it.

Adverse events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in greater than 1/100 subjects; infrequent adverse events are those occurring in 1/100 to 1/1,000 patients; rare events are those occurring in less than 1/1,000 patients.

Autonomic nervous system:  Infrequent: increased sweating, pallor, postural hypotension, syncope. Rare: abnormal accommodation, altered saliva, flushing, glaucoma, hypotension, impotence, increased saliva, tenesmus.

Body as a whole:  Frequent: asthenia. Infrequent: edema, falling, fatigue, fever, malaise, trauma. Rare: allergic reaction, allergy aggravated, anaphylactic shock, face edema, hot flashes, increased ESR, pain, restless legs, rigors, tolerance increased, weight decrease.

Cardiovascular system:  Infrequent: cerebrovascular disorder, hypertension, tachycardia. Rare: angina pectoris, arrhythmia, arteritis, circulatory failure, extrasystoles, hypertension aggravated, myocardial infarction, phlebitis, pulmonary embolism, pulmonary edema, varicose veins, ventricular tachycardia.

Central and peripheral nervous system:  Frequent: ataxia, confusion, euphoria, headache, insomnia, vertigo. Infrequent: agitation, anxiety, decreased cognition, detached, difficulty concentrating, dysarthria, emotional lability, hallucination, hypoesthesia, illusion, leg cramps, migraine, nervousness, paresthesia, sleeping (after daytime dosing), speech disorder, stupor, tremor. Rare: abnormal gait, abnormal thinking, aggressive reaction, apathy, appetite increased, decreased libido, delusion, dementia, depersonalization, dysphasia, feeling strange, hypokinesia, hypotonia, hysteria, intoxicated feeling, manic reaction, neuralgia, neuritis, neuropathy, neurosis, panic attacks, paresis, personality disorder, somnambulism, suicide attempts, tetany, yawning.

Gastrointestinal system:  Frequent: dyspepsia, hiccup, nausea. Infrequent: anorexia, constipation, dysphagia, flatulence, gastroenteritis, vomiting. Rare: enteritis, eructation, esophagospasm, gastritis, hemorrhoids, intestinal obstruction, rectal hemorrhage, tooth caries.

Hematologic and lymphatic system:  Rare: anemia, hyperhemoglobinemia, leukopenia, lymphadenopathy, macrocytic anemia, purpura, thrombosis.

Immunologic system:  Infrequent: infection. Rare: abscess, herpes simplex, herpes zoster, otitis externa, otitis media.

Liver and biliary system:  Infrequent: abnormal hepatic function, increased SGPT. Rare: bilirubinemia, increased SGOT.

Metabolic and nutritional:  Infrequent: hyperglycemia, thirst. Rare: gout, hypercholesteremia, hyperlipidemia, increased alkaline phosphatase, increased BUN, periorbital edema.

Musculoskeletal system:  Frequent: arthralgia, myalgia. Infrequent: arthritis. Rare: arthrosis, muscle weakness, sciatica, tendinitis.

Reproductive system:  Infrequent: menstrual disorder, vaginitis. Rare: breast fibroadenosis, breast neoplasm, breast pain.

Respiratory system:  Frequent: upper respiratory infection. Infrequent: bronchitis, coughing, dyspnea, rhinitis. Rare: bronchospasm, epistaxis, hypoxia, laryngitis, pneumonia.

Skin and appendages:  Infrequent: pruritus. Rare: acne, bullous eruption, dermatitis, furunculosis, injection-site inflammation, photosensitivity reaction, urticaria.

Special senses:  Frequent: diplopia, vision abnormal. Infrequent: eye irritation, eye pain, scleritis, taste perversion, tinnitus. Rare: conjunctivitis, corneal ulceration, lacrimation abnormal, parosmia, photopsia.

Urogenital system:  Frequent: urinary tract infection. Infrequent: cystitis, urinary incontinence. Rare: acute renal failure, dysuria, micturition frequency, nocturia, polyuria, pyelonephritis, renal pain, urinary retention.

Since the systematic evaluations of zolpidem in combination with other CNS-active drugs have been limited, careful consideration should be given to the pharmacology of any CNS-active drug to be used with zolpidem. Any drug with CNS-depressant effects could potentially enhance the CNS-depressant effects of zolpidem.

Zolpidem tartrate tablets were evaluated in healthy subjects in single-dose interaction studies for several CNS drugs. Imipramine in combination with zolpidem produced no pharmacokinetic interaction other than a 20% decrease in peak levels of imipramine, but there was an additive effect of decreased alertness. Similarly, chlorpromazine in combination with zolpidem produced no pharmacokinetic interaction, but there was an additive effect of decreased alertness and psychomotor performance. A study involving haloperidol and zolpidem revealed no effect of haloperidol on the pharmacokinetics or pharmacodynamics of zolpidem. The lack of a drug interaction following single-dose administration does not predict a lack following chronic administration.

An additive effect on psychomotor performance between alcohol and zolpidem was demonstrated [see Warnings and Precautions (5.5)].

A single-dose interaction study with zolpidem 10 mg and fluoxetine 20 mg at steady-state levels in male volunteers did not demonstrate any clinically significant pharmacokinetic or pharmacodynamic interactions. When multiple doses of zolpidem and fluoxetine at steady-state concentrations were evaluated in healthy females, the only significant change was a 17% increase in the zolpidem half-life. There was no evidence of an additive effect in psychomotor performance.

Following five consecutive nightly doses of zolpidem 10 mg in the presence of sertraline 50 mg (17 consecutive daily doses, at 7:00 am, in healthy female volunteers), zolpidem Cmax was significantly higher (43%) and Tmax was significantly decreased (53%). Pharmacokinetics of sertraline and N-desmethylsertraline were unaffected by zolpidem.

Some compounds known to inhibit CYP3A may increase exposure to zolpidem. The effect of inhibitors of other P450 enzymes has not been carefully evaluated.

A randomized, double-blind, crossover interaction study in ten healthy volunteers between itraconazole (200 mg once daily for 4 days) and a single dose of zolpidem (10 mg) given 5 hours after the last dose of itraconazole resulted in a 34% increase in AUC0-8 of zolpidem. There were no significant pharmacodynamic effects of zolpidem on subjective drowsiness, postural sway, or psychomotor performance.

A randomized, placebo-controlled, crossover interaction study in eight healthy female subjects between five consecutive daily doses of rifampin (600 mg) and a single dose of zolpidem (20 mg) given 17 hours after the last dose of rifampin showed significant reductions of the AUC (-73%), Cmax (-58%), and T½ (-36%) of zolpidem together with significant reductions in the pharmacodynamic effects of zolpidem.

A randomized double-blind crossover interaction study in twelve healthy subjects showed that co-administration of a single 5 mg dose of zolpidem tartrate with ketoconazole, a potent CYP3A4 inhibitor, given as 200 mg twice daily for 2 days increased Cmax of zolpidem by a factor of 1.3 and increased the total AUC of zolpidem by a factor of 1.7 compared to zolpidem alone and prolonged the elimination half-life by approximately 30% along with an increase in the pharmacodynamic effects of zolpidem. Caution should be used when ketoconazole is given with zolpidem and consideration should be given to using a lower dose of zolpidem when ketoconazole and zolpidem are given together. Patients should be advised that use of zolpidem tartrate tablets with ketoconazole may enhance the sedative effects.

A study involving cimetidine/zolpidem and ranitidine/zolpidem combinations revealed no effect of either drug on the pharmacokinetics or pharmacodynamics of zolpidem.

Zolpidem had no effect on digoxin pharmacokinetics and did not affect prothrombin time when given with warfarin in normal subjects.

Zolpidem is not known to interfere with commonly employed clinical laboratory tests. In addition, clinical data indicate that zolpidem does not cross-react with benzodiazepines, opiates, barbiturates, cocaine, cannabinoids, or amphetamines in two standard urine drug screens.

Pregnancy Category C
There are no adequate and well-controlled studies of zolpidem tartrate tablets in pregnant women. Zolpidem tartrate tablets should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.

Administration of zolpidem to pregnant rats and rabbits resulted in adverse effects on offspring development at doses greater than the zolpidem tartrate maximum recommended human dose (MRHD) of 10 mg/day (approximately 8 mg/day zolpidem base); however, teratogenicity was not observed.

When zolpidem was administered at oral doses of 4, 20, and 100 mg base/kg approximately 5, 24 and 120 times the MRHD on a mg/m2 basis) to pregnant rats during the period of organogenesis, dose-related decreases in fetal skull ossification occurred at all but the lowest dose, which is approximately 5 times the MRHD on a mg/m2 basis. In rabbits treated during organogenesis with zolpidem at oral doses of 1, 4, and 16 mg base/kg (approximately 2.5, 10 and 40 times the MRHD on a mg/m2 basis), increased embryo-fetal death and incomplete fetal skeletal ossification occurred at the highest dose. The no-effect dose for embryo-fetal toxicity in rabbits is approximately 10 times the MRHD on a mg/m2 basis. Administration of zolpidem to rats at oral doses of 4, 20, and 100 mg base/kg (approximately 5, 24 and 120 times the MRHD on a mg/m2 basis) during the latter part of pregnancy and throughout lactation produced decreased offspring growth and survival at all but the lowest dose, which is approximately 5 times the MRHD on a mg/m2 basis.

Neonatal Complications
Studies in children to assess the effects of prenatal exposure to zolpidem have not been conducted; however, cases of severe neonatal respiratory depression have been reported when zolpidem was used at the end of pregnancy, especially when taken with other CNS depressants.

Children born to mothers taking sedative-hypnotic drugs may be at some risk for withdrawal symptoms during the postnatal period. Neonatal flaccidity has also been reported in infants born to mothers who received sedative-hypnotic drugs during pregnancy.

Zolpidem tartrate tablets have no established use in labor and delivery [see Pregnancy (8.1)].

Zolpidem is excreted in human milk. Studies in lactating mothers indicate that the half-life of zolpidem is similar to that in non-lactating women (2.6 ± 0.3 hr). The effect of zolpidem on the nursing infant is not known. Caution should be exercised when zolpidem tartrate tables are administered to a nursing woman.

Safety and effectiveness of zolpidem have not been established in pediatric patients.

In an 8-week controlled study, 201 pediatric patients (aged 6–17 years) with insomnia associated with attention-deficit/hyperactivity disorder (90% of the patients were using psychoanaleptics) were treated with an oral solution of zolpidem (n=136), or placebo (n=65). Zolpidem did not significantly decrease latency to persistent sleep, compared to placebo, as measured by polysomnography after 4 weeks of treatment. Psychiatric and nervous system disorders comprised the most frequent (>5%) treatment emergent adverse reactions observed with zolpidem versus placebo and included dizziness (23.5% vs. 1.5%), headache (12.5% vs. 9.2%), and hallucinations (7.4% vs. 0%) [see Warnings and Precautions (5.6)].  Ten patients on zolpidem (7.4%) discontinued treatment due to an adverse reaction.

A total of 154 patients in U.S. controlled clinical trials and 897 patients in non-U.S. clinical trials who received zolpidem were =60 years of age. For a pool of U.S. patients receiving zolpidem at doses of =10 mg or placebo, there were three adverse reactions occurring at an incidence of at least 3% for zolpidem and for which the zolpidem incidence was at least twice the placebo incidence (i.e., they could be considered drug related).

A total of 30/1,959 (1.5%) non-U.S. patients receiving zolpidem reported falls, including 28/30 (93%) who were =70 years of age. Of these 28 patients, 23 (82%) were receiving zolpidem doses >10 mg. A total of 24/1,959 (1.2%) non-U.S. patients receiving zolpidem reported confusion, including 18/24 (75%) who were =70 years of age. Of these 18 patients, 14 (78%) were receiving zolpidem doses >10 mg.

The dose of zolpidem tartrate tablets in elderly patients is 5 mg to minimize adverse effects related to impaired motor and/or cognitive performance and unusual sensitivity to sedative/hypnotic drugs [see Warnings and Precautions (5.6)].

Zolpidem tartrate is classified as a Schedule IV controlled substance by federal regulation.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Abuse is characterized by misuse of the drug for non-medical purposes, often in combination with other psychoactive substances. Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug effects over time. Tolerance may occur to both desired and undesired effects of drugs and may develop at different rates for different effects.

Addiction is a primary, chronic, neurobiological disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease, using a multidisciplinary approach, but relapse is common.

Studies of abuse potential in former drug abusers found that the effects of single doses of zolpidem tartrate 40 mg were similar, but not identical, to diazepam 20 mg, while zolpidem tartrate 10 mg was difficult to distinguish from placebo.

Because persons with a history of addiction to, or abuse of, drugs or alcohol are at increased risk for misuse, abuse and addiction of zolpidem, they should be monitored carefully when receiving zolpidem or any other hypnotic.

Physical dependence is a state of adaptation that is manifested by a specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.

Sedative/hypnotics have produced withdrawal signs and symptoms following abrupt discontinuation. These reported symptoms range from mild dysphoria and insomnia to a withdrawal syndrome that may include abdominal and muscle cramps, vomiting, sweating, tremors, and convulsions. The following adverse events which are considered to meet the DSM-III-R criteria for uncomplicated sedative/hypnotic withdrawal were reported during U.S. clinical trials following placebo substitution occurring within 48 hours following last zolpidem treatment: fatigue, nausea, flushing, lightheadedness, uncontrolled crying, emesis, stomach cramps, panic attack, nervousness, and abdominal discomfort. These reported adverse events occurred at an incidence of 1% or less. However, available data cannot provide a reliable estimate of the incidence, if any, of dependence during treatment at recommended doses. Postmarketing reports of abuse, dependence and withdrawal have been received.

In postmarketing experience of overdose with zolpidem tartrate alone, or in combination with CNS-depressant agents, impairment of consciousness ranging from somnolence to coma, cardiovascular and/or respiratory compromise, and fatal outcomes have been reported.

General symptomatic and supportive measures should be used along with immediate gastric lavage where appropriate. Intravenous fluids should be administered as needed. Zolpidem's sedative hypnotic effect was shown to be reduced by flumazenil and therefore may be useful; however, flumazenil administration may contribute to the appearance of neurological symptoms (convulsions). As in all cases of drug overdose, respiration, pulse, blood pressure, and other appropriate signs should be monitored and general supportive measures employed. Hypotension and CNS depression should be monitored and treated by appropriate medical intervention. Sedating drugs should be withheld following zolpidem overdosage, even if excitation occurs. The value of dialysis in the treatment of overdosage has not been determined, although hemodialysis studies in patients with renal failure receiving therapeutic doses have demonstrated that zolpidem is not dialyzable.

As with the management of all overdosage, the possibility of multiple drug ingestion should be considered. The physician may wish to consider contacting a poison control center for up-to-date information on the management of hypnotic drug product overdosage.

Zolpidem tartrate is a non-benzodiazepine hypnotic of the imidazopyridine class and is available in 5 mg and 10 mg strength tablets for oral administration.

Chemically, zolpidem is N,N,6-trimethyl-2-p-tolylimidazo[1,2-a] pyridine-3-acetamide L-(+)-tartrate (2:1). It has the following structure:

Zolpidem tartrate is a white to off-white crystalline powder that is sparingly soluble in water, alcohol, and propylene glycol. It has a molecular weight of 764.88.

Each zolpidem tartrate tablet includes the following inactive ingredients: hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, and titanium dioxide; the 5-mg tablet also contains FD&C Blue #2 Aluminum Lake, FD&C Red #40 Aluminum Lake, polyethylene glycol, polyvinyl alcohol, and talc; the 10-mg tablet also contains stearic acid and triacetin.

Zolpidem, the active moiety of zolpidem tartrate, is a hypnotic agent with a chemical structure unrelated to benzodiazepines, barbiturates or other drugs with known hypnotic properties. It interacts with a GABA-BZ receptor complex and shares some of the pharmacological properties of the benzodiazepines. In contrast to the benzodiazepines, which nonselectively bind to and activate all BZ receptor subtypes, zolpidem in vitro  binds the BZ1 receptor preferentially with a high affinity ratio of the a1/a5 subunits. This selective binding of zolpidem on the BZ1 receptor is not absolute, but it may explain the relative absence of myorelaxant and anticonvulsant effects in animal studies as well as the preservation of deep sleep (stages 3 and 4) in human studies of zolpidem tartrate at hypnotic doses.

The pharmacokinetic profile of zolpidem tartrate tablets is characterized by rapid absorption from the gastrointestinal tract and a short elimination half-life (T½) in healthy subjects.

In a single-dose crossover study in 45 healthy subjects administered 5 and 10 mg zolpidem tartrate tablets, the mean peak concentrations (Cmax) were 59 (range: 29 to 113) and 121 (range: 58 to 272) ng/mL, respectively, occurring at a mean time (Tmax) of 1.6 hours for both. The mean zolpidem tartrate tablets elimination half-life was 2.6 (range: 1.4 to 4.5) and 2.5 (range: 1.4 to 3.8) hours, for the 5 and 10 mg tablets, respectively. Zolpidem tartrate tablets are converted to inactive metabolites that are eliminated primarily by renal excretion. Zolpidem tartrate tablets demonstrated linear kinetics in the dose range of 5 to 20 mg. Total protein binding was found to be 92.5 ± 0.1% and remained constant, independent of concentration between 40 and 790 ng/mL. Zolpidem did not accumulate in young adults following nightly dosing with 20 mg zolpidem tartrate tablets for 2 weeks.

A food-effect study in 30 healthy male subjects compared the pharmacokinetics of zolpidem tartrate tablets 10 mg when administered while fasting or 20 minutes after a meal. Results demonstrated that with food, mean AUC and Cmax were decreased by 15% and 25%, respectively, while mean Tmax was prolonged by 60% (from 1.4 to 2.2 hr). The half-life remained unchanged. These results suggest that, for faster sleep onset, zolpidem tartrate tablets should not be administered with or immediately after a meal.

Special Populations
Elderly:
In the elderly, the dose for zolpidem tartrate tablets should be 5 mg [see Warnings and Precautions (5) and Dosage and Administration (2)]. This recommendation is based on several studies in which the mean Cmax, T½, and AUC were significantly increased when compared to results in young adults. In one study of eight elderly subjects (>70 years), the means for Cmax, T½, and AUC significantly increased by 50% (255 vs. 384 ng/mL), 32% (2.2 vs. 2.9 hr), and 64% (955 vs. 1,562 ng·hr/mL), respectively, as compared to younger adults (20 to 40 years) following a single 20 mg oral dose. Zolpidem tartrate tablets did not accumulate in elderly subjects following nightly oral dosing of 10 mg for 1 week.

Hepatic Impairment:
The pharmacokinetics of zolpidem tartrate tablets in eight patients with chronic hepatic insufficiency were compared to results in healthy subjects. Following a single 20 mg oral zolpidem tartrate dose, mean Cmax and AUC were found to be two times (250 vs. 499 ng/mL) and five times (788 vs. 4,203 ng·hr/mL) higher, respectively, in hepatically compromised patients. Tmax did not change. The mean half-life in cirrhotic patients of 9.9 hr (range: 4.1 to 25.8 hr) was greater than that observed in normal subjects of 2.2 hr (range: 1.6 to 2.4 hr). Dosing should be modified accordingly in patients with hepatic insufficiency [see Dosage and Administration (2.2) and Warnings and Precautions (5.6)].

Renal Impairment:
The pharmacokinetics of zolpidem tartrate were studied in 11 patients with end-stage renal failure (mean ClCr = 6.5 ± 1.5 mL/min) undergoing hemodialysis three times a week, who were dosed with zolpidem tartrate 10 mg orally each day for 14 or 21 days. No statistically significant differences were observed for Cmax, Tmax, half-life, and AUC between the first and last day of drug administration when baseline concentration adjustments were made. On day 1, Cmax was 172 ± 29 ng/mL (range: 46 to 344 ng/mL). After repeated dosing for 14 or 21 days, Cmax was 203 ± 32 ng/mL (range: 28 to 316 ng/mL). On day 1, Tmax was 1.7 ± 0.3 hr (range: 0.5 to 3.0 hr); after repeated dosing Tmax was 0.8 ± 0.2 hr (range: 0.5 to 2.0 hr). This variation is accounted for by noting that last-day serum sampling began 10 hours after the previous dose, rather than after 24 hours. This resulted in residual drug concentration and a shorter period to reach maximal serum concentration. On day 1, T½ was 2.4 ± 0.4 hr (range: 0.4 to 5.1 hr). After repeated dosing, T½ was 2.5 ± 0.4 hr (range: 0.7 to 4.2 hr). AUC was 796 ± 159 ng·hr/mL after the first dose and 818 ± 170 ng·hr/mL after repeated dosing. Zolpidem was not hemodialyzable. No accumulation of unchanged drug appeared after 14 or 21 days. Zolpidem pharmacokinetics were not significantly different in renally impaired patients. No dosage adjustment is necessary in patients with compromised renal function. However, as a general precaution, these patients should be closely monitored.

Carcinogenesis:
Zolpidem was administered to mice and rats for 2 years at dietary dosages of 4, 18, and 80 mg base/kg. In mice, these doses are approximately 2.5, 10, and 50 times the maximum recommended human dose (MRHD) of 10 mg/day (8 mg zolpidem base) on mg/m2 basis. In rats, these doses are approximately 5, 20, and 100 times the MRHD on a mg/m2 basis. No evidence of carcinogenic potential was observed in mice. In rats, renal tumors (lipoma, liposarcoma) were seen at the mid- and high doses.

Mutagenesis:
Zolpidem was negative in in vitro (bacterial reverse mutation, mouse lymphoma, and chromosomal aberration) and in vivo (mouse micronucleus) genetic toxicology assays.

Impairment of fertility:
Oral administration of zolpidem (doses of 4, 20, and 100 mg base/kg or approximately 5, 24, and 120 times the MRHD on a mg/m2 basis) to rats prior to and during mating, and continuing in females through postpartum day 25, resulted in irregular estrus cycles and prolonged precoital intervals. The no-effect dose for these findings is approximately 24 times the MRHD on a mg/m2 basis. There was no impairment of fertility at any dose tested.

Normal adults experiencing transient insomnia (n=462) during the first night in a sleep laboratory were evaluated in a double-blind, parallel group, single-night trial comparing two doses of zolpidem (7.5 and 10 mg) and placebo. Both zolpidem doses were superior to placebo on objective (polysomnographic) measures of sleep latency, sleep duration, and number of awakenings.

Normal elderly adults (mean age 68) experiencing transient insomnia (n=35) during the first two nights in a sleep laboratory were evaluated in a double-blind, crossover, 2-night trial comparing four doses of zolpidem (5, 10, 15 and 20 mg) and placebo. All zolpidem doses were superior to placebo on the two primary PSG parameters (sleep latency and efficiency) and all four subjective outcome measures (sleep duration, sleep latency, number of awakenings, and sleep quality).

Zolpidem was evaluated in two controlled studies for the treatment of patients with chronic insomnia (most closely resembling primary insomnia, as defined in the APA Diagnostic and Statistical Manual of Mental Disorders, DSM-IV™). Adult outpatients with chronic insomnia (n=75) were evaluated in a double-blind, parallel group, 5-week trial comparing two doses of zolpidem tartrate and placebo. On objective (polysomnographic) measures of sleep latency and sleep efficiency, zolpidem 10 mg was superior to placebo on sleep latency for the first 4 weeks and on sleep efficiency for weeks 2 and 4. Zolpidem was comparable to placebo on number of awakenings at both doses studied.

Adult outpatients (n=141) with chronic insomnia were also evaluated, in a double-blind, parallel group, 4-week trial comparing two doses of zolpidem and placebo. Zolpidem 10 mg was superior to placebo on a subjective measure of sleep latency for all 4 weeks, and on subjective measures of total sleep time, number of awakenings, and sleep quality for the first treatment week.

Increased wakefulness during the last third of the night as measured by polysomnography has not been observed in clinical trials with zolpidem tartrate tablets.

Next-day residual effects:  Next-day residual effects of zolpidem tartrate tablets were evaluated in seven studies involving normal subjects. In three studies in adults (including one study in a phase advance model of transient insomnia) and in one study in elderly subjects, a small but statistically significant decrease in performance was observed in the Digit Symbol Substitution Test (DSST) when compared to placebo. Studies of zolpidem tartrate tablets in nonelderly patients with insomnia did not detect evidence of next-day residual effects using the DSST, the Multiple Sleep Latency Test (MSLT), and patient ratings of alertness.

Rebound effects: There was no objective (polysomnographic) evidence of rebound insomnia at recommended doses seen in studies evaluating sleep on the nights following discontinuation of zolpidem tartrate tablets. There was subjective evidence of impaired sleep in the elderly on the first post-treatment night at doses above the recommended elderly dose of 5 mg.

Memory impairment: Controlled studies in adults utilizing objective measures of memory yielded no consistent evidence of next-day memory impairment following the administration of zolpidem tartrate tablets. However, in one study involving zolpidem doses of 10 and 20 mg, there was a significant decrease in next-morning recall of information presented to subjects during peak drug effect (90 minutes post-dose), i.e., these subjects experienced anterograde amnesia. There was also subjective evidence from adverse event data for anterograde amnesia occurring in association with the administration of zolpidem tartrate tablets, predominantly at doses above 10 mg.

Effects on sleep stages: In studies that measured the percentage of sleep time spent in each sleep stage, zolpidem tartrate tablets have generally been shown to preserve sleep stages. Sleep time spent in stages 3 and 4 (deep sleep) was found comparable to placebo with only inconsistent, minor changes in REM (paradoxical) sleep at the recommended dose.

Zolpidem Tartrate Tablets are available as:

5 mg, pink, film-coated, capsule-shaped, unscored, debossed "6468" on one side and debossed "V" on the reverse side, in bottles of 10, 20, 30, 100, 500 and 1000.

10 mg, white, film-coated, capsule-shaped, unscored, debossed "6469" on one side and debossed "V" on the reverse side, in bottles of 10, 15, 20, 30, 60, 90, 100, 500 and 1000.

Store at controlled room temperature 20°-25°C (68°-77°F) [see USP Controlled Room Temperature].

Prescribers or other healthcare professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with sedative-hypnotics, should counsel them in its appropriate use, and should instruct them to read the accompanying Medication Guide [see Medication Guide (17.4)].

Inform patients that severe anaphylactic and anaphylactoid reactions have occurred with zolpidem. Describe the signs/symptoms of these reactions and advise patients to seek medical attention immediately if any of them occur.

There have been reports of people getting out of bed after taking a sedative-hypnotic and driving their cars while not fully awake, often with no memory of the event. If a patient experiences such an episode, it should be reported to his or her doctor immediately, since "sleep-driving" can be dangerous. This behavior is more likely to occur when zolpidem tartrate tablets are taken with alcohol or other central nervous system depressants [see Warnings and Precautions (5.3)]. Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative-hypnotic. As with "sleep-driving", patients usually do not remember these events.

In addition, patients should be advised to report all concomitant medications to the prescriber. Patients should be instructed to report events such as "sleep-driving" and other complex behaviors immediately to the prescriber.

Patients should be counseled to take zolpidem tartrate tablets right before they get into bed and only when they are able to stay in bed a full night (7–8 hours) before being active again. Zolpidem tartrate tablets should not be taken with or immediately after a meal. Advise patients NOT to take zolpidem tartrate tablets when drinking alcohol.

MEDICATION GUIDE
ZOLPIDEM TARTRATE TABLETS

Read the Medication Guide that comes with zolpidem tartrate tablets before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor about your medical condition or treatment.

What is the most important information I should know about zolpidem tartrate tablets?

After taking zolpidem tartrate tablets, you may get up out of bed while not being fully awake and do an activity that you do not know you are doing. The next morning, you may not remember that you did anything during the night. You have a higher chance for doing these activities if you drink alcohol or take other medicines that make you sleepy with zolpidem tartrate tablets. Reported activities include:

driving a car ("sleep-driving") making and eating food talking on the phone having sex sleep-walking

Call your doctor right away if you find out that you have done any of the above activities after taking zolpidem tartrate tablets.

Important:

1. Take zolpidem tartrate tablets exactly as prescribed

Do not take more zolpidem tartrate tablets than prescribed. Take zolpidem tartrate tablets right before you get in bed, not sooner.

2. Do not take zolpidem tartrate tablets if you:

drink alcohol take other medicines that can make you sleepy. Talk to your doctor about all of your medicines. Your doctor will tell you if you can take zolpidem tartrate tablets with your other medicines. cannot get a full night's sleep

What is zolpidem tartrate tablets?

Zolpidem tartrate tablets is a sedative-hypnotic (sleep) medicine.

Zolpidem tartrate tablets is used in adults for the short-term treatment of a sleep problem called insomnia.

Symptoms of insomnia include:

Zolpidem tartrate tablets is not for children.

Zolpidem tartrate tablets is a federally controlled substance (C-IV) because it can be abused or lead to dependence. Keep zolpidem tartrate tablets in a safe place to prevent misuse and abuse. Selling or giving away zolpidem tartrate tablets may harm others, and is against the law. Tell your doctor if you have ever abused or have been dependent on alcohol, prescription medicines or street drugs.

Who should not take zolpidem tartrate tablets?

Do not take zolpidem tartrate tablets if you are allergic to anything in it.

See the end of this Medication Guide for a complete list of ingredients in zolpidem tartrate tablets.

Zolpidem tartrate tablets may not be right for you. Before starting zolpidem tartrate tablets, tell your doctor about all of your health conditions, including if you:

have a history of depression, mental illness, or suicidal thoughts have a history of drug or alcohol abuse or addiction have kidney or liver disease have a lung disease or breathing problems are pregnant, planning to become pregnant, or breastfeeding

Tell your doctor about all of the medicines you take including prescription and nonprescription medicines, vitamins and herbal supplements. Medicines can interact with each other, sometimes causing serious side effects. Do not take zolpidem tartrate tablets with other medicines that can make you sleepy.

Know the medicines you take. Keep a list of your medicines with you to show your doctor and pharmacist each time you get a new medicine.

How should I take zolpidem tartrate tablets?

Take zolpidem tartrate tablets exactly as prescribed. Do not take more zolpidem tartrate tablets than prescribed for you. Take zolpidem tartrate tablets right before you get into bed. Do not take zolpidem tartrate tablets unless you are able to stay in bed a full night (7–8 hours) before you must be active again. For faster sleep onset, zolpidem tartrate tablets should NOT be taken with or immediately after a meal. Call your doctor if your insomnia worsens or is not better within 7 to 10 days. This may mean that there is another condition causing your sleep problem. If you take too much zolpidem tartrate tablets or overdose, call your doctor or poison control center right away, or get emergency treatment.

What are the possible side effects of zolpidem tartrate tablets?

Serious side effects of zolpidem tartrate tablets include:

getting out of bed while not being fully awake and do an activity that you do not know you are doing. (See "What is the most important information I should know about zolpidem tartrate tablets?") abnormal thoughts and behavior. Symptoms include more outgoing or aggressive behavior than normal, confusion, agitation, hallucinations, worsening of depression, and suicidal thoughts or actions. memory loss anxiety severe allergic reactions. Symptoms include swelling of the tongue or throat, trouble breathing, and nausea and vomiting. Get emergency medical help if you get these symptoms after taking zolpidem tartrate tablets.

Call your doctor right away if you have any of the above side effects or any other side effects that worry you while using zolpidem tartrate tablets.

The most common side effects of zolpidem tartrate tablets are:

drowsiness dizziness diarrhea "drugged feelings" You may still feel drowsy the next day after taking zolpidem tartrate tablets. Do not drive or do other dangerous activities after taking zolpidem tartrate tablets until you feel fully awake.

After you stop taking a sleep medicine, you may have symptoms for 1 to 2 days such as: trouble sleeping, nausea, flushing, lightheadedness, uncontrolled crying, vomiting, stomach cramps, panic attack, nervousness, and stomach area pain.

These are not all the side effects of zolpidem tartrate tablets. Ask your doctor or pharmacist for more information.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store zolpidem tartrate tablets?

Store zolpidem tartrate tablets at room temperature, 68° to 77°F (20° to 25°C). Keep zolpidem tartrate tablets and all medicines out of reach of children.

General information about zolpidem tartrate tablets

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use zolpidem tartrate tablets for a condition for which it was not prescribed. Do not share zolpidem tartrate tablets with other people, even if you think they have the same symptoms that you have. It may harm them and it is against the law.

This Medication Guide summarizes the most important information about zolpidem tartrate tablets. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about zolpidem tartrate tablets that is written for healthcare professionals.

What are the ingredients in zolpidem tartrate tablets?

Active ingredient: Zolpidem tartrate

Inactive Ingredients: hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, and titanium dioxide; the 5-mg tablet also contains FD&C Blue #2 Aluminum Lake, FD&C Red #40 Aluminum Lake, polyethylene glycol, polyvinyl alcohol, and talc; the 10-mg tablet also contains stearic acid and triacetin.

Rx Only

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Manufactured for:
QUALITEST PHARMACEUTICALS
Huntsville, AL 35811

8182348
Revised: 8/2010
R2

A SUPPLY OF MEDICATION GUIDES AS PRINTED AT THE END OF THIS INSERT IS AVAILABLE, FREE OF CHARGE, BY CALLING
(800) 444-4011.

CIV

ZOLPIDEM TARTRATE TABLETS

Read the Medication Guide that comes with zolpidem tartrate tablets before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor about your medical condition or treatment.

What is the most important information I should know about zolpidem tartrate tablets?

After taking zolpidem tartrate tablets, you may get up out of bed while not being fully awake and do an activity that you do not know you are doing. The next morning, you may not remember that you did anything during the night. You have a higher chance for doing these activities if you drink alcohol or take other medicines that make you sleepy with zolpidem tartrate tablets. Reported activities include:

driving a car ("sleep-driving") making and eating food talking on the phone having sex sleep-walking

Call your doctor right away if you find out that you have done any of the above activities after taking zolpidem tartrate tablets.

Important:

1. Take zolpidem tartrate tablets exactly as prescribed

Do not take more zolpidem tartrate tablets than prescribed. Take zolpidem tartrate tablets right before you get in bed, not sooner.

2. Do not take zolpidem tartrate tablets if you:

drink alcohol take other medicines that can make you sleepy. Talk to your doctor about all of your medicines. Your doctor will tell you if you can take zolpidem tartrate tablets with your other medicines. cannot get a full night's sleep

What is zolpidem tartrate tablets?

Zolpidem tartrate tablets is a sedative-hypnotic (sleep) medicine.

Zolpidem tartrate tablets is used in adults for the short-term treatment of a sleep problem called insomnia.

Symptoms of insomnia include:

Zolpidem tartrate tablets is not for children.

Zolpidem tartrate tablets is a federally controlled substance (C-IV) because it can be abused or lead to dependence. Keep zolpidem tartrate tablets in a safe place to prevent misuse and abuse. Selling or giving away zolpidem tartrate tablets may harm others, and is against the law. Tell your doctor if you have ever abused or have been dependent on alcohol, prescription medicines or street drugs.

Who should not take zolpidem tartrate tablets?

Do not take zolpidem tartrate tablets if you are allergic to anything in it.

See the end of this Medication Guide for a complete list of ingredients in zolpidem tartrate tablets.

Zolpidem tartrate tablets may not be right for you. Before starting zolpidem tartrate tablets, tell your doctor about all of your health conditions, including if you:

have a history of depression, mental illness, or suicidal thoughts have a history of drug or alcohol abuse or addiction have kidney or liver disease have a lung disease or breathing problems are pregnant, planning to become pregnant, or breastfeeding

Tell your doctor about all of the medicines you take including prescription and nonprescription medicines, vitamins and herbal supplements. Medicines can interact with each other, sometimes causing serious side effects. Do not take zolpidem tartrate tablets with other medicines that can make you sleepy.

Know the medicines you take. Keep a list of your medicines with you to show your doctor and pharmacist each time you get a new medicine.

How should I take zolpidem tartrate tablets?

Take zolpidem tartrate tablets exactly as prescribed. Do not take more zolpidem tartrate tablets than prescribed for you. Take zolpidem tartrate tablets right before you get into bed. Do not take zolpidem tartrate tablets unless you are able to stay in bed a full night (7–8 hours) before you must be active again. For faster sleep onset, zolpidem tartrate tablets should NOT be taken with or immediately after a meal. Call your doctor if your insomnia worsens or is not better within 7 to 10 days. This may mean that there is another condition causing your sleep problem. If you take too much zolpidem tartrate tablets or overdose, call your doctor or poison control center right away, or get emergency treatment.

What are the possible side effects of zolpidem tartrate tablets?

Serious side effects of zolpidem tartrate tablets include:

getting out of bed while not being fully awake and do an activity that you do not know you are doing. (See "What is the most important information I should know about zolpidem tartrate tablets?") abnormal thoughts and behavior. Symptoms include more outgoing or aggressive behavior than normal, confusion, agitation, hallucinations, worsening of depression, and suicidal thoughts or actions. memory loss anxiety severe allergic reactions. Symptoms include swelling of the tongue or throat, trouble breathing, and nausea and vomiting. Get emergency medical help if you get these symptoms after taking zolpidem tartrate tablets.

Call your doctor right away if you have any of the above side effects or any other side effects that worry you while using zolpidem tartrate tablets.

The most common side effects of zolpidem tartrate tablets are:

drowsiness dizziness diarrhea "drugged feelings" You may still feel drowsy the next day after taking zolpidem tartrate tablets. Do not drive or do other dangerous activities after taking zolpidem tartrate tablets until you feel fully awake.

After you stop taking a sleep medicine, you may have symptoms for 1 to 2 days such as: trouble sleeping, nausea, flushing, lightheadedness, uncontrolled crying, vomiting, stomach cramps, panic attack, nervousness, and stomach area pain.

These are not all the side effects of zolpidem tartrate tablets. Ask your doctor or pharmacist for more information.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store zolpidem tartrate tablets?

Store zolpidem tartrate tablets at room temperature, 68° to 77°F (20° to 25°C). Keep zolpidem tartrate tablets and all medicines out of reach of children.

General information about zolpidem tartrate tablets

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use zolpidem tartrate tablets for a condition for which it was not prescribed. Do not share zolpidem tartrate tablets with other people, even if you think they have the same symptoms that you have. It may harm them and it is against the law.

This Medication Guide summarizes the most important information about zolpidem tartrate tablets. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about zolpidem tartrate tablets that is written for healthcare professionals.

What are the ingredients in zolpidem tartrate tablets?

Active ingredient: Zolpidem tartrate

Inactive Ingredients: hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, and titanium dioxide; the 5-mg tablet also contains FD&C Blue #2 Aluminum Lake, FD&C Red #40 Aluminum Lake, polyethylene glycol, polyvinyl alcohol, and talc; the 10-mg tablet also contains stearic acid and triacetin.

Rx Only

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Manufactured for:
QUALITEST PHARMACEUTICALS
Huntsville, AL 35811

8182493
Revised: 1/2009
R0

ZOLPIDEM TARTRATE 
zolpidem tartrate   tablet, film coatedActive Ingredient/Active MoietySODIUM STARCH GLYCOLATE TYPE A POTATO20 TABLET In 1 BOTTLE, PLASTIC10 TABLET In 1 BOTTLE, PLASTIC30 TABLET In 1 BOTTLE, PLASTIC100 TABLET In 1 BOTTLE, PLASTIC500 TABLET In 1 BOTTLE, PLASTIC1000 TABLET In 1 BOTTLE, PLASTIC
Application Number or Monograph Citation
ZOLPIDEM TARTRATE 
zolpidem tartrate   tablet, film coatedActive Ingredient/Active MoietySODIUM STARCH GLYCOLATE TYPE A POTATO90 TABLET In 1 BOTTLE, PLASTIC20 TABLET In 1 BOTTLE, PLASTIC10 TABLET In 1 BOTTLE, PLASTIC15 TABLET In 1 BOTTLE, PLASTIC30 TABLET In 1 BOTTLE, PLASTIC60 TABLET In 1 BOTTLE, PLASTIC100 TABLET In 1 BOTTLE, PLASTIC500 TABLET In 1 BOTTLE, PLASTIC1000 TABLET In 1 BOTTLE, PLASTIC
Application Number or Monograph Citation
Labeler - Qualitest Pharmaceuticals (011103059) Vintage Pharmaceuticals-HuntsvilleRevised: 08/2010Qualitest Pharmaceuticals