Do-it-yourself leadership kit [PDF]

Do-it-yourself leadership kit. 1. Choose a committee. 2. Sign up.

As a volunteer for any of The Endocrine Society committees, you’ll shape the direction of the Society, make a lasting impression in the field of endocrinology and take a proactive step in your career development. To volunteer yourself or someone else, visit http://www.endosociety.org/membership/nominate_volunteer.cfm. You can check out all the different committees, volunteer for service and start becoming the leader you were meant to be.

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3. Participate.

Important Safety Information: • Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders. • Patients started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior. • Cymbalta is not approved for use in pediatric patients.

Cymbalta should not be used concomitantly with monoamine oxidase inhibitors (MAOIs) or thioridazine and not in patients with a known hypersensitivity or with uncontrolled narrow-angle glaucoma. Clinical worsening and suicide risk: All adult and pediatric patients being treated with an antidepressant for any indication should be observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially when initiating drug therapy and when increasing or decreasing the dose. A health professional

References: 1. Data on file, Lilly Research Laboratories: a: CYM20050901A; b: CYM20050314B; c: CYM20050314D. 2. Goldstein DJ, et al. Pain. 2005;116:109-118.

* Cymbalta vs placebo (P≤.001) by MMRM on 24-hour average pain severity score Cymbalta vs placebo (P≤.009) by MMRM on 24-hour night pain severity score MMRM = Mixed-effects Models Repeated Measures analysis

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In just days, he started putting years of pain behind him.1a

Patients with diabetic peripheral neuropathic pain (DPNP) want rapid relief. Now it may be possible.

Visit www.insideCymbalta.com/DPNP to learn more.

should be immediately notified if the depression is persistently worse or there are symptoms that are severe, sudden, or were not part of the patient’s presentation. If discontinuing treatment, taper the medication. Cymbalta should not be administered to patients with any hepatic insufficiency or patients with end-stage renal disease (requiring dialysis) or severe renal impairment (CrCl <30 mL/min). Postmarketing, severe elevations of liver enzymes or liver injury with a cholestatic or mixed pattern have been reported.

Cymbalta should generally not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease. Most common adverse events (≥5% and at least twice placebo) in MDD premarketing clinical trials were: nausea, dry mouth, constipation, fatigue, decreased appetite, somnolence, and increased sweating. Most common adverse events in diabetic peripheral neuropathic pain (DPNP) premarketing clinical trials were: nausea, somnolence, dizziness, constipation, dry mouth, increased sweating, decreased appetite, and asthenia.

DD 38386 PRINTED IN USA. COPYRIGHT © 2005, ELI LILLY AND COMPANY. ALL RIGHTS RESERVED. Cymbalta is a registered trademark of Eli Lilly and Company.

See Brief Summary of full Prescribing Information, including Boxed Warning, on adjacent page.

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Burning, shooting, stabbing pain has kept many patients with DPNP off their feet for years. Imagine being able to start giving them relief in just a few days. It’s possible with Cymbalta—the first FDA-approved medication indicated for the management of DPNP. It significantly reduces pain throughout the day and night,1b,c,2* so he can take life in stride again.

CYMBALTA姞

Cymbalta姞 (duloxetine hydrochloride) Delayed-release Capsules

Cymbalta姞 (duloxetine hydrochloride) Delayed-release Capsules

Brief Summary: Consult the package insert for complete prescribing information. WARNING Suicidality in Children and Adolescents—Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of Cymbalta or any other antidepressant in a child or adolescent must balance this risk with the clinical need. Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Cymbalta is not approved for use in pediatric patients. (See WARNINGS and PRECAUTIONS, Pediatric Use.) Pooled analyses of short-term (4 to 16 weeks) placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal thinking or behavior (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. No suicides occurred in these trials. INDICATIONS AND USAGE: Cymbalta is indicated for the treatment of major depressive disorder (MDD). Cymbalta is indicated for the management of neuropathic pain associated with diabetic peripheral neuropathy (DPN). CONTRAINDICATIONS: Hypersensitivity—Known hypersensitivity to duloxetine or any of the inactive ingredients. Monoamine Oxidase Inhibitors (MAOIs)—Concomitant use with Cymbalta is contraindicated (see WARNINGS). Uncontrolled Narrow-Angle Glaucoma—In clinical trials, Cymbalta use was associated with an increased risk of mydriasis; therefore, its use is not recommended in patients with uncontrolled narrow-angle glaucoma. WARNINGS: Clinical Worsening and Suicide Risk—Patients with MDD, both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. There has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients. Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with MDD and other psychiatric disorders. Pooled analyses of short-term placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with MDD, OCD, or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal behavior or thinking (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. There was considerable variation in risk among drugs, but a tendency toward an increase for almost all drugs studied. The risk of suicidality was most consistently observed in the MDD trials, but there were signals of risk arising from some trials in other psychiatric indications (obsessive compulsive disorder and social anxiety disorder) as well. No suicides occurred in any of these trials. It is unknown whether the suicidality risk in pediatric patients extends to longer-term use, ie, beyond several months. It is also unknown whether the suicidality risk extends to adults. All pediatric patients being treated with antidepressants for any indication should be observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Such observation would generally include at least weekly face-to-face contact with patients or their family members or caregivers during the first 4 weeks of treatment, then every other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks. Additional contact by telephone may be appropriate between face to face visits. Adults with MDD or co-morbid depression in the setting of other psychiatric illness being treated with antidepressants should be observed similarly for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for MDD as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS, Discontinuation of Treatment with Cymbalta). Families and caregivers of pediatric patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Cymbalta should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. Families and caregivers of adults being treated for depression should be similarly advised. Screening Patients for Bipolar Disorder—A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Cymbalta is not approved for use in treating bipolar depression. MAOIs—In patients receiving a serotonin reuptake inhibitor (SSRI) in combination with an MAOI, there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued SSRIs and are then started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. The effects of combined use of Cymbalta and MAOIs have not been evaluated in humans or animals. Therefore, because Cymbalta is an inhibitor of both serotonin and norepinephrine reuptake, it is recommended that Cymbalta not be used in combination with an MAOI, or within at least 14 days of discontinuing treatment with an MAOI. Based on the half-life of Cymbalta, at least 5 days should be allowed after stopping Cymbalta before starting an MAOI.

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PRECAUTIONS: General—Hepatotoxicity—Cymbalta increases the risk of elevation of serum transaminase levels. Liver transaminase elevations resulted in the discontinuation of 0.4% (31/8454) of Cymbalta-treated patients. In these patients, the median time to detection of the transaminase elevation was about two months. In controlled trials in MDD, elevations of alanine transaminase (ALT) to >3 times the upper limit of normal occurred in 0.9% (8/930) of Cymbalta-treated patients and in 0.3% (2/652) of placebo-treated patients. In controlled trials in DPN, elevations of ALT to >3 times the upper limit of normal occurred in

1.68% (8/477) of Cymbalta-treated patients and in 0% (0/187) of placebo-treated patients. In the full cohort of placebo-controlled trials in any indication, 1% (39/3732) of Cymbalta-treated patients had a >3 times the upper limit of normal elevation of ALT compared to 0.2% (6/2568) of placebo-treated patients. In placebocontrolled studies using a fixed-dose design, there was evidence of a dose-response relationship for ALT and AST elevation of >3 times the upper limit of normal and >5 times the upper limit of normal, respectively. Postmarketing reports have described cases of hepatitis with abdominal pain, hepatomegaly and elevation of transaminase levels to more than twenty times the upper limit of normal with or without jaundice, reflecting a mixed or hepatocellular pattern of liver injury. Cases of cholestatic jaundice with minimal elevation of transaminase levels have also been reported. The combination of transaminase elevations and elevated bilirubin, without evidence of obstruction, is generally recognized as an important predictor of severe liver injury. In clinical trials, three Cymbalta patients had elevations of transaminases and bilirubin, but also had elevation of alkaline phosphatase, suggesting an obstructive process; in these patients, there was evidence of heavy alcohol use and this may have contributed to the abnormalities seen. Two placebo-treated patients also had transaminase elevations with elevated bilirubin. Postmarketing reports indicate that elevated transaminases, bilirubin and alkaline phosphatase have occurred in patients with chronic liver disease or cirrhosis. Because it is possible that duloxetine and alcohol may interact to cause liver injury or that duloxetine may aggravate pre-existing liver disease, Cymbalta should ordinarily not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease. Effect on Blood Pressure—In MDD clinical trials, Cymbalta treatment was associated with mean increases in blood pressure, averaging 2 mm Hg systolic and 0.5 mm Hg diastolic and an increase in the incidence of at least one measurement of systolic blood pressure over 140 mm Hg compared to placebo. Blood pressure should be measured prior to initiating treatment and periodically measured throughout treatment (see ADVERSE REACTIONS, Vital Sign Changes). Activation of Mania/ Hypomania—In placebo-controlled trials in patients with MDD, activation of mania or hypomania was reported in 0.1% (1/1139) of Cymbalta-treated patients and 0.1% (1/777) of placebo-treated patients. Activation of mania/hypomania has been reported in a small proportion of patients with mood disorders who were treated with other marketed drugs effective in the treatment of MDD. As with these other agents, Cymbalta should be used cautiously in patients with a history of mania. Seizures—Cymbalta has not been systematically evaluated in patients with a seizure disorder, and such patients were excluded from clinical studies. In placebo-controlled clinical trials in patients with MDD, seizures occurred in 0.1% (1/1139) of Cymbalta-treated patients and 0% (0/777) of placebo treated patients. In placebo-controlled clinical trials in patients with diabetic peripheral neuropathy, seizures did not occur in any patients treated with either Cymbalta or placebo. Cymbalta should be prescribed with care in patients with a history of a seizure disorder. Controlled Narrow-Angle Glaucoma—In clinical trials, Cymbalta was associated with an increased risk of mydriasis; therefore, it should be used cautiously in patients with controlled narrow-angle glaucoma (see CONTRAINDICATIONS, Uncontrolled Narrow-Angle Glaucoma). Discontinuation of Treatment with Cymbalta— Discontinuation symptoms have been systematically evaluated in patients taking Cymbalta. Following abrupt discontinuation in MDD placebo-controlled clinical trials of up to 9 weeks duration, the following symptoms occurred at a rate greater than or equal to 2% and at a significantly higher rate in Cymbalta-treated patients compared to those discontinuing from placebo: dizziness; nausea; headache; paresthesia; vomiting; irritability; and nightmare. During marketing of other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (eg, paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. Although these events are generally self-limiting, some have been reported to be severe. Patients should be monitored for these symptoms when discontinuing treatment with Cymbalta. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. Use in Patients with Concomitant Illness—Clinical experience with Cymbalta in patients with concomitant systemic illnesses is limited. There is no information on the effect that alterations in gastric motility may have on the stability of Cymbalta’s enteric coating. As duloxetine is rapidly hydrolyzed in acidic media to naphthol, caution is advised in using Cymbalta in patients with conditions that may slow gastric emptying (eg, some diabetics). Cymbalta has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable coronary artery disease. Patients with these diagnoses were generally excluded from clinical studies during the product’s premarketing testing. However, the electrocardiograms of 321 patients who received Cymbalta in MDD placebo-controlled clinical trials and had qualitatively normal ECGs at baseline were evaluated; Cymbalta was not associated with the development of clinically significant ECG abnormalities (see ADVERSE REACTIONS, Electrocardiogram Changes). In DPN placebocontrolled clinical trials, Cymbalta-treated patients did not develop abnormal ECGs at a rate different from that in placebo-treated patients (see ADVERSE REACTIONS, Electrocardiogram Changes). In clinical trials of Cymbalta for the management of neuropathic pain associated with diabetic peripheral neuropathy, the mean duration of diabetes was approximately 11 years, the mean baseline fasting blood glucose was 163 mg/dL, and the mean baseline hemoglobin A1c (HbA1c) was 7.8%. In these studies, small increases in fasting blood glucose were observed in Cymbalta-treated patients compared to placebo at 12 weeks and routine care at 52 weeks. The increase was similar at both time points. Overall diabetic control did not worsen as evidenced by stable HbA1c values and by no differences in incidence of serious and non-serious diabetes-related adverse events relative to placebo or routine care. Increased plasma concentrations of duloxetine, and especially of its metabolites, occur in patients with end-stage renal disease (requiring dialysis). For this reason, Cymbalta is not recommended for patients with end-stage renal disease or severe renal impairment (creatinine clearance <30 mL/min) Markedly increased exposure to duloxetine occurs in patients with hepatic insufficiency and Cymbalta should not be administered to these patients. Laboratory Tests—No specific laboratory tests are recommended. Drug Interactions—Potential for Other Drugs to Affect Cymbalta—Both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism. Inhibitors of CYP1A2—Concomitant use of duloxetine with fluvoxamine, an inhibitor of CYP1A2, results in approximately a 6-fold increase in AUC and about a 2.5-fold increase in Cmax of duloxetine. Some quinolone antibiotics would be expected to have similar effects and these combinations should be avoided. Inhibitors of CYP2D6—Because CYP2D6 is involved in duloxetine metabolism, concomitant use of duloxetine with potent inhibitors of CYP2D6 may result in higher concentrations of duloxetine. Paroxetine (20 mg QD) increased the concentration of duloxetine (40 mg QD) by about 60%, and greater degrees of inhibition are expected with higher doses of paroxetine. Similar effects would be expected with other potent CYP2D6 inhibitors (eg, fluoxetine, quinidine). Potential for Duloxetine to Affect Other Drugs—Drugs Metabolized by CYP1A2—In vitro drug interaction studies demonstrate that duloxetine does not induce CYP1A2 activity, and it is unlikely to have a clinically significant effect on the metabolism of CYP1A2 substrates. Drugs Metabolized by CYP2D6—Cymbalta is a moderate inhibitor of CYP2D6. When duloxetine was administered (at a dose of 60 mg BID) in conjunction with a single 50-mg dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased 3-fold. Therefore, co-administration of Cymbalta with other drugs that are extensively metabolized by this isozyme and which have a narrow therapeutic index, including certain antidepressants (tricyclic antidepressants [TCAs], such as nortriptyline, amitriptyline, and imipramine), phenothiazines and Type 1C antiarrhythmics (eg, propafenone, flecainide), should be approached with caution. Plasma TCA concentrations may need to be monitored and the dose of the TCA may need to be reduced if a TCA is co-administered with Cymbalta. Because of the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, Cymbalta and thioridazine should not be co-administered. Drugs Metabolized by CYP3A—Results of in vitro studies demonstrate that duloxetine does not inhibit or induce CYP3A activity. Cymbalta May Have a Clinically Important Interaction with the Following Other Drugs—Alcohol—When Cymbalta and ethanol were administered several hours apart so that peak concentrations of each would coincide, Cymbalta did not increase the impairment of mental and motor skills caused by alcohol. In the Cymbalta clinical trials database, three Cymbalta-treated patients had liver injury as manifested by ALT and total bilirubin elevations, with evidence of obstruction. Substantial intercurrent ethanol use was present in each of these cases, and this may have contributed to the abnormalities seen (see PRECAUTIONS, Hepatotoxicity). CNS-Acting Drugs—Given the primary CNS effects of Cymbalta, it should be used with caution when it is taken in combination with or substituted for other centrally acting drugs, including those with a similar mechanism of action. Potential for Interaction with Drugs that Affect Gastric Acidity—Cymbalta has an enteric coating that resists dissolution until reaching a segment of the gastrointestinal tract where the pH exceeds 5.5. In extremely acidic conditions, Cymbalta, unprotected by the enteric coating, may undergo hydrolysis to form naphthol. Caution is advised in using Cymbalta in patients with conditions that may slow gastric emptying (eg, some diabetics). Drugs that raise the

(duloxetine hydrochloride) Delayed-release Capsules

ADVERSE REACTIONS: Cymbalta has been evaluated for safety in 2418 patients diagnosed with MDD who participated in multiple-dose premarketing trials, representing 1099 patient-years of exposure. Among these 2418 Cymbalta-treated patients, 1139 patients participated in eight 8 or 9 week, placebo-controlled trials at doses ranging from 40 to 120 mg/day, while the remaining 1279 patients were followed for up to 1 year in an open-label safety study using flexible doses from 80 to 120 mg/day. Two placebo-controlled studies with doses of 80 and 120 mg/day had 6-month maintenance extensions. Of these 2418 patients, 993 Cymbalta-treated patients were exposed for at least 180 days and 445 Cymbalta-treated patients were exposed for at least 1 year. Cymbalta has also been evaluated for safety in 1074 patients with diabetic peripheral neuropathy representing 472 patient-years of exposure. Among these 1074 Cymbalta-treated patients, 568 patients participated in two 12 to 13 week, placebo-controlled trials at doses ranging from 20 to 120 mg/day. An additional 449 patients were enrolled in an open-label safety study using 120 mg/day for a duration of 6 months. Another 57 patients, originally treated with placebo, were exposed to Cymbalta for up to 12 months at 60 mg twice daily in an extension phase. Among these 1074 patients, 484 had 6 months of exposure to Cymbalta, and 220 had 12 months of exposure. For both MDD and DPN clinical trials, adverse reactions were assessed by collecting adverse events, results of physical examinations, vital signs, weights, laboratory analyses, and ECGs. Clinical investigators recorded adverse events using descriptive terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals experiencing adverse events, grouping similar types of events into a smaller number of standardized event categories is necessary. MedDRA terminology was used to classify reported adverse events. The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Events reported during the studies were not necessarily caused by the therapy, and the frequencies do not reflect investigator impression (assessment) of causality. Adverse Events Reported as Reasons for Discontinuation of Treatment in Placebo-Controlled Trials— Major Depressive Disorder—Approximately 10% of the 1139 patients who received Cymbalta in the MDD placebo-controlled trials discontinued treatment due to an adverse event, compared with 4% of the 777 patients receiving placebo. Nausea (Cymbalta 1.4%, placebo 0.1%) was the only common adverse event reported as reason for discontinuation and considered to be drug-related (ie, discontinuation occurring in at least 1% of the Cymbalta-treated patients and at a rate of at least twice that of placebo). Diabetic Peripheral Neuropathic Pain—Approximately 14% of the 568 patients who received Cymbalta in the DPN placebo-controlled trials discontinued treatment due to an adverse event, compared with 7% of the 223 patients receiving placebo. Nausea (Cymbalta 3.5%, placebo 0.4%), dizziness (Cymbalta 1.6%, placebo 0.4%), somnolence (Cymbalta 1.6%, placebo 0%) and fatigue (Cymbalta 1.1%, placebo 0%) were the common adverse events reported as reasons for discontinuation and considered to be drug-related (ie, discontinuation occurring in at least 1% of the Cymbalta-treated patients and at a rate of at least twice that of placebo). Adverse Events Occurring at an Incidence of 2% or More Among Cymbalta-Treated Patients in Placebo-Controlled Trials—Major Depressive Disorder—Treatment-emergent adverse events that occurred in 2% or more of patients treated with Cymbalta in the premarketing acute phase of MDD placebocontrolled trials (N=1139 Cymbalta; N=777 placebo) with an incidence greater than placebo were: Gastrointestinal Disorders—nausea, dry mouth, constipation, diarrhea, vomiting; Metabolism and Nutrition Disorders—appetite decreased (includes anorexia); Investigations—weight decreased; General Disorders and Administration Site Conditions—fatigue; Nervous System Disorders—dizziness, somnolence, tremors; Skin and Subcutaneous Tissue Disorders—sweating increased; Vascular Disorders—hot flushes; Eye Disorders—vision blurred; Psychiatric Disorders—insomnia (includes middle insomnia), anxiety, libido Cymbalta姞 (duloxetine hydrochloride) Delayed-release Capsules

decreased, orgasm abnormal (includes anorgasmia); Reproductive System and Breast Disorders—males only: erectile dysfunction, ejaculation delayed, ejaculatory dysfunction (includes ejaculation disorder and ejaculation failure). The following events were reported by at least 2% of patients treated with Cymbalta for MDD and had an incidence ≤ placebo: upper abdominal pain, palpitations, dyspepsia, back pain, arthralgia, headache, pharyngitis, cough, nasopharyngitis, and upper respiratory tract infection. The most commonly observed adverse events in Cymbalta-treated MDD patients (incidence ≥5% and at least twice the incidence in placebo patients) were: nausea; dry mouth; constipation; decreased appetite; fatigue; somnolence; and increased sweating. Diabetic Peripheral Neuropathic Pain—Treatment emergent adverse events that occurred in 2% or more of patients treated with Cymbalta in the premarketing acute phase of DPN placebo-controlled trials (N=225 Cymbalta 60 mg BID; N=228 Cymbalta 60 mg QD; N=115 Cymbalta 20 mg QD; N=223 placebo) with an incidence greater than placebo were: Gastrointestinal Disorders—nausea, constipation, diarrhea, dry mouth, vomiting, dyspepsia, loose stools; General Disorders and Administration Site Conditions—fatigue, asthenia, pyrexia; Infections and Infestations—nasopharyngitis; Metabolism and Nutrition Disorders— decreased appetite, anorexia; Musculoskeletal and Connective Tissue Disorders—muscle cramp, myalgia; Nervous System Disorders—somnolence, headache, dizziness, tremor; Psychiatric Disorders—insomnia; Renal and Urinary Disorders—pollakiuria; Reproductive System and Breast Disorders—erectile dysfunction; Respiratory, Thoracic and Mediastinal Disorders—cough, pharyngolaryngeal pain; Skin and Subcutaneous Tissue Disorders—hyperhidrosis. The following events were reported by at least 2% of patients treated with Cymbalta for DPN and had an incidence ≤ placebo: edema peripheral, influenza, upper respiratory tract infection, back pain, arthralgia, pain in extremity, and pruritus. The most commonly observed adverse events in Cymbalta-treated DPN patients (incidence ≥5% and at least twice the incidence in placebo patients) were: nausea; somnolence; dizziness; constipation; dry mouth; hyperhidrosis; decreased appetite; and asthenia. Adverse events seen in men and women were generally similar except for effects on sexual function (described below). Clinical studies of Cymbalta did not suggest a difference in adverse event rates in people over or under 65 years of age. There were too few non-Caucasian patients studied to determine if these patients responded differently from Caucasian patients. Effects on Male and Female Sexual Function—Although changes in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling are likely to underestimate their actual incidence. Sexual side effects spontaneously reported by at least 2% of either male or female patients taking Cymbalta in MDD placebo-controlled trials were: Males (N=378 Cymbalta; N=247 placebo): orgasm abnormal (includes anorgasmia), ejaculatory dysfunction (includes ejaculation disorder and ejaculation failure), libido decreased, erectile dysfunction, ejaculation delayed. Females (N=761 Cymbalta; N=530 placebo): orgasm abnormal, libido decreased. Because adverse sexual events are presumed to be voluntarily underreported, the Arizona Sexual Experience Scale (ASEX), a validated measure designed to identify sexual side effects, was used prospectively in 4 MDD placebo-controlled trials. In these trials, patients treated with Cymbalta experienced significantly more sexual dysfunction, as measured by the total score on the ASEX, than did patients treated with placebo. Gender analysis showed that this difference occurred only in males. Males treated with Cymbalta experienced more difficulty with ability to reach orgasm (ASEX Item 4) than males treated with placebo. Females did not experience more sexual dysfunction on Cymbalta than on placebo as measured by ASEX total score. These studies did not, however, include an active control drug with known effects on female sexual dysfunction, so that there is no evidence that its effects differ from other antidepressants. Physicians should routinely inquire about possible sexual side effects. See Table 4 in full PI for specific ASEX results. Urinary Hesitation—Cymbalta is in a class of drugs known to affect urethral resistance. If symptoms of urinary hesitation develop during treatment with Cymbalta, consideration should be given to the possibility that they might be drug-related. Laboratory Changes—Cymbalta treatment, for up to 9 weeks in MDD or 13 weeks in DPN placebo-controlled clinical trials, was associated with small mean increases from baseline to endpoint in ALT, AST, CPK, and alkaline phosphatase; infrequent, modest, transient, abnormal values were observed for these analytes in Cymbalta-treated patients when compared with placebo-treated patients (see PRECAUTIONS). Vital Sign Changes—Cymbalta treatment, for up to 9 weeks in MDD placebocontrolled clinical trials of 40 to 120 mg daily doses caused increases in blood pressure, averaging 2 mm Hg systolic and 0.5 mm Hg diastolic compared to placebo and an increase in the incidence of at least one measurement of systolic blood pressure over 140 mm Hg (see PRECAUTIONS). Cymbalta treatment, for up to 9 weeks in MDD placebo-controlled clinical trials and for up to 13 weeks in DPN placebo-controlled trials caused a small increase in heart rate compared to placebo of about 2 beats per minute. Weight Changes—In MDD placebo-controlled clinical trials, patients treated with Cymbalta for up to 9 weeks experienced a mean weight loss of approximately 0.5 kg, compared with a mean weight gain of approximately 0.2 kg in placebo-treated patients. In DPN placebo-controlled clinical trials, patients treated with Cymbalta for up to 13 weeks experienced a mean weight loss of approximately 1.1 kg, compared with a mean weight gain of approximately 0.2 kg in placebo-treated patients. Electrocardiogram Changes— Electrocardiograms were obtained from 321 Cymbalta-treated patients with MDD and 169 placebo-treated patients in clinical trials lasting up to 8 weeks. The rate-corrected QT (QTc) interval in Cymbalta-treated patients did not differ from that seen in placebo-treated patients. No clinically significant differences were observed for QT, PR, and QRS intervals between Cymbalta-treated and placebo-treated patients. Electrocardiograms were obtained from 528 Cymbalta-treated patients with DPN and 205 placebo-treated patients in clinical trials lasting up to 13 weeks. The rate-corrected QT (QTc) interval in Cymbalta-treated patients did not differ from that seen in placebo-treated patients. No clinically significant differences were observed for QT, PR, QRS, or QTc measurements between Cymbalta-treated and placebo-treated patients. Postmarketing Spontaneous Reports—Adverse events reported since market introduction that were temporally related to Cymbalta therapy include rash reported rarely and the following adverse events reported very rarely: alanine aminotransferase increased, alkaline phosphatase increased, anaphylactic reaction, angioneurotic edema, aspartate aminotransferase increased, bilirubin increased, glaucoma, hepatitis hyponatremia, jaundice, orthostatic hypotension (especially at the initiation of treatment), Stevens-Johnson Syndrome, syncope (especially at initiation of treatment), and urticaria. DRUG ABUSE AND DEPENDENCE: Controlled Substance Class—Duloxetine is not a controlled substance. Physical and Psychological Dependence—In animal studies, duloxetine did not demonstrate barbituratelike (depressant) abuse potential. In drug dependence studies, duloxetine did not demonstrate dependenceproducing potential in rats. While Cymbalta has not been systematically studied in humans for its potential for abuse, there was no indication of drug-seeking behavior in the clinical trials. However, it is not possible to predict on the basis of premarketing experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of Cymbalta (eg, development of tolerance, incrementation of dose, drug-seeking behavior). OVERDOSAGE: There is limited clinical experience with Cymbalta overdose in humans. In premarketing clinical trials, as of October 2003, no cases of fatal acute overdose of Cymbalta have been reported. Four non-fatal acute ingestions of Cymbalta (300 to 1400 mg), alone or in combination with other drugs, have been reported. Management of Overdose—There is no specific antidote to Cymbalta. In case of acute overdose, treatment should consist of those general measures employed in the management of overdose with any drug. Literature revised September 22, 2005 PV 3605 AMP

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Eli Lilly and Company Indianapolis, IN 46285, USA www.Cymbalta.com Copyright 䊚 2005, Eli Lilly and Company. All rights reserved. Cymbalta姞 (duloxetine hydrochloride) Delayed-release Capsules

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gastrointestinal pH may lead to an earlier release of duloxetine. However, co-administration of Cymbalta with aluminum- and magnesium-containing antacids (51 mEq) or Cymbalta with famotidine, had no significant effect on the rate or extent of duloxetine absorption after administration of a 40-mg oral dose. It is unknown whether the concomitant administration of proton pump inhibitors affects duloxetine absorption. Monoamine Oxidase Inhibitors—See CONTRAINDICATIONS and WARNINGS. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis—Duloxetine was administered in the diet to mice and rats for 2 years. In female mice receiving duloxetine at 140 mg/kg/day (11 times the maximum recommended human dose [MRHD, 60 mg/day] and 6 times the human dose of 120 mg/day on a mg/m2 basis), there was an increased incidence of hepatocellular adenomas and carcinomas. The no-effect dose was 50 mg/kg/day (4 times the MRHD and 2 times the human dose of 120 mg/day on a mg/m2 basis). Tumor incidence was not increased in male mice receiving duloxetine at doses up to 100 mg/kg/day (8 times the MRHD and 4 times the human dose of 120 mg/day on a mg/m2 basis). In rats, dietary doses of duloxetine up to 27 mg/kg/day in females (4 times the MRHD and 2 times the human dose of 120 mg/day on a mg/m2 basis) and up to 36 mg/kg/day in males (6 times the MRHD and 3 times the human dose of 120 mg/day on a mg/m2 basis) did not increase the incidence of tumors. Mutagenesis— Duloxetine was not mutagenic in the in vitro bacterial reverse mutation assay (Ames test) and was not clastogenic in an in vivo chromosomal aberration test in mouse bone marrow cells. Additionally, duloxetine was not genotoxic in an in vitro mammalian forward gene mutation assay in mouse lymphoma cells or in an in vitro unscheduled DNA synthesis (UDS) assay in primary rat hepatocytes, and did not induce sister chromatid exchange in Chinese hamster bone marrow in vivo. Impairment of Fertility—Duloxetine administered orally to either male or female rats prior to and throughout mating at daily doses up to 45 mg/kg/day (7 times the maximum recommended human dose of 60 mg/day and 4 times the human dose of 120 mg/day on a mg/m2 basis) did not alter mating or fertility. Pregnancy—Pregnancy Category C—In animal reproduction studies, duloxetine has been shown to have adverse effects on embryo/fetal and postnatal development. When duloxetine was administered orally to pregnant rats and rabbits during the period of organogenesis, there was no evidence of teratogenicity at doses up to 45 mg/kg/day (7 times the maximum recommended human dose [MRHD, 60 mg/day] and 4 times the human dose of 120 mg/day on a mg/m2 basis, in rats; 15 times the MRHD and 7 times the human dose of 120 mg/day on a mg/m2 basis in rabbits). However, fetal weights were decreased at this dose, with a no-effect dose of 10 mg/kg/day (2 times the MRHD and =1 times the human dose of 120 mg/day on a mg/m2 basis in rats; 3 times the MRHD and 2 times the human dose of 120 mg/day on a mg/m2 basis in rabbits). When duloxetine was administered orally to pregnant rats throughout gestation and lactation, the survival of pups to 1 day postpartum and pup body weights at birth and during the lactation period were decreased at a dose of 30 mg/kg/day (5 times the MRHD and 2 times the human dose of 120 mg/day on a mg/m2 basis) ; the no-effect dose was 10 mg/kg/day. Furthermore, behaviors consistent with increased reactivity, such as increased startle response to noise and decreased habituation of locomotor activity, were observed in pups following maternal exposure to 30 mg/kg/day. Post-weaning growth and reproductive performance of the progeny were not affected adversely by maternal duloxetine treatment. There are no adequate and well-controlled studies in pregnant women; therefore, duloxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects—Neonates exposed to SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see WARNINGS, Monoamine Oxidase Inhibitors). When treating a pregnant woman with Cymbalta during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. Labor and Delivery—The effect of duloxetine on labor and delivery in humans is unknown. Duloxetine should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers—Duloxetine and/or its metabolites are excreted into the milk of lactating rats. It is unknown whether or not duloxetine and/or its metabolites are excreted into human milk, but nursing while on Cymbalta is not recommended. Pediatric Use—Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS, Clinical Worsening and Suicide Risk). Anyone considering the use of Cymbalta in a child or adolescent must balance the potential risks with the clinical need. Geriatric Use—Of the 2418 patients in clinical studies of Cymbalta for MDD, 5.9% (143) were 65 years of age or over. Of the 1074 patients in the DPN studies, 33% (357) were 65 years of age or over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

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*Randomized Multi-Center Study with patients on insulin therapy. Test Group used OneTouch UltraSmart /Control Group used conventional meter and logbook. Both groups received monthly counseling from HCP. Both groups saw decrease in A1c; however, Test Group saw decrease .2% greater than Control Group. It is uncertain if this change will result in improved health outcomes. † As compared to a meter and paper logbook. ‡ Allows for a less painful stick when used with OneTouch UltraSoft Adjustable Blood Sampler and OneTouch UltraSoft Lancets. 1. LifeScan data on file: Self-monitoring of blood glucose study #1: The Ability of People with Diabetes to Use OneTouch UltraSmart to Improve Glycemic Control Through Behavioral and Therapeutic Changes (RTP 1039775, November 2004). © 2006 LifeScan, Inc. Milpitas, CA 95035 1/06 AW 086-048B ®

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IMPORTANT SAFETY INFORMATION Lantus® is indicated for once-daily, at the same time each day, subcutaneous administration for the treatment of adult and pediatric patients (6 years and older) with type 1 diabetes mellitus or adult patients with type 2 diabetes mellitus who require basal (long-acting) insulin for the control of hyperglycemia. LANTUS® MUST NOT BE DILUTED OR MIXED WITH ANY OTHER INSULIN OR SOLUTION. If mixed or diluted, the solution may become cloudy, and the onset of action/time to peak effect may be altered in an unpredictable manner. Lantus® is contraindicated in patients hypersensitive to insulin glargine or the excipients. Hypoglycemia is the most common adverse effect of insulin, including Lantus®. As with all insulins, the timing of

hypoglycemia may differ among various insulin formulations. Glucose monitoring is recommended for all patients with diabetes. Any change of insulin type and/or regimen should be made cautiously and only under medical supervision. Concomitant oral antidiabetes treatment may need to be adjusted. Other adverse events commonly associated with Lantus® include the following: lipodystrophy, skin reactions (such as injection-site reaction, pruritus, rash), and allergic reactions. OptiClik® is a reusable insulin delivery device (insulin Pen) for use with a 3-mL Lantus® cartridge (U-100). *Based on PNRx. IMS Health. National Prescription Audit Plus™. September 2003 - August 2005.

Visit us at www.lantus.com Please see brief summary of prescribing information on adjacent page. USA.GLA.05.10.25 © 2005 Aventis Pharmaceuticals Inc.

Aventis Pharmaceuticals, a member of the sanofi-aventis Group

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The only once-daily, 24-hour basal insulin analog with no pronounced peak is available with

Brief Summary of Prescribing Information August 2004

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LANTUS® (insulin glargine [rDNA origin] injection) LANTUS® must NOT be diluted or mixed with any other insulin or solution. INDICATIONS AND USAGE LANTUS is indicated for once-daily subcutaneous administration for the treatment of adult and pediatric patients with type 1 diabetes mellitus or adult patients with type 2 diabetes mellitus who require basal (long-acting) insulin for the control of hyperglycemia. CONTRAINDICATIONS LANTUS is contraindicated in patients hypersensitive to insulin glargine or the excipients. WARNINGS Hypoglycemia is the most common adverse effect of insulin, including LANTUS. As with all insulins, the timing of hypoglycemia may differ among various insulin formulations. Glucose monitoring is recommended for all patients with diabetes. Any change of insulin should be made cautiously and only under medical supervision. Changes in insulin strength, timing of dosing, manufacturer, type (e.g., regular, NPH, or insulin analogs), species (animal, human), or method of manufacture (recombinant DNA versus animal-source insulin) may result in the need for a change in dosage. Concomitant oral antidiabetes treatment may need to be adjusted.

ADVERSE REACTIONS The adverse events commonly associated with LANTUS include the following: Body as a whole: allergic reactions (see PRECAUTIONS). Skin and appendages: injection site reaction, lipodystrophy, pruritus, rash (see PRECAUTIONS). Other: hypoglycemia (see WARNINGS and PRECAUTIONS) In clinical studies in adult patients, there was a higher incidence of treatment-emergent injection site pain in LANTUStreated patients (2.7%) compared to NPH insulin-treated patients (0.7%). The reports of pain at the injection site were usually mild and did not result in discontinuation of therapy. Other treatment-emergent injection site reactions occurred at similar incidences with both insulin glargine and NPH human insulin. Retinopathy was evaluated in the clinical studies by means of retinal adverse events reported and fundus photography. The numbers of retinal adverse events reported for LANTUS and NPH treatment groups were similar for patients with type 1 and type 2 diabetes. Progression of retinopathy was investigated by fundus photography using a grading protocol derived from the Early Treatment Diabetic Retinopathy Study (ETDRS). In one clinical study involving patients with type 2 diabetes, a difference in the number of subjects with ≥3-step progression in ETDRS scale over a 6-month period was noted by fundus photography (7.5% in LANTUS group versus 2.7% in NPH treated group). The overall relevance of this isolated finding cannot be determined due to the small number of patients involved, the short follow-up period, and the fact that this finding was not observed in other clinical studies. OVERDOSAGE An excess of insulin relative to food intake, energy expenditure, or both may lead to severe and sometimes long-term and life-threatening hypoglycemia. Mild episodes of hypoglycemia can usually be treated with oral carbohydrates. Adjustments in drug dosage, meal patterns, or exercise may be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. After apparent clinical recovery from hypoglycemia, continued observation and additional carbohydrate intake may be necessary to avoid reoccurrence of hypoglycemia. DOSAGE AND ADMINISTRATION LANTUS is a recombinant human insulin analog. Its potency is approximately the same as human insulin. It exhibits a relatively constant glucose-lowering profile over 24 hours that permits once-daily dosing. LANTUS may be administered at any time during the day. LANTUS should be administered subcutaneously once a day at the same time every day. For patients adjusting timing of dosing with LANTUS, see WARNINGS and PRECAUTIONS, Hypoglycemia. LANTUS is not intended for intravenous administration (see PRECAUTIONS). Intravenous administration of the usual subcutaneous dose could result in severe hypoglycemia. The desired blood glucose levels as well as the doses and timing of antidiabetes medications must be determined individually. Blood glucose monitoring is recommended for all patients with diabetes. The prolonged duration of activity of LANTUS is dependent on injection into subcutaneous space. As with all insulins, injection sites within an injection area (abdomen, thigh, or deltoid) must be rotated from one injection to the next. In clinical studies, there was no relevant difference in insulin glargine absorption after abdominal, deltoid, or thigh subcutaneous administration. As for all insulins, the rate of absorption, and consequently the onset and duration of action, may be affected by exercise and other variables. LANTUS is not the insulin of choice for the treatment of diabetes ketoacidosis. Intravenous short-acting insulin is the preferred treatment. Pediatric Use: LANTUS can be safely administered to pediatric patients ≥6 years of age. Administration to pediatric patients <6 years has not been studied. Based on the results of a study in pediatric patients, the dose recommendation for changeover to LANTUS is the same as described for adults in DOSAGE AND ADMINISTRATION, Changeover to LANTUS. Initiation of LANTUS Therapy: In a clinical study with insulin naïve patients with type 2 diabetes already treated with oral antidiabetes drugs, LANTUS was started at an average dose of 10 IU once daily, and subsequently adjusted according to the patient’s need to a total daily dose ranging from 2 to 100 IU. Changeover to LANTUS: If changing from a treatment regimen with an intermediate- or long-acting insulin to a regimen with LANTUS, the amount and timing of short-acting insulin or fast-acting insulin analog or the dose of any oral antidiabetes drug may need to be adjusted. In clinical studies, when patients were transferred from once-daily NPH human insulin or ultralente human insulin to once-daily LANTUS, the initial dose was usually not changed. However, when patients were transferred from twice-daily NPH human insulin to LANTUS once daily, to reduce the risk of hypoglycemia, the initial dose (IU) was usually reduced by approximately 20% (compared to total daily IU of NPH human insulin) and then adjusted based on patient response (see PRECAUTIONS, Hypoglycemia). A program of close metabolic monitoring under medical supervision is recommended during transfer and in the initial weeks thereafter. The amount and timing of short-acting insulin or fast-acting insulin analog may need to be adjusted. This is particularly true for patients with acquired antibodies to human insulin needing high-insulin doses and occurs with all insulin analogs. Dose adjustment of LANTUS and other insulins or oral antidiabetes drugs may be required; for example, if the patient’s timing of dosing, weight or lifestyle changes, or other circumstances arise that increase susceptibility to hypoglycemia or hyperglycemia (see PRECAUTIONS, Hypoglycemia). The dose may also have to be adjusted during intercurrent illness (see PRECAUTIONS, Intercurrent Conditions). Brief Summary of Prescribing Information August 2004 Manufactured by: Aventis Pharma Deutschland GmbH D-65926 Frankfurt am Main Frankfurt, Germany Manufactured for: Aventis Pharmaceuticals Inc. Kansas City, MO 64137 USA US Patents 5,656,722, 5,370,629, and 5,509,905 Made in Germany www.lantus.com ©2004 Aventis Pharmaceuticals Inc. LAN-AUG04-B-Aa

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PRECAUTIONS General: LANTUS is not intended for intravenous administration. The prolonged duration of activity of insulin glargine is dependent on injection into subcutaneous tissue. Intravenous administration of the usual subcutaneous dose could result in severe hypoglycemia. LANTUS must NOT be diluted or mixed with any other insulin or solution. If LANTUS is diluted or mixed, the solution may become cloudy, and the pharmacokinetic/pharmacodynamic profile (e.g., onset of action, time to peak effect) of LANTUS and/or the mixed insulin may be altered in an unpredictable manner. When LANTUS and regular human insulin were mixed immediately before injection in dogs, a delayed onset of action and time to maximum effect for regular human insulin was observed. The total bioavailability of the mixture was also slightly decreased compared to separate injections of LANTUS and regular human insulin. The relevance of these observations in dogs to humans is not known. As with all insulin preparations, the time course of LANTUS action may vary in different individuals or at different times in the same individual and the rate of absorption is dependent on blood supply, temperature, and physical activity. Insulin may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy. Hypoglycemia: As with all insulin preparations, hypoglycemic reactions may be associated with the administration of LANTUS. Hypoglycemia is the most common adverse effect of insulins. Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as long duration of diabetes, diabetes nerve disease, use of medications such as beta-blockers, or intensified diabetes control (see PRECAUTIONS, Drug Interactions). Such situations may result in severe hypoglycemia (and, possibly, loss of consciousness) prior to patients’ awareness of hypoglycemia. The time of occurrence of hypoglycemia depends on the action profile of the insulins used and may, therefore, change when the treatment regimen or timing of dosing is changed. Patients being switched from twice daily NPH insulin to once-daily LANTUS should have their initial LANTUS dose reduced by 20% from the previous total daily NPH dose to reduce the risk of hypoglycemia (see DOSAGE AND ADMINISTRATION, Changeover to LANTUS). The prolonged effect of subcutaneous LANTUS may delay recovery from hypoglycemia. In a clinical study, symptoms of hypoglycemia or counterregulatory hormone responses were similar after intravenous insulin glargine and regular human insulin both in healthy subjects and patients with type 1 diabetes. Renal Impairment: Although studies have not been performed in patients with diabetes and renal impairment, LANTUS requirements may be diminished because of reduced insulin metabolism, similar to observations found with other insulins (see CLINICAL PHARMACOLOGY, Special Populations). Hepatic Impairment: Although studies have not been performed in patients with diabetes and hepatic impairment, LANTUS requirements may be diminished due to reduced capacity for gluconeogenesis and reduced insulin metabolism, similar to observations found with other insulins (see CLINICAL PHARMACOLOGY, Special Populations). Injection Site and Allergic Reactions: As with any insulin therapy, lipodystrophy may occur at the injection site and delay insulin absorption. Other injection site reactions with insulin therapy include redness, pain, itching, hives, swelling, and inflammation. Continuous rotation of the injection site within a given area may help to reduce or prevent these reactions. Most minor reactions to insulins usually resolve in a few days to a few weeks. Reports of injection site pain were more frequent with LANTUS than NPH human insulin (2.7% insulin glargine versus 0.7% NPH). The reports of pain at the injection site were usually mild and did not result in discontinuation of therapy. Immediate-type allergic reactions are rare. Such reactions to insulin (including insulin glargine) or the excipients may, for example, be associated with generalized skin reactions, angioedema, bronchospasm, hypotension, or shock and may be life threatening. Intercurrent Conditions: Insulin requirements may be altered during intercurrent conditions such as illness, emotional disturbances, or stress. Information for Patients: LANTUS must only be used if the solution is clear and colorless with no particles visible (see DOSAGE AND ADMINISTRATION, Preparation and Handling). Patients must be advised that LANTUS must NOT be diluted or mixed with any other insulin or solution (see PRECAUTIONS, General). Patients should be instructed on self-management procedures including glucose monitoring, proper injection technique, and hypoglycemia and hyperglycemia management. Patients must be instructed on handling of special situations such as intercurrent conditions (illness, stress, or emotional disturbances), an inadequate or skipped insulin dose, inadvertent administration of an increased insulin dose, inadequate food intake, or skipped meals. Refer patients to the LANTUS “Patient Information” circular for additional information. As with all patients who have diabetes, the ability to concentrate and/or react may be impaired as a result of hypoglycemia or hyperglycemia. Patients with diabetes should be advised to inform their health care professional if they are pregnant or are contemplating pregnancy. Drug Interactions: A number of substances affect glucose metabolism and may require insulin dose adjustment and particularly close monitoring. The following are examples of substances that may increase the blood-glucose-lowering effect and susceptibility to hypoglycemia: oral antidiabetes products, ACE inhibitors, disopyramide, fibrates, fluoxetine, MAO inhibitors, propoxyphene, salicylates, somatostatin analog (e.g., octreotide), sulfonamide antibiotics. The following are examples of substances that may reduce the blood-glucose-lowering effect of insulin: corticosteroids, danazol, diuretics, sympathomimetic agents (e.g., epinephrine, albuterol, terbutaline), isoniazid, phenothiazine derivatives, somatropin, thyroid hormones, estrogens, progestogens (e.g., in oral contraceptives). Beta-blockers, clonidine, lithium salts, and alcohol may either potentiate or weaken the blood-glucose-lowering effect of insulin. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. In addition, under the influence of sympatholytic medicinal products such as beta-blockers, clonidine, guanethidine, and reserpine, the signs of hypoglycemia may be reduced or absent. Carcinogenesis, Mutagenesis, Impairment of Fertility: In mice and rats, standard two-year carcinogenicity studies with insulin glargine were performed at doses up to 0.455 mg/kg, which is for the rat approximately 10 times and for the mouse approximately 5 times the recommended human subcutaneous starting dose of 10 IU (0.008 mg/kg/day), based on mg/m2. The findings in female mice were not conclusive due to excessive mortality in all dose groups during the study. Histiocytomas were found at injection sites in male rats (statistically significant) and male mice (not statistically significant) in acid vehicle containing groups. These tumors were not found in female animals, in saline control, or insulin comparator groups using a different vehicle. The relevance of these findings to humans is unknown. Insulin glargine was not mutagenic in tests for detection of gene mutations in bacteria and mammalian cells (Ames- and HGPRT-test) and in tests for detection of chromosomal aberrations (cytogenetics in vitro in V79 cells and in vivo in Chinese hamsters). In a combined fertility and prenatal and postnatal study in male and female rats at subcutaneous doses up to 0.36 mg/kg/day, which is approximately 7 times the recommended human subcutaneous starting dose of 10 IU (0.008 mg/kg/day), based on mg/m2, maternal toxicity due to dose-dependent hypoglycemia, including some deaths,

was observed. Consequently, a reduction of the rearing rate occurred in the high-dose group only. Similar effects were observed with NPH human insulin. Pregnancy: Teratogenic Effects: Pregnancy Category C. Subcutaneous reproduction and teratology studies have been performed with insulin glargine and regular human insulin in rats and Himalayan rabbits. The drug was given to female rats before mating, during mating, and throughout pregnancy at doses up to 0.36 mg/kg/day, which is approximately 7 times the recommended human subcutaneous starting dose of 10 IU (0.008 mg/kg/day), based on mg/m2. In rabbits, doses of 0.072 mg/kg/day, which is approximately 2 times the recommended human subcutaneous starting dose of 10 IU (0.008 mg/kg/day), based on mg/m2, were administered during organogenesis. The effects of insulin glargine did not generally differ from those observed with regular human insulin in rats or rabbits. However, in rabbits, five fetuses from two litters of the high-dose group exhibited dilation of the cerebral ventricles. Fertility and early embryonic development appeared normal. There are no well-controlled clinical studies of the use of insulin glargine in pregnant women. It is essential for patients with diabetes or a history of gestational diabetes to maintain good metabolic control before conception and throughout pregnancy. Insulin requirements may decrease during the first trimester, generally increase during the second and third trimesters, and rapidly decline after delivery. Careful monitoring of glucose control is essential in such patients. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers: It is unknown whether insulin glargine is excreted in significant amounts in human milk. Many drugs, including human insulin, are excreted in human milk. For this reason, caution should be exercised when LANTUS is administered to a nursing woman. Lactating women may require adjustments in insulin dose and diet. Pediatric Use: Safety and effectiveness of LANTUS have been established in the age group 6 to 15 years with type 1 diabetes. Geriatric Use: In controlled clinical studies comparing insulin glargine to NPH human insulin, 593 of 3890 patients with type 1 and type 2 diabetes were 65 years and older. The only difference in safety or effectiveness in this subpopulation compared to the entire study population was an expected higher incidence of cardiovascular events in both insulin glargine and NPH human insulin-treated patients. In elderly patients with diabetes, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemic reactions. Hypoglycemia may be difficult to recognize in the elderly (see PRECAUTIONS, Hypoglycemia).

displacement. In vitro and in vivo studies showed that LYRICA is unlikely to be involved in significant pharmacokinetic drug interactions. Specifically, there are no pharmacokinetic interactions between pregabalin and the following antiepileptic drugs: carbamazepine, valproic acid, lamotrigine, phenytoin, phenobarbital, and topiramate. Important pharmacokinetic interactions would also not be expected to occur between pregabalin and other commonly used antiepileptic drugs. Pharmacodynamics Multiple oral doses of pregabalin were co-administered with oxycodone, lorazepam, or ethanol. Although no pharmacokinetic interactions were seen, additive effects on cognitive and gross motor functioning were seen when pregabalin was co-administered with those drugs. No clinically important effects on respiration were seen (see PRECAUTIONS, Dizziness and Somnolence and Information for Patients). Animal Toxicology: Dermatopathy Skin lesions ranging from erythema to necrosis were seen in repeated-dose toxicology studies in both rats and monkeys. The etiology of these skin lesions is unknown. At the maximum recommended human dose (MRD) of 600 mg/day, there is a 2-fold safety margin for the dermatological lesions. The more severe dermatopathies involving necrosis were associated with pregabalin exposures (as expressed by plasma AUCs) of approximately 3 to 8 times those achieved in humans given the MRD. No increase in incidence of skin lesions was observed in clinical studies. Ocular Lesions Ocular lesions (characterized by retinal atrophy [including loss of photoreceptor cells] and/or corneal inflammation/mineralization) were observed in two lifetime carcinogenicity studies in Wistar rats. These findings were observed at plasma pregabalin exposures (AUC) ≥2 times those achieved in humans given the maximum recommended dose of 600 mg/day. A no-effect dose for ocular lesions was not established. Similar lesions were not observed in lifetime carcinogenicity studies in two strains of mice or in monkeys treated for 1 year. Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis A dose-dependent increase in the incidence of malignant vascular tumors (hemangiosarcomas) was observed in two strains of mice (B6C3F1 and CD-1) given pregabalin (200, 1000, or 5000 mg/kg) in the diet for two years. Plasma pregabalin exposure (AUC) in mice receiving the lowest dose that increased hemangiosarcomas was approximately equal to the human exposure at the maximum recommended dose (MRD) of 600 mg/day. A no-effect dose for induction of hemangiosarcomas in mice was not established. No evidence of carcinogenicity was seen in two studies in Wistar rats following dietary administration of pregabalin for two years at doses (50, 150, or 450 mg/kg in males and 100, 300, or 900 mg/kg in females) that were associated with plasma exposures in males and females up to approximately 14 and 24 times, respectively, human exposure at the MRD. Mutagenesis Pregabalin was not mutagenic in bacteria or in mammalian cells in vitro, was not clastogenic in mammalian systems in vitro and in vivo, and did not induce unscheduled DNA synthesis in mouse or rat hepatocytes. Impairment of Fertility In fertility studies in which male rats were orally administered pregabalin (50 to 2500 mg/kg) prior to and during mating with untreated females, a number of adverse reproductive and developmental effects were observed. These included decreased sperm counts and sperm motility, increased sperm abnormalities, reduced fertility, increased preimplantation embryo loss, decreased litter size, decreased fetal body weights, and an increased incidence of fetal abnormalities. Effects on sperm and fertility parameters were reversible in studies of this duration (3-4 months). The no-effect dose for male reproductive toxicity in these studies (100 mg/kg) was associated with a plasma pregabalin exposure (AUC) approximately 3 times human exposure at the maximum recommended dose (MRD) of 600 mg/day. In addition, adverse effects on reproductive organ (testes, epididymides) histopathology were observed in male rats exposed to pregabalin (500 to 1250 mg/kg) in general toxicology studies of four weeks or greater duration. The no-effect dose for male reproductive organ histopathology in rats (250 mg/kg) was associated with a plasma exposure approximately 8 times human exposure at the MRD. In a fertility study in which female rats were given pregabalin (500, 1250, or 2500 mg/kg) orally prior to and during mating and early gestation, disrupted estrous cyclicity and an increased number of days to mating were seen at all doses, and embryolethality occurred at the highest dose. The low dose in this study produced a plasma exposure approximately 9 times that in humans receiving the MRD. A no-effect dose for female reproductive toxicity in rats was not established. Human Data In a doubleblind, placebo-controlled clinical trial to assess the effect of pregabalin on sperm motility, 30 healthy male subjects were exposed to pregabalin at a dose of 600 mg/day. After 3 months of treatment (one complete sperm cycle), the difference between placebo- and pregabalin-treated subjects in mean percent sperm with normal motility was <4% and neither group had a mean change from baseline of more than 2%. Effects on other male reproductive parameters in humans have not been adequately studied. Pregnancy: Pregnancy Category C Increased incidences of fetal structural abnormalities and other manifestations of developmental toxicity, including lethality, growth retardation, and nervous and reproductive system functional impairment, were observed in the offspring of rats and rabbits given pregabalin during pregnancy, at doses that produced plasma pregabalin exposures (AUC) ≥5 times human exposure at the maximum recommended dose (MRD) of 600 mg/day. When pregnant rats were given pregabalin (500, 1250, or 2500 mg/kg) orally throughout the period of organogenesis, incidences of specific skull alterations attributed to abnormally advanced ossification (premature fusion of the jugal and nasal sutures) were increased at ≥1250 mg/kg, and incidences of skeletal variations and retarded ossification were increased at all doses. Fetal body weights were decreased at the highest dose. The low dose in this study was associated with a plasma exposure (AUC) approximately 17 times human exposure at the MRD of 600 mg/day. A noeffect dose for rat embryo-fetal developmental toxicity was not established. When pregnant rabbits were given pregabalin (250, 500, or 1250 mg/kg) orally throughout the period of organogenesis, decreased fetal body weight and increased incidences of skeletal malformations, visceral variations, and retarded ossification were observed at the highest dose. The no-effect dose for developmental toxicity in rabbits (500 mg/kg) was associated with a plasma exposure approximately 16 times human exposure at the MRD. In a study in which female rats were dosed with pregabalin (50, 100, 250, 1250, or 2500 mg/kg) throughout gestation and lactation, offspring growth was reduced at ≥100 mg/kg and offspring survival was decreased at ≥250 mg/kg. The effect on offspring survival was pronounced at doses ≥1250 mg/kg, with 100% mortality in high-dose litters. When offspring were tested as adults, neurobehavioral abnormalities (decreased auditory startle responding) were observed at ≥250 mg/kg and reproductive impairment (decreased fertility and litter size) was seen at 1250 mg/kg. The no-effect dose for pre- and postnatal developmental toxicity in rats (50 mg/kg) produced a plasma exposure approximately 2 times human exposure at the MRD. There are no adequate and well-controlled studies in pregnant women. LYRICA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Labor and Delivery: The effects of pregabalin on labor and delivery in pregnant women are unknown. In the prenatal-postnatal study in rats, pregabalin prolonged gestation and induced dystocia at exposures ≥50 times the mean human exposure (AUC (0-24) of 123 µg•hr/mL) at the maximum recommended clinical dose of 600 mg/day. Use in Nursing Mothers: It is not known if pregabalin is excreted in human milk; it is, however, present in the milk of rats. Because many drugs are excreted in human milk, and because of the potential for tumorigenicity shown for pregabalin in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and efficacy of pregabalin in pediatric patients have not been established. In studies in which pregabalin (50 to 500 mg/kg) was orally administered to young rats from early in the postnatal period (Postnatal Day 7) through sexual maturity, neurobehavioral abnormalities (deficits in learning and memory, altered locomotor activity, decreased auditory startle responding and habituation) and reproductive impairment (delayed sexual maturation and decreased fertility in males and females) were observed at doses ≥50 mg/kg. The neurobehavioral changes persisted in animals tested after cessation of dosing and, thus, were considered to represent long-term effects. The low effect dose for developmental neurotoxicity and reproductive impairment in juvenile rats (50 mg/kg) was associated with a plasma pregabalin exposure (AUC) approximately equal to human exposure at the maximum recommended dose of 600 mg/day. A no-effect dose was not established. Geriatric Use In controlled clinical studies of LYRICA in neuropathic pain associated with diabetic peripheral neuropathy, 306 patients were 65 to 74 years of age, and 88 patients were 75 years of age or older. In controlled clinical studies of LYRICA in neuropathic pain associated with postherpetic neuralgia, 282 patients were 65 to 74 years of age, and 379 patients were 75 years of age or older. In controlled clinical studies of LYRICA in epilepsy, there were only 10 patients 65 to 74 years of age, and 2 patients who were 75 years of age or older. No overall differences in safety and efficacy were observed between these patients and younger patients. Even though the incidence of adverse events did not increase with age, greater sensitivity of some older individuals cannot be ruled out. LYRICA is known to be substantially excreted by the kidney, and the risk of toxic reactions to LYRICA may be greater in patients with impaired renal function. Because LYRICA is eliminated primarily by renal excretion, the dose should be adjusted for elderly patients with renal impairment. ADVERSE REACTIONS In all controlled and uncontrolled trials across various patient populations during the premarketing development of pregabalin, more than 10,000 patients have received pregabalin. Approximately 5000 patients were treated for 6 months or more, over 3100 patients were treated for 1 year or longer, and over 1400 patients were treated for at least 2 years. Adverse Events Most Commonly Leading to Discontinuation in All Controlled Clinical Studies In controlled trials of all populations combined, 14% of patients treated with pregabalin and 7% of patients treated with placebo discontinued prematurely due to adverse events. In the pregabalin treatment group, the adverse events most frequently leading to discontinuation were dizziness (4%) and somnolence (3%). In the placebo group, 1% of patients withdrew due to dizziness and <1% withdrew due to somnolence. Other adverse events that led to discontinuation from controlled trials more frequently in the pregabalin group compared to the placebo group were ataxia, confusion, asthenia, thinking abnormal, blurred vision, incoordination, and peripheral edema (1% each). Most Common Adverse Events in All Controlled Clinical Studies In controlled trials of all patient populations combined, dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, and “thinking abnormal” (primarily difficulty with concentration/attention) were more commonly reported by subjects treated with pregabalin than by subjects treated with placebo (≥5% and twice the rate of that seen in placebo). Controlled Studies with Neuropathic Pain Associated with Diabetic Peripheral Neuropathy: Adverse Events Leading to Discontinuation In clinical trials in patients with neuropathic pain associated with diabetic peripheral neuropathy, 9% of patients treated with pregabalin and 4% of patients treated with placebo discontinued prematurely due to adverse events. In the pregabalin treatment group, the most common reasons for discontinuation due to adverse events were dizziness (3%) and somnolence (2%). In comparison, <1% of placebo patients withdrew due to dizziness and somnolence. Other reasons for discontinuation from the trials, occurring with greater frequency in the pregabalin group than in the placebo group, were asthenia, confusion, and peripheral edema. Each of these events led to withdrawal in approximately 1% of patients. Most Common Adverse Events Table 1 lists all adverse events, regardless of causality, occurring in ≥1% of patients with neuropathic pain associated with diabetic neuropathy in the combined pregabalin group for which the incidence was greater in this combined pregabalin group than in the placebo group. A majority of pregabalin-treated patients in clinical studies had adverse events with a maximum intensity of “mild” or “moderate.”

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LYRICA® (PREGABALIN) CAPSULES BRIEF SUMMARY: For full prescribing information, see package insert. INDICATIONS AND USAGE LYRICA is indicated for management of • Neuropathic pain associated with diabetic peripheral neuropathy • Postherpetic neuralgia LYRICA is indicated as adjunctive therapy for adult patients with partial onset seizures. CONTRAINDICATIONS LYRICA is contraindicated in patients with known hypersensitivity to pregabalin or any of its components. WARNINGS Withdrawal of Antiepileptic Drugs (AEDs) As with all AEDs, pregabalin should be withdrawn gradually to minimize the potential of increased seizure frequency in patients with seizure disorders. If pregabalin is discontinued this should be done gradually over a minimum of 1 week. Tumorigenic Potential In standard preclinical in vivo lifetime carcinogenicity studies of pregabalin, an unexpectedly high incidence of hemangiosarcoma was identified in two different strains of mice (see PRECAUTIONS: Carcinogenesis, Mutagenesis, Impairment of Fertility). The clinical significance of this finding is unknown. Clinical experience during pregabalin’s premarketing development provides no direct means to assess its potential for inducing tumors in humans. In clinical studies across various patient populations, comprising 6396 patientyears of exposure in patients >12 years of age, new or worsening-preexisting tumors were reported in 57 patients. Without knowledge of the background incidence and recurrence in similar populations not treated with LYRICA, it is impossible to know whether the incidence seen in these cohorts is or is not affected by treatment. PRECAUTIONS Dizziness and Somnolence Pregabalin causes dizziness and somnolence. Patients should be informed that pregabalinrelated dizziness and somnolence may impair their ability to perform tasks such as driving or operating machinery (see PRECAUTIONS-Information for Patients). In the pregabalin controlled trials, dizziness was experienced by 29% of pregabalin-treated patients compared to 9% of placebo-treated patients; somnolence was experienced by 22% of pregabalin-treated patients compared to 8% of placebo-treated patients. Dizziness and somnolence generally began shortly after the initiation of pregabalin therapy and occurred more frequently at higher doses. Dizziness and somnolence were the adverse events most frequently leading to withdrawal (4% each) from controlled studies. In pregabalin-treated patients reporting these adverse events in short-term, controlled studies, dizziness persisted until the last dose in 31% and somnolence persisted until the last dose in 46% of patients. Ophthalmological Effects In controlled studies, a higher proportion of patients treated with pregabalin reported blurred vision (6%) than did patients treated with placebo (2%), which resolved in a majority of cases with continued dosing. Less than 1% of patients discontinued pregabalin treatment due to vision-related events (primarily blurred vision). Prospectively planned ophthalmologic testing, including visual acuity testing, formal visual field testing and dilated funduscopic examination, was performed in over 3600 patients. In these patients, visual acuity was reduced in 7% of patients treated with pregabalin, and 5% of placebo-treated patients. Visual field changes were detected in 13% of pregabalin-treated, and 12% of placebo-treated patients. Funduscopic changes were observed in 2% of pregabalin-treated, and 2% of placebo-treated patients. Although the clinical significance of the ophthalmologic findings is unknown, patients should be informed that if changes in vision occur, they should notify their physician. If visual disturbance persists, further assessment should be considered. More frequent assessment should be considered for patients who are already routinely monitored for ocular conditions (See PRECAUTIONS-Information for Patients). Abrupt or Rapid Discontinuation Following abrupt or rapid discontinuation of pregabalin, some patients reported symptoms including insomnia, nausea, headache, and diarrhea. Pregabalin should be tapered gradually over a minimum of 1 week rather than discontinued abruptly. Weight Gain Pregabalin treatment caused weight gain. In pregabalin controlled clinical trials of up to 13 weeks, a gain of 7% or more over baseline weight was observed in 8% of pregabalin-treated patients and 2% of placebo-treated patients. Few patients treated with pregabalin (0.2%) withdrew from controlled trials due to weight gain. Pregabalin associated weight gain was related to dose and duration of exposure, but did not appear to be associated with baseline BMI, gender, or age. Weight gain was not limited to patients with edema (see PRECAUTIONS-Peripheral Edema). Although weight gain was not associated with clinically important changes in blood pressure in short-term controlled studies, the long-term cardiovascular effects of pregabalin-associated weight gain are unknown. Among diabetic patients, pregabalin-treated patients gained an average of 1.6 kg (range: -16 to 16 kg), compared to an average 0.3 kg (range: -10 to 9 kg) weight gain in placebo patients. In a cohort of 333 diabetic patients who received pregabalin for at least 2 years, the average weight gain was 5.2 kg. While the effects of pregabalinassociated weight gain on glycemic control have not been systematically assessed, in controlled and longer-term open label clinical trials with diabetic patients, pregabalin treatment did not appear to be associated with loss of glycemic control (as measured by HbA1C). Peripheral Edema Pregabalin treatment caused edema, primarily described as peripheral edema. In short-term trials of patients without clinically significant heart or peripheral vascular disease, there was no apparent association between peripheral edema and cardiovascular complications such as hypertension or congestive heart failure. Peripheral edema was not associated with laboratory changes suggestive of deterioration in renal or hepatic function. In controlled clinical trials the incidence of peripheral edema was 6% in the pregabalin group compared with 2% in the placebo group. In controlled clinical trials, 0.6% of pregabalin patients and no placebo patients withdrew due to peripheral edema. Higher frequencies of weight gain and peripheral edema were observed in patients taking both LYRICA and a thiazolidinedione antidiabetic agent compared to patients taking either drug alone. The majority of patients using thiazolidinedione antidiabetic agents in the overall safety database were participants in studies of pain associated with diabetic peripheral neuropathy. In this population, peripheral edema was reported in 3% (2/60) of patients who were using thiazolidinedione antidiabetic agents only, 8% (69/859) of patients who were treated with pregabalin only, and 19% (23/120) of patients who were on both pregabalin and thiazolidinedione antidiabetic agents. Similarly, weight gain was reported in 0% (0/60) of patients on thiazolidinediones only; 4% (35/859) of patients on pregabalin only; and 7.5% (9/120) of patients on both drugs. As the thiazolidinedione class of antidiabetic drugs can cause weight gain and/or fluid retention, possibly exacerbating or leading to heart failure, care should be taken when co-administering LYRICA and these agents. Because there are limited data on congestive heart failure patients with New York Heart Association (NYHA) Class III or IV cardiac status, LYRICA should be used with caution in these patients. Creatine Kinase Elevations Pregabalin treatment was associated with creatine kinase elevations. Mean changes in creatine kinase from baseline to the maximum value were 60 U/L for pregabalin-treated patients and 28 U/L for the placebo patients. In all controlled trials across multiple patient populations, 2% of patients on pregabalin and 1% of placebo patients had a value of creatine kinase at least three times the upper limit of normal. Three pregabalin-treated subjects had events reported as rhabdomyolysis in premarketing clinical trials. The relationship between these myopathy events and pregabalin is not completely understood because the cases had documented factors that may have caused or contributed to these events. Prescribers should instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if these muscle symptoms are accompanied by malaise or fever. Pregabalin treatment should be discontinued if myopathy is diagnosed or suspected or if markedly elevated creatine kinase levels occur. Laboratory Changes: Decreased Platelet Count Pregabalin treatment was associated with a decrease in platelet count. Pregabalin-treated subjects experienced a mean maximal decrease in platelet count of 20 x 10 3/µL, compared to 11 x 10 3/µL in placebo patients. In the overall database of controlled trials, 2% of placebo patients and 3% of pregabalin patients experienced a potentially clinically significant decrease in platelets, defined as 20% below baseline value and <150 x 10 3/µL. In randomized controlled trials, pregabalin was not associated with an increase in bleeding-related adverse events. ECG Changes: PR Interval Prolongation Pregabalin treatment was associated with mild PR interval prolongation. In analyses of clinical trial ECG data, the mean PR interval increase was 3-6 msec at pregabalin doses ≥300 mg/day. This mean change difference was not associated with an increased risk of PR increase ≥25% from baseline, an increased percentage of subjects with on-treatment PR >200 msec, or an increased risk of adverse events of second or third degree AV block. Subgroup analyses did not identify an increased risk of PR prolongation in patients with baseline PR prolongation or in patients taking other PR prolonging medications. However, these analyses cannot be considered definitive because of the limited number of patients in these categories. Information for Patients Patients should be counseled that LYRICA may cause dizziness, somnolence, blurred vision and other CNS signs and symptoms. Accordingly, they should be advised not to drive, operate complex machinery, or engage in other hazardous activities until they have gained sufficient experience on pregabalin to gauge whether or not it affects their mental, visual, and/or motor performance adversely. Patients should be counseled that LYRICA may cause visual disturbances. Patients should be informed that if changes in vision occur, they should notify their physician (see PRECAUTIONS). Patients should be advised to take LYRICA as prescribed. Abrupt or rapid discontinuation may result in insomnia, nausea, headache, or diarrhea. Patients should be counseled that LYRICA may cause edema and weight gain. Patients should be advised that concomitant treatment with LYRICA and a thiazolidinedione antidiabetic agent may lead to an additive effect on edema and weight gain. For patients with preexisting cardiac conditions, this may increase the risk of heart failure. Patients should be instructed to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Patients who require concomitant treatment with central nervous system depressants such as opiates or benzodiazepines should be informed that they may experience additive CNS side effects, such as somnolence. Patients should be told to avoid consuming alcohol while taking LYRICA, as LYRICA may potentiate the impairment of motor skills and sedation of alcohol. Patients should be instructed to notify their physician if they become pregnant or intend to become pregnant during therapy, and to notify their physician if they are breast feeding or intend to breast feed during therapy. Men being treated with LYRICA who plan to father a child should be informed of the potential risk of male-mediated teratogenicity. In preclinical studies in rats, pregabalin was associated with an increased risk of male-mediated teratogenicity. The clinical significance of this finding is uncertain (see PRECAUTIONS, Carcinogenesis and Impairment of Fertility). Diabetic patients should be instructed to pay particular attention to skin integrity while being treated with LYRICA. Some animals treated with pregabalin developed skin ulcerations, although no increased incidence of skin lesions associated with LYRICA was observed in clinical trials (see Animal Toxicology). Patients should be informed of the availability of a patient information leaflet, and they should be instructed to read the leaflet prior to taking LYRICA. Drug Interactions Since pregabalin is predominantly excreted unchanged in the urine, undergoes negligible metabolism in humans (<2% of a dose recovered in urine as metabolites), and does not bind to plasma proteins, its pharmacokinetics are unlikely to be affected by other agents through metabolic interactions or protein binding

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Controlled Studies in Postherpetic Neuralgia: Adverse Events Leading to Discontinuation In clinical trials in patients with postherpetic neuralgia, 14% of patients treated with pregabalin and 7% of patients treated with placebo discontinued prematurely due to adverse events. In the pregabalin treatment group, the most common reasons for discontinuation due to adverse events were dizziness (4%) and somnolence (3%). In comparison, less than 1% of placebo patients withdrew due to dizziness and somnolence. Other reasons for discontinuation from the trials, occurring in greater frequency in the pregabalin group than in the placebo group, were confusion (2%), as well as peripheral edema, asthenia, ataxia, and abnormal gait (1% each). Most Common Adverse Events Table 2 lists all adverse events, regardless of causality, occurring in ≥1% of patients with neuropathic pain associated with postherpetic neuralgia in the combined pregabalin group for which the incidence was greater in this combined pregabalin group than in the placebo group. In addition, an event is included, even if the incidence in the all pregabalin group is not greater than in the placebo group, if the incidence of the event in the 600 mg/day group is more than twice that in the placebo group. A majority of pregabalin-treated patients in clinical studies had adverse events with a maximum intensity of “mild” or “moderate.” Table 2. Treatment-emergent adverse event incidence in controlled trials in Neuropathic Pain Associated with Postherpetic Neuralgia (Events in at least 1% of all LYRICA-treated patients and at least numerically more in all pregabalin than in the placebo group) 75 mg/d 150 mg/d 300 mg/d 600 mg/d All PGB* Placebo Body System [N=84] [N=302] [N=312] [N=154] [N=852] [N=398] Preferred term % % % % % % Body as a whole Infection 14 8 6 3 7 4 Headache 5 9 5 8 7 5 Pain 5 4 5 5 5 4 Accidental injury 4 3 3 5 3 2 Flu syndrome 1 2 2 1 2 1 Face edema 0 2 1 3 2 1 Digestive system Dry mouth 7 7 6 15 8 3 Constipation 4 5 5 5 5 2 Flatulence 2 1 2 3 2 1 Vomiting 1 1 3 3 2 1 Metabolic and nutritional disorders Peripheral edema 0 8 16 16 12 4 Weight gain 1 2 5 7 4 0 Edema 0 1 2 6 2 1 Musculoskeletal system Myasthenia 1 1 1 1 1 0 Nervous system Dizziness 11 18 31 37 26 9 Somnolence 8 12 18 25 16 5 Ataxia 1 2 5 9 5 1 Abnormal gait 0 2 4 8 4 1 Confusion 1 2 3 7 3 0 Thinking abnormala 0 2 1 6 2 2 Incoordination 2 2 1 3 2 0 Amnesia 0 1 1 4 2 0 Speech disorder 0 0 1 3 1 0 Respiratory system Bronchitis 0 1 1 3 1 1 Special senses Blurry visionb 1 5 5 9 5 3 Diplopia 0 2 2 4 2 0 Abnormal vision 0 1 2 5 2 0 Eye disorder 0 1 1 2 1 0 Urogenital system Urinary incontinence 0 1 1 2 1 0 *PGB: pregabalin a Thinking abnormal primarily consists of events related to difficulty with concentration/attention but also includes events related to cognition and language problems and slowed thinking. b Investigator term; summary level term is amblyopia. Controlled Add-on Studies in Epilepsy: Adverse Events Leading to Discontinuation Approximately 15% of patients receiving pregabalin and 6% of patients receiving placebo in add-on epilepsy trials discontinued prematurely due to adverse events. In the pregabalin treatment group, the adverse events most frequently leading to discontinuation were dizziness (6%), ataxia (4%), and somnolence (3%). In comparison, <1% of patients in the placebo group withdrew due to each of these events. Other adverse events that led to discontinuation of at least 1% of patients in the pregabalin group and at least twice as frequently compared to the placebo group were asthenia, diplopia, blurred vision, thinking abnormal, nausea, tremor, vertigo, headache, and confusion (which each led to withdrawal in 2% or less of patients). Most Common Adverse Events Table 3 lists all dose-related adverse events, regardless of causality, occurring in at least 2% of all LYRICA-treated patients. Doserelatedness was defined as the incidence of the adverse event in the 600 mg/day group was at least 2% greater than the rate

in both the placebo and 150 mg/day groups. In these studies, 758 patients received pregabalin and 294 patients received placebo for up to 12 weeks. Because patients were also treated with 1 to 3 other AEDs, it is not possible to determine whether the following adverse events can be ascribed to pregabalin alone, or the combination of pregabalin and other AEDs. A majority of pregabalin-treated patients in these studies had adverse events with a maximum intensity of “mild” or “moderate.” Table 3. Dose-related treatment-emergent adverse event incidence in controlled trials in Epilepsy (Events in at least 2% of all LYRICA-treated patients and the adverse event in the 600 mg/day group was ≥2% the rate in both the placebo and 150 mg/day groups) 150 mg/d 300 mg/d 600 mg/d All PGB* Placebo [N=294] Body System [N=185] [N=90] [N=395] [N=670]a Preferred term % % % % % Body as a whole Accidental injury 7 11 10 9 5 Pain 3 2 5 4 3 Digestive system Increased appetite 2 3 6 5 1 Dry mouth 1 2 6 4 1 Constipation 1 1 7 4 2 Metabolic and nutritional disorders Weight gain 5 7 16 12 1 Peripheral edema 3 3 6 5 2 Nervous system Dizziness 18 31 38 32 11 Somnolence 11 18 28 22 11 Ataxia 6 10 20 15 4 Tremor 3 7 11 8 4 4 8 9 8 2 Thinking abnormalb Amnesia 3 2 6 5 2 Speech disorder 1 2 7 5 1 Incoordination 1 3 6 4 1 Abnormal gait 1 3 5 4 0 Twitching 0 4 5 4 1 Confusion 1 2 5 4 2 Myoclonus 1 0 4 2 0 Special senses 5 8 12 10 4 Blurred visionc Diplopia 5 7 12 9 4 Abnormal vision 3 1 5 4 1 *PGB: pregabalin a Excludes patients who received the 50 mg dose in Study E1 (included in full prescribing information). b Thinking abnormal primarily consists of events related to difficulty with concentration/attention but also includes events related to cognition and language problems and slowed thinking. c Investigator term; summary level term is amblyopia. Adverse events occurring in ≥2% of patients with partial onset seizures in the combined pregabalin group for which the incidence was greater in this combined pregabalin group than in the placebo group, but did not show dose-relatedness, include the following: asthenia, infection, chest pain, vomiting, nervousness, nystagmus, paresthesias, visual field defect. Other Adverse Events Observed During the Clinical Studies of LYRICA (pregabalin) Following is a list of treatment-emergent adverse events reported by patients treated with LYRICA during all clinical trials. The listing does not include those events already listed in the previous tables or elsewhere in labeling, those events for which a drug cause was remote, those events which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life-threatening. Events are categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Events of major clinical importance are described in the WARNINGS and PRECAUTIONS sections. Body as a Whole–Frequent: Abdominal pain, Allergic reaction, Fever; Infrequent: Abscess, Cellulitis, Chills, Malaise, Neck rigidity, Overdose, Pelvic pain, Photosensitivity reaction, Suicide attempt; Rare: Anaphylactoid reaction, Ascites, Granuloma, Hangover effect, Intentional injury, Retroperitoneal fibrosis, Shock, Suicide Cardiovascular System–Infrequent: Deep thrombophlebitis, Heart failure, Hypotension, Postural hypotension, Retinal vascular disorder, Syncope; Rare: ST depressed, Ventricular fibrillation Digestive System–Frequent: Gastroenteritis, Increased appetite; Infrequent: Cholecystitis, Cholelithiasis, Colitis, Dysphagia, Esophagitis, Gastritis, Gastrointestinal hemorrhage, Melena, Mouth ulceration, Pancreatitis, Rectal hemorrhage, Tongue edema; Rare: Aphthous stomatitis, Esophageal ulcer Hemic and Lymphatic System–Frequent: Ecchymosis; Infrequent: Anemia, Eosinophilia, Hypochromic anemia, Leukocytosis, Leukopenia, Lymphadenopathy, Thrombocytopenia; Rare: Myelofibrosis, Polycythemia, Prothrombin decreased, Purpura, Thrombocythemia Metabolic and Nutritional Disorders–Rare: Glucose tolerance decreased, Urate crystalluria Musculoskeletal System–Frequent: Arthralgia, Leg cramps, Myalgia, Myasthenia; Infrequent: Arthrosis; Rare: Generalized spasm Nervous System–Frequent: Anxiety, Depersonalization, Hypertonia, Hypesthesia, Libido decreased, Nystagmus, Paresthesia, Stupor, Twitching; Infrequent: Abnormal dreams, Agitation, Apathy, Aphasia, Circumoral paresthesia, Dysarthria, Hallucinations, Hostility, Hyperalgesia, Hyperesthesia, Hyperkinesia, Hypokinesia, Hypotonia, Libido increased, Myoclonus, Neuralgia; Rare: Addiction, Cerebellar syndrome, Cogwheel rigidity, Coma, Delirium, Delusions, Dysautonomia, Dyskinesia, Dystonia, Encephalopathy, Extrapyramidal syndrome, Guillain-Barré syndrome, Hypalgesia, Intracranial hypertension, Manic reaction, Paranoid reaction, Peripheral neuritis, Psychotic depression, Schizophrenic reaction, Torticollis, Trismus Respiratory System–Rare: Apnea, Atelectasis, Bronchiolitis, Hiccup, Laryngismus, Lung edema, Lung fibrosis, Yawn Skin and Appendages–Frequent: Pruritus; Infrequent: Alopecia, Dry skin, Eczema, Hirsutism, Skin ulcer, Urticaria, Vesiculobullous rash; Rare: Angioedema, Exfoliative dermatitis, Lichenoid dermatitis, Melanosis, Petechial rash, Purpuric rash, Pustular rash, Skin atrophy, Skin necrosis, Skin nodule, Stevens-Johnson syndrome, Subcutaneous nodule Special Senses–Frequent: Conjunctivitis, Diplopia, Otitis media, Tinnitus; Infrequent: Abnormality of accommodation, Blepharitis, Dry eyes, Eye hemorrhage, Hyperacusis, Photophobia, Retinal edema, Taste loss, Taste perversion; Rare: Anisocoria, Blindness, Corneal ulcer, Exophthalmos, Extraocular palsy, Iritis, Keratitis, Keratoconjunctivitis, Miosis, Mydriasis, Night blindness, Ophthalmoplegia, Optic atrophy, Papilledema, Parosmia, Ptosis, Uveitis Urogenital System–Frequent: Anorgasmia, Impotence, Urinary frequency, Urinary incontinence; Infrequent: Abnormal ejaculation, Albuminuria, Amenorrhea, Dysmenorrhea, Dysuria, Hematuria, Kidney calculus, Leukorrhea, Menorrhagia, Metrorrhagia, Nephritis, Oliguria, Urinary retention; Rare: Acute kidney failure, Balanitis, Bladder neoplasm, Cervicitis, Dyspareunia, Epididymitis, Female lactation, Glomerulitis Comparison of Gender and Race The overall adverse event profile of pregabalin was similar between women and men. There are insufficient data to support a statement regarding the distribution of adverse experience reports by race. DRUG ABUSE AND DEPENDENCE Controlled Substance Class: LYRICA is a Schedule V controlled substance. In a study of recreational users (N=15) of sedative/hypnotic drugs, including alcohol, LYRICA (450 mg, single dose) received subjective ratings of “good drug effect,” “high” and “liking” to a degree that was similar to diazepam (30 mg, single dose). In controlled clinical studies in over 5500 patients, 4% of LYRICA-treated subjects and 1% of placebo-treated patients overall reported euphoria as an adverse event, though in some patient populations studied, this reporting rate was higher and ranged from 1 to 12%. In clinical studies, following abrupt or rapid discontinuation of pregabalin, some patients reported symptoms including insomnia, nausea, headache or diarrhea (see PRECAUTIONS, Abrupt Discontinuation), suggestive of physical dependence. Pregabalin is not known to be active at receptor sites associated with drugs of abuse. As with any CNS active drug, physicians should carefully evaluate patients for history of drug abuse and observe them for signs of LYRICA misuse or abuse (e.g., development of tolerance, dose escalation, drug-seeking behavior). OVERDOSAGE Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans There is limited experience with overdose of pregabalin. The highest reported accidental overdose of pregabalin during the clinical development program was 8000 mg, and there were no notable clinical consequences. In clinical studies, some patients took as much as 2400 mg/day. The types of adverse events experienced by patients exposed to higher doses (≥900 mg) were not clinically different from those of patients administered recommended doses of pregabalin. Treatment or Management of Overdose There is no specific antidote for overdose with pregabalin. If indicated, elimination of unabsorbed drug may be attempted by emesis or gastric lavage; usual precautions should be observed to maintain the airway. General supportive care of the patient is indicated including monitoring of vital signs and observation of the clinical status of the patient. A Certified Poison Control Center should be contacted for upto-date information on the management of overdose with pregabalin. Although hemodialysis has not been performed in the few known cases of overdose, it may be indicated by the patients clinical state or in patients with significant renal impairment. Standard hemodialysis procedures result in significant clearance of pregabalin (approximately 50% in 4 hours). Rx Only Issued July 2005

PB262637A

© 2005 Pfizer Inc.

All rights reserved.

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Table 1. Treatment-emergent adverse event incidence in controlled trials in Neuropathic Pain Associated with Diabetic Peripheral Neuropathy (Events in at least 1% of all LYRICA-treated patients and at least numerically more in all pregabalin than in the placebo group) 75 mg/d 150 mg/d 300 mg/d 600 mg/d All PGB* Placebo Body System [N=77] [N=212] [N=321] [N=369] [N=979] [N=459] Preferred term % % % % % % Body as a whole Asthenia 4 2 4 7 5 2 Accidental injury 5 2 2 6 4 3 Back pain 0 2 1 2 2 0 Chest pain 4 1 1 2 2 1 Face edema 0 1 1 2 1 0 Digestive system Dry mouth 3 2 5 7 5 1 Constipation 0 2 4 6 4 2 Flatulence 3 0 2 3 2 1 Metabolic and nutritional disorders Peripheral edema 4 6 9 12 9 2 Weight gain 0 4 4 6 4 0 Edema 0 2 4 2 2 0 Hypoglycemia 1 3 2 1 2 1 Nervous system Dizziness 8 9 23 29 21 5 Somnolence 4 6 13 16 12 3 Neuropathy 9 2 2 5 4 3 Ataxia 6 1 2 4 3 1 Vertigo 1 2 2 4 3 1 Confusion 0 1 2 3 2 1 Euphoria 0 0 3 2 2 0 Incoordination 1 0 2 2 2 0 1 0 1 3 2 0 Thinking abnormala Tremor 1 1 1 2 1 0 Abnormal gait 1 0 1 3 1 0 Amnesia 3 1 0 2 1 0 Nervousness 0 1 1 1 1 0 Respiratory system Dyspnea 3 0 2 2 2 1 Special senses 3 1 3 6 4 2 Blurry visionb Abnormal vision 1 0 1 1 1 0 *PGB: pregabalin a Thinking abnormal primarily consists of events related to difficulty with concentration/attention but also includes events related to cognition and language problems and slowed thinking. b Investigator term; summary level term is amblyopia.

0021-972X/06/$15.00/0 Printed in U.S.A.

The Journal of Clinical Endocrinology & Metabolism 91(1) Copyright © 2006 by The Endocrine Society

Instructions to Authors for The Journal of Clinical Endocrinology & Metabolism Purpose and Scope The Journal of Clinical Endocrinology & Metabolism (JCEM) publishes original research articles, reviews, and other special features related to endocrinology and metabolism in humans and human tissues. JCEM is published by The Endocrine Society, which also publishes the following journals: Endocrinology primarily publishes original subcellular biochemical and physiological studies. Endocrine Reviews publishes scholarly review articles in all areas of experimental and clinical endocrinology. Molecular Endocrinology publishes papers that apply a molecular approach to study the regulatory mechanisms of hormones and related substances in nonprimate and primate cells.

Manuscripts must be written in idiomatic English and conform to the specifications described below. Papers that do not meet these requirements will be returned to the author for necessary revision before formal review. Manuscripts submitted to JCEM are evaluated by peer reviewers who remain anonymous. Authors of manuscripts requiring modifications have three months to resubmit a revision of their paper. Manuscripts returned after more than three months will be treated as new submissions. An unsolicited revision of a rejected manuscript will either be returned, or treated as a new submission, at the editor’s discretion. Manuscript Categories Reports of original research may be submitted to JCEM as an Original Article, Rapid Communication, or Brief Report. Note that all manuscripts must follow the recommended word counts. The word count is for text only; it does not include the abstract, references, or figure/table legends. You must include the word count on the title page, along with the number of figures and tables. Original Articles should be no longer than 3600 words, and include no more than six figures and tables and 40 references. The Journal has a special interest in publishing results of major clinical trials. Rapid Communications are concise reports of novel observations that are of unusual interest, importance, or immediate benefit to the endocrine community. They should not be merely preliminary reports, incomplete studies, or descriptions of methodologies. These manuscripts should be no longer than 2400 words, and include no more than four figures and tables and 30 references. Brief Reports are succinct descriptions of focused studies with important, but very straightforward, negative or confirmatory results. These manuscripts should be no longer than 1800 words, and include no more than two figures and tables and 20 references. Clinical Reviews and other Reviews should address topics of importance to clinical endocrinologists and endocrine clinical investigators, including scholarly updates regarding the molecular and biochemical basis for normal physiology and disease states; the state-of-the-art in diagnosis and management of endocrine and metabolic disorders; and other topics relevant to the practice of clinical endocrinology. Authors considering the submission of uninvited reviews should contact the editors in advance to determine if the topic that they propose is of current potential interest to the Journal. These manuscripts should be no longer than 4000 words, and include no more than five figures and tables and 120 references. Clinical Case Seminars are descriptions of a case or small number of cases revealing novel and important insights into a condition’s pathogenesis, presentation, and/or management. The case report is to be accompanied by a concise scholarly review of

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General Information

the literature regarding relevant aspects of the disorder. These manuscripts should be 2400 words or less, with four or fewer figures and tables and 30 or fewer references. Extensive Clinical Experiences are learned descriptions of substantial clinical experience with a specific endocrine or metabolic disorder, or class of disorders, by a single clinical endocrinologist or facility. This experience should expose novel aspects of the condition’s presentation, diagnosis, natural history, and/or treatment. These manuscripts should be no longer than 3600 words, and include no more than four figures and tables and 40 references. Position and Consensus Statements related to the endocrine and metabolic health standards and healthcare practices may be submitted by professional societies, task forces, and other consortia. All such submissions will be subjected to peer review, must be modifiable in response to criticisms, and will be published only if they meet the Journal’s usual editorial standards. These manuscripts should typically be no longer than 3600 words, and include no more than six figures and tables and 120 references. Controversies in Clinical Endocrinology describe and justify different approaches to diagnosis and/or management of patients with an endocrine or metabolic condition. These manuscripts are typically authored by two individuals who thoughtfully describe their respective practices and the rationale and evidence supporting them. The entire manuscript should be no longer than 2400 words, and include no more than two figures and tables and 30 references. Images in Endocrinology are to be comprised of a single figure or two closely related figures that illustrate the value of visual information in clinical diagnosis of endocrine and metabolic disorders, with a caption that is 50 words or less, an accompanying commentary that is 250 words or less, and five or fewer references. Commentaries are essentially uninvited editorials, which should concisely address and take a well-reasoned position on a timely issue of importance to clinical endocrinologists and/or endocrine clinical investigators. These manuscripts should be no longer than 1200 words with no more than 10 references; no figures or tables are permitted. Letters to the Editor may be submitted in response to work that has been published in the Journal. Letters should be short commentaries related to specific points of agreement or disagreement with the published work. Letters are not intended for presentation of original data unrelated to a published article. Letters can only be submitted electronically via the Journal website (http://jcem.endojournals.org/), by clicking on the link entitled “Submit a Letter to the Editor” on the abstract page or the article itself. Letters should be no longer than 500 words with no more than five complete references, and may not include any figures or tables. Manuscript Submission Procedures JCEM only uses electronic manuscript submission. See the link to E-Review on the JCEM homepage, http://jcem.endojournals.org. If you have never had a manuscript reviewed through E-Review, click on “New to Rapid Review?” to create an author account. If you already have an account from a previous submission, enter your username and password to submit a new or revised manuscript. If you have forgotten your username and/or password, e-mail the editorial office ([email protected]) for assistance. Note that your author account is the same for JCEM, Endocrinology, Molecular Endocrinology, and Endocrine Reviews. Authors should be aware that in submitting a manuscript for consideration by JCEM, they are submitting their paper to The Endocrine Society Central Journals Office database, which is accessible by the editors of all The Society’s journals.

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Authors must complete the online submission forms. If unable to successfully upload the files click “Submit Manuscript by Mail” to create an account number, contact the editorial office that you have created the account and send files if possible by email. If the files are too large, you can send the electronic files to the address below. Send CD or disks by mail to: Paul W. Ladenson, M.D., Editor-in-Chief JCEM Editorial Office 8401 Connecticut Avenue, Suite 900 Chevy Chase, MD 20815-5817 USA Phone: 301-951-2615 Fax: 301-951-2617 Email: [email protected] There is no submission fee for The Endocrine Society journals. Manuscript Preparation Requirements General Format The manuscript should be typed in 12-point font, with all text double-spaced (including references, tables and legends). Margins should be 1” or wider. All pages must be numbered. The following sections must begin on separate pages: title page, references, footnotes, tables, legends. Title The title page should include the following: • Full title (a concise statement of the article’s major contents) • Authors’ names and institutions • All papers with US federal funding must include the paragraph indicated in the The Endocrine Society NIH statement available at http://www.endo-society.org/journalspublications/ nih_author_policy.cfm. • Abbreviated title of not more than 40 characters for page headings • At least three key words for indexing and information retrieval • Word count (excluding abstract, tables, figure captions, and references) • Corresponding author’s email and ground mail addresses, telephone and fax numbers

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• Name and address of person to whom reprint requests should be addressed • Any grants or fellowships supporting the writing of the paper Structured Abstracts (Modified from The Journal of the American Medical Association) All Original Articles, Rapid Communications, Brief Reports, Clinical Reviews, Clinical Case Seminars, Consensus and Position Statements, Controversies in Endocrinology, and Extensive Clinical Experiences should be submitted with structured abstracts of no more than 250 words, as described below. All information reported in the abstract must appear in the manuscript. The abstract should not include references. Write the abstract with a general medical audience in mind. Please use complete sentences for all sections of the abstract. Reports of Original Data (i.e., Original Articles, Rapid Communications, and Brief Reports) should include an abstract with the following headings. Parts of the abstract may be written as phrases. Each section should include the following content: 1. Context. The abstract should begin with 1–2 sentences explaining the clinical (or other) importance of the study question. 2. Objective. State the precise objective or study question addressed in the report. If more than one objective is addressed, the main objective and only key secondary objectives should be stated. If a hypothesis was tested, it should be stated. 3. Design. Describe the basic design of the study, years of study performance, and duration of follow-up. If applicable, include the study name (e.g., the Framingham Heart Study). 4. Setting. Describe the study setting, for example, general community, a primary care or referral center, private or institutional practice, or ambulatory or hospitalized care. 5. Patients or Other Participants. State the clinical disorders, number, eligibility criteria, key sociodemographic features, and method of selection of patients. If matching is used for comparison groups, characteristics matched should be specified. In follow-up studies, the proportion of participants who completed the study must be indicated. In intervention studies, the number of patients withdrawn because of adverse effects should be given. 6. Intervention(s). The key features of any interventions should be described, including their method and duration. The intervention should be named by its most common clinical name, and nonproprietary drug names should be used. 7. Main Outcome Measure(s). Indicate the primary study outcome measurement(s) planned before data collection began. If the manuscript does not report the main planned outcomes of a study, this should be stated and the reason indicated. State clearly if the hypothesis being tested was formulated during or after data collection. 8. Results. The main outcomes of the study should be provided and quantified, including confidence intervals or P values. For comparative studies, confidence intervals should relate to the differences between groups. If relevant, indicate whether observers were blinded to patient groupings, particularly for subjective measurements. If differences for the major study outcome measure(s) are not significant, the clinically important difference sought should be stated and the confidence interval for the difference between the groups should be given. When risk changes or effect sizes are given, absolute values should be indicated. Studies of screening and diagnostic tests should report sensitivity, specificity, and likelihood ratio. If predictive value or accuracy is given, prevalence or pretest likelihood should be given as well. All randomized controlled trials should include the results of inten-

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All submissions MUST INCLUDE: 1. A cover letter requesting that the manuscript be evaluated for publication in JCEM and any information relevant to your manuscript. Elsewhere on the submission form authors may suggest up to 5 specific reviewers and/or request the exclusion of up to 3 others. 2. A completed Copyright Assignment & Affirmation of Originality form, available at http://jcem.endojournals.org/misc/ origcopy.pdf. This form should be faxed to the JCEM Editorial Office at 301-951-2617 and should include the manuscript number in the space provided on the form. 3. At least three (3) key terms. 4. Completed Disclosure of Potential Conflict of Interest Form, available at http://jcem.endojournals.org/misc/disclosure. pdf. IMPORTANT: The corresponding author is expected to gather EACH AUTHOR’S completed disclosure form and fax them, together, to the editorial office along with the Author Disclosure Summary. Do not fax them individually. Revised manuscripts will not be processed until all signatures and the summary are received. 5. Authors are encouraged to submit a PDF for the initial submission. See the instructions on the JCEM homepage (http:// jcem.endojournals.org). If you do submit original files, E-Review will create a PDF of your files, but the process may take some time depending on the size of the files.

tion-to-treat analysis, and all surveys should include response rates. 9. Conclusions. Provide only conclusions directly supported by the results, along with implications for clinical practice; avoid speculation and overgeneralization. Indicate whether additional study is required before the information should be used in usual clinical settings. Give equal emphasis to positive and negative findings of equal scientific merit. Meta-analyses should include an abstract with the following headings:

Clinical Reviews should include an abstract with the following sections: 1. Context. Include 1 or 2 sentences describing the clinical question or issue and its importance in clinical practice or public heath. 2. Evidence Acquisition. Describe the data sources used, including the search strategies, years searched, and other sources of material, such as subsequent reference searches of retrieved articles. Methods used for quality assessment and inclusion of identified articles should be explained. 3. Evidence Synthesis. The major findings of the review of the

Consensus and Position Statements should include an abstract with the following sections: 1. Objective. Describe the issue and purpose of the statement. For example, the issue may be a health problem or practice options. The purpose may be to guide clinical practice or to set policy standards. 2. Participants. Explain how people became participants, the number of participants, whether meetings were open or closed. Disclose the funding source. 3. Evidence. Describe how data sources were obtained, selected, and synthesized. Explain the use of unpublished data and the influence of expert opinion. 4. Consensus Process. Described the process by which consensus was achieved such as voting, the Delphi process, or group meetings. Explain who wrote the statement (an individual or a committee). Explain who reviewed the statement and how suggestions for revision were incorporated. 5. Conclusions. Summarize the statement. Include important minority views if they exist. Controversies in Endocrinology should include an abstract with the following sections: 1. Context. The abstract should begin with 1–2 sentences explaining the clinical (or other) importance of the study question. 2. Objective. State the precise objective or clinical issue addressed in the dialog. 3. Case. If appropriate, briefly describe the exemplary case employed to focus the discussion. 4. Intervention(s). The specific diagnostic and therapeutic alternatives discussed should be specified. 5. Positions. The specific diagnosis and/or management strategies advocated by each author should be summarized in separate sections, with their justifications generally enumerated. 6. Conclusions. The principal points of agreement and contention should be concisely stated. Extensive Clinical Experiences should include an abstract with the following sections: 1. Context. Include 1 or 2 sentences describing the relevant condition and its importance in clinical practice or public heath. 2. Setting. Describe the setting in which the experience was acquired, for example, general community, a primary care or referral center, private or institutional practice, or ambulatory or hospitalized care. 3. Patients or Other Participants. State the clinical disorders, eligibility criteria, key sociodemographic features, and number of patients described. 4. Intervention(s). The key features of any interventions should be described. 5. Main Outcome Measure(s). Indicate the primary study outcome measurement(s) 6. Results. The main outcomes of the study should be provided and quantified 8. Conclusions. Provide conclusions supported by the clinical experience, along with implications for clinical practice.

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1. Context. Include 1 or 2 sentences explaining the importance of the review question. 2. Objective. State the precise primary objective of the review. Indicate whether the review emphasizes factors such as cause, diagnosis, prognosis, therapy, or prevention and include information about the specific population, intervention, exposure, and tests or outcomes that are being reviewed. 3. Data Sources. Summarize data sources and years searched. Potential sources include computerized databases and published indexes, registries, abstract booklets, conference proceedings, references identified from bibliographies of pertinent articles and books, experts or research institutions active in the field, and companies or manufacturers of tests or agents being reviewed. Additional information about data sources can be described in the Methods section, e.g., exact indexing terms and constraints (for example, English language or human subjects) used. 4. Study Selection. Describe inclusion and exclusion criteria used to select studies for detailed review (e.g., particular populations, interventions, outcomes, or methodological designs). The method used to apply these criteria should be specified (for example, blinded review, consensus, multiple reviewers). State the proportion of initially identified studies that met selection criteria. 5. Data Extraction. Describe guidelines used for abstracting data and assessing data quality and validity (such as criteria for causal inference). The method by which the guidelines were applied should be stated (for example, independent extraction by multiple observers). 6. Data Synthesis. State the main results of the review, whether qualitative or quantitative, and outline the methods used to obtain these results. Meta-analyses should state the major outcomes that were pooled and include odds ratios or effect sizes and, if possible, sensitivity analyses. Numerical results should be accompanied by confidence intervals, if applicable, and exact levels of statistical significance. Evaluations of screening and diagnostic tests should include sensitivity, specificity, likelihood ratios, receiver operating characteristic curves, and predictive values. Assessments of prognosis should summarize survival characteristics and related variables. Major identified sources of variation between studies should be stated, including differences in treatment protocols, co-interventions, confounders, outcome measures, length of follow-up, and dropout rates. 7. Conclusions. The conclusions and their applications should be clearly stated, limiting interpretation to the domain of the review.

clinical issue or topic should be addressed in an evidencebased, objective, and balanced fashion, with the highest quality evidence available receiving the greatest emphasis. 4. Conclusions. The conclusions should clearly answer the questions posed if applicable, be based on available evidence, and emphasize how clinicians should apply current knowledge.

Introduction The article should begin with a brief introductory statement that places the work to follow in historical perspective and explains its intent and significance.

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Experimental Subjects To be considered, all clinical investigation described in submitted manuscripts must have been conducted in accordance with the guidelines in The Declaration of Helsinki (http://www.wma.net) and have been formally approved by the appropriate institutional review committees or its equivalent. All manuscripts must indicate that such approval was obtained and that informed consent was obtained from subjects in all experiments involving humans. The study populations should be described in detail. In many studies details of age, race, and sex are important. However, subjects must be identified only by number or letter, not by initials or names. Photographs of patients’ faces should be included only if scientifically relevant. Authors must obtain written consent from the patient for use of such photographs. For further details, see the Ethical Guidelines following these Instructions and at http://jcem. endojournals.org/misc/endoethics.shtml.

appropriate places in the text, in parentheses and without serial number, or be presented in the footnotes. The citation of manuscripts in press (i.e., accepted for publication) is permitted in the bibliography; the name of the journal in which they appear must be supplied. If references to personal communications are made, authors are encouraged to keep written proof of the exchange. If it is necessary to cite an abstract because it contains substantive data not published elsewhere, it must be designated at the end of the reference [e.g., . . .68:313 (Abstract)]. Books: List all authors or editors.

Results and Discussion

Tables

The Results section should briefly present the experimental data in text, tables, and/or figures. For details on preparation of tables and figures, see below. The Discussion should focus on the interpretation and significance of the findings with concise objective comments that describe their relation to other work in that area. The Discussion should not reiterate the Results.

Tables must be constructed as simply as possible and be intelligible without reference to the text. Each table must have a concise heading. A description of experimental conditions may appear together with footnotes at the foot of the table. Tables must not simply duplicate the text or figures. The width of the table must be designed to occupy one or two journal columns, with no more than four table columns or 8 –10 table columns, respectively.

Experimental Animals A statement confirming that all animal experimentation described in the submitted manuscript was conducted in accord with accepted standards of humane animal care, as outlined in the Ethical Guidelines, should be included in the manuscript. Materials and Methods

Acknowledgments (not required for submission) A note of acknowledgment is appropriate recognition for contributors who may not be listed as authors, or for noting grant support of the research. At the time of submitting their article, authors must confirm that all individuals acknowledged for contributions to the study have explicitly agreed to this designation.

Figure Legends Figure legends and titles should be submitted on a separate page. Figure legends should add meaning and significance to the figure, and should not require reference back to the text. Titles should be clear and informative. Figures

References References to the literature should be cited in numerical order (in parentheses) in the text and listed in the same numerical order at the end of the manuscript on a separate page or pages. The author is responsible for the accuracy of references. The number of references cited should be limited, as indicated above for each category of submission. Appropriate recent reviews should be cited whenever possible. Examples of the reference style that should be used are given below. Further examples will be found in the articles describing the Uniform Requirements for Manuscripts Submitted to Biomedical Journals (Ann Intern Med.1988; 208:258 –265, Br Med J. 1988; 296:401– 405). The titles of journals should be abbreviated according to the style used in the Index Medicus. Journal articles and abstracts: List all authors. The citation of unpublished observations, of personal communications, and of manuscripts in preparation or submitted for publication is not permitted in the bibliography. Such citations should be inserted at

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Digital art: Authors are encouraged to submit digital art to expedite the review and publication processes. Please review the detailed instructions for preparing digital art at http://cpc.cadmus. com/da/index.asp. E-mail queries can be sent to digitalart@cadmus. com. Authors must also review the instructions for submitting through http://www.endo-society.org/journals/e-review.cfm. Authors should also use the Rapid Inspector program (http:// rapidinspector.cadmus.com/RapidInspector/zea/index.jsp) to ensure their figure files have been prepared correctly for density and color. While authors are encouraged to submit a PDF for the initial submission, figures should be created following Digital Art guidelines and should pass Rapid Inspector. Figure formats: All digital art should pass Rapid Inspector and be in one of the three acceptable formats: TIFF, EPS, or PowerPoint. PowerPoint figures may experience problems when converted to PDF; therefore, carefully inspect the PDF after it is created by E-Review. Staff will not be able to note any problems from PowerPoint files once the PDF is sent. Please follow the instructions at http://cpc.cadmus.com/da/index.asp as to acceptable fonts and density of figures.

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These should be described and referenced in sufficient detail for other investigators to repeat the work. The source of hormones, unusual chemicals and reagents, and special pieces of apparatus should be specified. For modified methods, only the modifications need be described.

Sample References 1. Binoux M, Hossenlopp P 1986 Insulin-like growth factor (IGF) and IGF-binding proteins: comparison of human serum and lymph. J Clin Endocrinol Metab 67:509 –514 2. MacLaughlin DT, Cigarros F, Donahoe PK 1988 Mechanism of action of Mullerian inhibiting substance. Program of the 70th Annual Meeting of The Endocrine Society, New Orleans, LA, 1988, p 19 3. Bonneville F, Cattin F, Dietemann J-L 1986 Computed tomography of the pituitary gland. Heidelberg: Springer-Verlag; 15–16 4. Burrow GN 1987 The thyroid: nodules and neoplasia. In: Felig P, Baxter JD, Broadus AE, Frohman LA, eds. Endocrinology and metabolism. 2nd ed. New York: McGraw-Hill; 473–507 For general aid in the preparation of manuscripts, authors should consult: CBE Style Manual: A Guide for Authors, Editors and Publishers. 5th ed. Bethesda, MD: Council of Biology Editors; 1983.

column width with uniform margins. Indicate magnification in the legends and by internal reference markers in the photographs. Their length should represent the fraction or multiple of a micrometer, appropriate to the magnification. Graphs: Graphs with axis measures containing very large or small numbers should convert to easily readable notations. Example: For an ordinate range of “counts per minute” values from 1,000 to 20,000, the true value may be multiplied by 10⫺3 (scale would read from 1 to 20) and the ordinate axis display “cpm (⫻10–3).” Similarly, for a Scatchard plot with values ranging from 0.1 to 2 femtomolar (10–15 M), the scale may run from 0.1 to 2 with the abscissa labeled “M(⫻1015).” Three-dimensional bar graphs will not be published if the information they refer to is only two-dimensional. Units of Measure Results should be expressed in metric units. Syste`me Internationale (SI units) must be added in parentheses. Temperature should be expressed in degrees Celsius (e.g., 28 C) and time of day using the 24-hour clock (e.g., 0800 h, 1500 h). Abbreviations and Nomenclature All nonstandard abbreviations used in the text must be defined immediately after the first use of the abbreviation. Standard abbreviations are listed below and require no definition.

Standard Abbreviations (Note that periods are omitted in most abbreviations. Units of measure should not be abbreviated if they do not appear with a specific amount. Abbreviations for elements listed on the periodic table of elements are considered standard abbreviations.) acquired immunodeficiency syndrome adenosine 5⬘-mono-, di-, and triphosphates adrenocorticotropin analysis of variance

AMP, ADP, ATP ACTH ANOVA

bovine serum albumin

BSA

complementary DNA complementary RNA corticotropin-releasing hormone 3⬘,5⬘-cyclic AMP cytidine 5⬘-mono-, di-, and triphosphates

cDNA cRNA CRH cAMP CMP, CDP, CTP

deoxyribonucleic acid Dulbecco’s modified Eagle’s medium

DNA DMEM

electrophoretic mobility shift assay enzyme-linked immunosorbent assay ethylenediamine tetra-acetate ethyleneglycol-bis-(␤-aminoethyl ether)-N,N,N⬘,N⬘-tetraacetic acid extracellularly regulated kinase follicle-stimulating hormone gonadotropin-releasing hormone growth hormone (somatotropin)

AIDS

GH-releasing hormone guanosine 5⬘-mono-, di-, and triphosphates GTP-binding protein

GHRH GDP, GMP, GTP G protein

N-2-hydroxyethylpiperazine-N⬘2-ethane sulfonic acid high-performance liquid chromatography human immunodeficiency virus 5-hydroxy-indole-acetic acid

HEPES

HIV 5-HIAA

intramuscular(-ly) intraperitoneal(-ly) intravenous(-ly)

Ig IGF IL (e.g., IL-1, IL-6) im ip iv

EMSA

luteinizing hormone log of the odds

LH LOD

ELISA

median effective concentration median effective dose median inhibitory concentration median lethal dose melanocyte-stimulating hormone messenger RNA minimal essential medium mitogen-activated protein kinase

EC50 ED50 IC50 LD50 MSH mRNA MEM MAPK

optical density

OD

parathyroid hormone phosphate-buffered saline

PTH PBS

EDTA EGTA ERK FSH GnRH (LHRH) GH

immunoglobulin insulin-like growth factor interleukin

HPLC

polyacrylamide gel electrophoresis polymerase chain reaction probability PTH-related peptide

PAGE PCR P PTHrP

radioimmunoassay reverse transcription-polymerase chain reaction ribonucleic acid ribosomal RNA

RIA RT-PCR

sex hormone-binding globulin sodium dodecyl sulfate-polyacrylamide gel electrophoresis standard deviation standard error standard error of the mean subcutaneous(-ly)

SHBG SDS-PAGE

thyrotropin thyroxine 3,5,3⬘-triiodothyronine 3,3⬘,5⬘-triiodothyronine transfer RNA transforming growth factor tris(hydroxymethyl)aminomethane TSH-releasing hormone tumor necrosis factor

TSH T4 T3 rT3 tRNA TGF Tris

ultraviolet

UV

versus

vs.

RNA rRNA

SD SE SEM

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Sizing and labeling figures: Authors are responsible for providing digital art that has been properly sized and cropped with sufficient space between images. Plan the size of the figure to fill 1, 1.5, or 2 columns in the printed journal. In most cases, figures should be prepared for 1-column width. Produce original art at the size it should appear in the printed journal: 1 column ⫽ 18 picas, 7.5 cm, 3.0 in.; 1.5 columns ⫽ 30 picas, 12.5 cm, 5.0 in.; 2 columns ⫽ 38 picas, 16.0 cm, 6.4 in. At 100% size, no lettering should be smaller than 8 point (0.3 cm high) or larger than 12 point (0.4 cm high). Use bold and solid lettering. Lines should be thick, solid, and no less than 1-point rule. Avoid the use of reverse type (white lettering on a darker background). Avoid lettering on top of shaded or textured areas. Special requirements for 4-color art: Save files in CMYK mode (cyan-magenta-yellow-black). Color saturation of the shadow portion cannot exceed 280% (%cyan ⫹ %magenta ⫹ %yellow ⫹ %black cannot exceed 280%). Shading: Avoid the use of shading, but if unavoidable, use a coarse rather than a fine screen setting (80 –100 line screen is preferred). Avoid 1–20% and 70 –99% shading; make differing shades vary by at least 20%, i.e., 25%, 45%, 65%. Instead of shading, denote variations in graphs or drawings by cross-hatching; solid black; or vertical, horizontal, or diagonal striping. Avoid the use of dots. Grouped figures: For grouped figures, indicate the layout in a diagram. Place grouped figures so that they can be printed in 1

sc

TRH TNF

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Nomenclature of Steroids 1. Steroids should be named, wherever possible, according to the IUPAC-IUB 1971 Definitive Rules for Steroid Nomenclature (Pure Appl Chem 31:285–322, 1972). 2. Trivial names may be used but, with the exception of cholesterol, estrone, 17␤-estradiol, estriol, aldosterone, androsterone, etiocholanolone, dehydroepiandrosterone, 5␣-dihydrotestosterone, testosterone, androstenedione, pregnenolone, progesterone, corticosterone, deoxycorticosterone, cortisone, cortisol, must be defined systematically in a single footnote. This footnote should also contain the definitions of all letter abbreviations.

3. Trivial names may be modified by prefixes indicating substituents (as in 17-hydroxyprogesterone for 17-hydroxy-4-pregnene-3,20-dione), double bonds (as in 7-dehydrocholesterol for 5,7-cholestadien-3␤-ol) and epimeric configurations of functional groups provided the locus of epimerization is indicated (as in 3-epiandrosterone for 3␤-hydroxy-5␣androstan-17-one).

Nomenclature of Vitamin D Metabolites: Analogous and Structurally Related Compounds

Manuscripts Reporting New Amino Acid or Nucleotide Sequences Manuscripts reporting amino acid or nucleotide sequences of proteins with sequences already known from other tissues or species will be considered only if they provide new biological insight. Manuscripts dealing with partial sequence data are not likely to be considered. The Endocrine Society has established policy that deals with submission of new protein or nucleic acid sequences. When a manuscript is accepted that contains novel sequences, such sequences must be deposited in the appropriate database (such as GenBank) and an accession number obtained before the manuscript is sent to the printer. It is recommended that the following statement containing the assigned accession number be inserted as a footnote: “These sequence data have been submitted to the DDBJ/EMBL/GenBank databases under accession number Ul2345.” Manuscripts Reporting on Novel Compounds Manuscripts describing experiments with new compounds must provide their chemical structures. For known compounds, the source and/or literature reference to the chemical structure and characterization must be provided. Validation of Data and Statistical Analysis Assay validation: Bioassay and radioimmunoassay potency estimates should be accompanied by an appropriate measure of the precision of these estimates. For bioassays, these usually will be the standard deviation, standard error of the mean, coefficient of variation, or 95% confidence limits. For both bioassays and immunoassays, it is necessary to include data relating to withinassay and between-assay variability. If all relevant comparisons are made within the same assay, the latter may be omitted. Authors should be aware that the precision of a measurement depends upon its position on the dose-response curve. In presenting results for new assays, it is necessary to include data on the following: 1) within-assay variability; 2) betweenassay variability; 3) slope of the dose-response curve; 4) mid-range of the assay; 5) least-detectable concentration (concentration resulting in a response two standard deviations away from the zero dose response); 6) data on specificity; 7) data on parallelism of standard and unknown and on recovery; and 8) comparison with an independent method for assay of the compound. When immunoassay kits are utilized or hormone measurements are conducted in other than the authors’ laboratories and the assay is central to the study, data regarding performance characteristics should be included. Pulse analysis: Data from studies of pulsatile hormone secretion should be analyzed using a validated, objective pulse detection

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25,26-dihydroxyvitamin D3, 25,26-dihydroxycholecalciferol, 25,26-(OH)2D3 1,25-dihydroxyvitamin D2, 1,25-dihydroxyergocalciferol, 1,25-(OH)2D2 1,25-hydroxyvitamin D, D3, D2 unspecified, 1,25-OHD dihydrotachysterol3, DHT3 dihydrotachysterol2, DHT2 25-hydroxydihydrotachysterol3, 25-OH-DHT3 25-hydroxydihydrotachysterol2, 25-OH-DHT2

algorithm. The algorithm used should require that false-positive rates of pulse detection be defined in relation to the measurement error of the data set being analyzed, and the methods used to determine the measurement error should be described. The author(s) also should describe the methods used: 1) to deal with missing or undetectable values; 2) to determine peak frequency, interpeak interval, and pulse amplitude; and 3) for statistical comparisons of peak parameters. Data analysis: It is the author’s responsibility to document that the results are reproducible and that the differences found are not due to random variation. No absolute rules can be applied, but in general quantitative data should be from no fewer than three replicate experiments. Appropriate statistical methods should be used to test the significance of differences in results. The term “significant” should not be used unless statistical analysis was performed, and the probability value used to identify significance (e.g., P ⬎ 0.05) should be specified. When several t tests are employed, authors should be aware that nominal probability levels no longer apply. Accordingly, the multiple t test, multiple range test, or similar techniques to permit simultaneous comparisons should be employed. Also, in lieu of using several t tests, it is often more appropriate to utilize an analysis of variance (ANOVA) to permit pooling of data, increase the number of degrees of freedom, and improve reliability of results. Authors should use appropriate nonparametric tests when the data depart substantially from a normal distribution. Analysis of variance tables should not be inserted in manuscripts. F values with the degrees of freedom as subscripts together with the P values are sufficient. In presenting results of linear regression analyses, it is desirable to show 95% confidence limits. When data points are fitted with lines (as in Scatchard or Lineweaver-Burk plots), the method used for fitting (graphical, least squares, computer program) should be specified. If differences in slopes and/or axis intercepts are claimed for plotted lines, these should be supported by statistical analysis. Publication and Production Guidelines Electronic Editing Acceptable formats for production are as follows: text and tables can in be Word, WordPerfect, or RTF formats. Graphics must be EPS, TIFF, or PowerPoint files, but note that MAC PowerPoint may not convert correctly in the PC-based E-Review system. If using MAC PowerPoint please contact the Editorial Office after submitting the files. Note that graphic files in Word are not acceptable formats for publication. The Journal cannot assure that there will not be errors in conversion of customized software, newly released software, or special

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vitamin D3, cholecalciferol vitamin D2, ergocalciferol 25-hydroxyvitamin D3, 25-hydroxycholecalciferol, 25OHD3 25-hydroxyvitamin D2, 25-hydroxyergocalciferol, 25OHD2 25-hydroxyvitamin D, D3, D2 unspecified, 25-OHD 1,25-dihydroxyvitamin D3, 1,25-dihydroxycholecalciferol, 1,25-(OH)2D3 1,24,25-trihydroxyvitamin D3, 1,24,25-trihydroxycholecalciferol, 1,24,25-(OH)3D3 24,25-dihydroxyvitamin D3, 24,25-dihydroxycholecalciferol, 24,25-(OH)2D3

characters. Recognition and correction of these is the responsibility of authors. Proofs and Reprints Proofs and a reprint order are sent to the corresponding author, unless the Editorial Office is advised otherwise. Questions about reprints should be referred to Cadmus Professional Communications at 410-819-3991 (direct) or 800-407-9190 (toll-free).

per color figure if the author submits usable digital art that passes Cadmus’s Rapid Inspector (http://rapidinspector.cadmus.com/ RapidInspector/zea/index.jsp). Queries on page charges may be directed to Joy Carter at Cadmus Professional Communications (410-691-6439; fax 410-691-6929). In extraordinary cases, the author may ask that the Editor-in-Chief appeal to The Endocrine Society Publications Committee to consider waiving a portion of the color figure charge. Archiving

Page and Other Charges There is no submission fee for The Endocrine Society journals. There is a charge of $90 per printed page in the Journal and $300

The editorial office will retain all manuscripts and related documentation (correspondence, reviews, etc.) for 12 months following the date of publication or rejection.

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0021-972X/06/$15.00/0 Printed in U.S.A.

The Journal of Clinical Endocrinology & Metabolism 91(1) Copyright © 2006 by The Endocrine Society

Ethical Guidelines Ethical Guidelines for Research Editorial Prerogative for Ethical Unsuitability

Experimental Subjects

All studies involving human subjects or human tissue must be in accordance with the principles set out in the Declaration of Helsinki and must have been formally approved by the appropriate institutional review board, ethical review committee, or equivalent. All manuscripts should indicate that such approval was obtained. The study populations should be described in detail. In many studies details of age, race, and sex are important. In experiments involving any significant risk or discomfort to subjects, it should be documented that informed consent was obtained from the subjects and that an institutional human research committee had approved the investigations. In text, tables, and figures subjects must be identified by number or letter rather than by initials or names. Photographs of patients’ faces should be included only if scientifically relevant. Authors should obtain written consent from the patient for use of such photographs. Guidelines for the Care and Use of Experimental Animals

The Society requires that all studies involving the use of animals published in its journals be conducted in accordance with mandated standards of humane care. The appropriateness of the experimental procedures, as well as the species and required number of animals used, must be considered in the design of any study. All research animals must be acquired and used in compliance with federal, state, and local laws and institutional regulations. In particular, The Society recommends that animals be maintained in accordance with the NIH Guide for the Care and Use of Laboratory Animals [1996 (7th ed.) Washington, DC: National Academy Press, aka National Research Council Guide. www.nap.edu/readingroom/books/labrats/] Research animals must receive appropriate tranquilizers, analgesics, anesthetics, and care to minimize pain and discomfort during preoperative, operative, and postoperative procedures. The choice and use of drugs must be

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Ethical Guidelines for Publication of Research in The Endocrine Society Journals The Publications Committee is keenly aware of the importance of formulating and disseminating rules of good conduct for authors, reviewers, and editors. Equally important is the establishment of due process for alleged or apparent improprieties. The Council of The Endocrine Society has approved the following Ethical Guidelines as prepared by the Publications Committee and has authorized periodic publication as well as distribution to members of our Editorial Boards, reviewers, and authors submitting manuscripts. The following statement is not meant to be all-inclusive but is provided in sufficient detail to give a clear understanding of ethical considerations to all concerned. For further detail on Ethical Guidelines, please refer to The Endocrine Society’s “Policies and Procedures Regarding Alleged Scientific Misconduct in The Endocrine Society Journals” at http:// www.endo-society.org. Introduction

The fundamentals of good conduct as they apply to research are honesty, fairness, good manners, and the subordination of self-interest to the common interest of our profession and our society. In these notes, the Publications Committee sets forth its rules of good conduct for authors, reviewers, and editors. Obligations of Authors

The foremost obligation of an author is to present a clear, honest, accurate, and complete account of the research performed. Each manuscript should describe a complete study or a completed phase of an extended study. Fragmentation of reports should be avoided. When some of the results are to appear in another journal, in publications of congresses, symposia, workshops, etc., details plus a copy of the other paper(s) should be sup-

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The editors reserve the right to reject manuscripts describing research that does not meet acceptable standards of research behavior as determined by the Belmont Report (http://ohsr.od.nih.gov/mpa/belmont.php3), Geneva Convention (http://www.un.org/Overview/rights.html), the Declaration of Helsinki (http://www.wma.net), and The Endocrine Society Code of Ethics (http://www.endo-society. org/about/index.cfm).

made in accordance with the NIH Guide. Where the use of anesthetics would negate the results of the experiment, the protocol must be clearly justified and approved by the Committee on Animal Care and Use of the local institution and according to accepted veterinary medical practice. The health of the animals must be properly monitored. If either the study or the condition of the animals requires that they be killed, it shall be done in a humane manner. The manuscript must indicate that the studies were approved by the authors’ institutional committee on animal care.

Definition of Scientific Misconduct

Scientific misconduct comprises several unethical acts including, but not limited to, plagiarism, fabrication, falsification, redundant or duplicate publication, violation of federal, state, or institutional rules, and honorary authorship. The Endocrine Society accepts the definitions of plagiarism, fabrication and falsification proposed in the ORI Handbook for Institutional Research Integrity Officers, February 1997, Office of Research Integrity, Public Health Service of the U.S. Department of Health and Human Services (Washington, DC). The following list includes, but is not limited to, the following prohibited acts: 1. Plagiarism, which includes the theft or misappropriation of intellectual property and the substantial unattributed textual copying of another’s work. It does not include authorship or credit disputes. The theft or misappropriation of intellectual property includes the unauthorized use of ideas or unique methods obtained via a privileged communication, such as a grant or manuscript review. Substantial unattributed textual copying of another’s work is defined as the unattributed verbatim or nearly verbatim copying of sentences and paragraphs which materially misleads the ordinary reader regarding the contributions of the author. It does not include the limited use of identical or nearly identical phrases which describe a commonly used methodology or previous research. The author must show the editor written permission to quote any information learned personally from another investigator or by reviewing applications for research grants. In the introduction, and especially in the discussion of a paper, the author should cite fairly the work of others that is relevant either to the origin or to the outcome of the research described.

2. Fabrication, which includes making up results and recording or reporting them, in whole or in part. 3. Falsification is manipulating research, materials, equipment, or processes, or changing or omitting data or results such that the research is not accurately represented in the research record. It includes the suppressing or altering of data not in agreement with one’s hypothesis. 4. Redundant or duplicate publication, which includes the submission of a paper, or portion thereof, that overlaps with one already submitted or published. An author may not submit reports of the same or substantially overlapping research to more than one journal at the same time, unless the author can justify it in letters to both editors. 5. Submission of animal or clinical research conducted without the approval of the institutional animal care and use committee or review board. 6. Honorary authorship, as defined by the Vancouver Working Group, is the inclusion of authors who have not contributed substantially to the conception, design, execution or analysis of the work. Only those who have made significant intellectual and scientific contributions to the work reported may be co-authors. A co-author’s signature on the copyright release form submitted with the manuscript indicates that the co-author has had a part in the writing and final editing of the report, has been given a copy of the manuscript, and agrees to share responsibility and accountability for the results. Alleged misconduct against an author on a manuscript will automatically entail investigation of all co-authors. Authorship Conditions

An author should have participated in the conception and planning of the work, the interpretation of the results and the writing of the paper. An acknowledgment accompanying the paper is appropriate recognition for others who have contributed to a lesser extent, e.g., provision of clones, antisera, or cell lines, or reading and reviewing manuscripts in draft. The signature of each author on the Affirmation of Originality and Copyright Release form that must be submitted with the manuscript indicates that all authors have had a part in the writing and final editing of the report, all have been given a copy of the manuscript, all have approved the final version of the manuscript, and all are prepared to take public responsibility for the work, sharing responsibility and accountability for the results.

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plied to the editor. Any preliminary accounts or abstracts of the work, already published, must be referenced in the complete report. The author has an obligation to: 1) describe the work in sufficient detail to allow others to repeat the work; 2) include all relevant data, including those which may not support the hypothesis being tested; 3) cite those publications which have a direct bearing on the novelty and interpretation of the results; 4) The Endocrine Society endorses the philosophy of open exchange of research materials and therefore requires that, as a condition of publication, all authors agree to make unique research resources available to other investigators for academic research purposes; 5) ensure no substitution, addition, or deletion of data or text during the proof correction process (after acceptance). Answers to author queries and changes to typographical or printer’s errors may be made to proofs. Any other changes will require that the proofs be returned to the editorial office for re-review of the manuscript; 6) clear any change in authorship with the Editor-in-Chief.

Prior Publication

Failure to notify the editor that some results in the manuscript are being or have been previously published will result in placement of a notice in the journal that the authors have violated the Ethical Guidelines for Publication of Research in Endocrine Society Journals. Copyright Assignment and Affirmation of Originality

Acceptance and publication of any article in The Endocrine Society journals is contingent upon the author’s

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warranty that the manuscript has not been published in total or in part, nor is it being submitted or considered for publication in total or in part elsewhere. In addition, the acceptance of any work for publication in The Endocrine Society journals is contingent upon the author’s assignment and transfer of rights and interest in and the copyright of that work in its current form, and in any subsequent form revised for publication to The Endocrine Society. Embargo Policy

Ingelfinger Rule

The Ingelfinger Rule is an agreement between authors and The Endocrine Society journals, whereby a paper is considered for publication on the condition that its substance has not been submitted or reported elsewhere. The Ingelfinger Rule specifically prohibits publicity about an unpublished report from the time of submission. This policy does not preclude the journal considering a paper that follows publication of a preliminary report, such as an abstract or poster displayed for colleagues at a scientific meeting. Press reports from these scheduled meetings will not usually be regarded as breaches of this rule, but such reports should not be amplified by additional data or copies of tables and illustrations. The Endocrine Society Publications Committee will investigate any breach of these policies and determine appropriate action. Obligations of Reviewers

The critical review of manuscripts is an essential stage of publication. Every scientist has an obligation to do a fair

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Obligations of Editors

The Editor-in-Chief directs and supervises the policies of a journal and is responsible for maintaining its scientific and literary quality. The first obligation of an Editor-inChief and the journal Editors is to make certain that all authors receive confidential, expert, critical, and unbiased reviews of their work in a timely fashion. The editors and members of the editor’s staff should not disclose any information about a manuscript submitted for review to anyone except the reviewers or consultants. An editor may not take part in the editorial management of any report of the editor’s own research, since that involves conflict of interest. An editor must also avoid conflict of interest in the editorial management of reports of research closely related to the editor’s own research. An editor may not use unpublished information of any kind from a submitted manuscript without written permission of the author. If an editor is presented with convincing evidence that the main substance or conclusions of a report published in an editor’s journal is erroneous, the editor should facilitate prompt publication of a report pointing out the

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The embargo policy is an agreement between reporters and the journal. All press activity and/or interactions with the media prior to the publication of an article in The Endocrine Society journals either in print or online will be initiated and coordinated by The Endocrine Society’s Department of Public Affairs in conjunction with the Society’s Media Advisory Committee. Neither authors nor their institutions and/or organizations may initiate press activity at any point while an article is under consideration for print or online publication in The Endocrine Society journals without the express prior consent of The Endocrine Society Department of Public Affairs. All articles published in The Endocrine Society journals are embargoed until 6:00 a.m. on the date of the specific issue of the journal in which that article will be published. Articles published online before the print edition of the journal are embargoed until they appear online. Additionally, The Endocrine Society’s Department of Public Affairs may alone authorize and/or coordinate press activities prior to the embargo date such as interviews, composition of press releases, and distribution of press releases before the online or print publication of an article. Any press releases that are distributed by The Endocrine Society’s Department of Public Affairs related to the journal article will carry the appropriate embargo date.

share of reviewing. The first obligation of a reviewer is to provide an expert, critical, and unbiased scientific and literary appraisal of reports of research in the fields of the reviewer’s knowledge and skills. The reviewer should return reviews promptly, within the editor’s deadline. If this cannot be done, the manuscript should be returned at once. A reviewer should not attempt to review a manuscript if: 1) the reviewer does not feel competent to judge the research described in it, or 2) the reviewer feels there may be a conflict of interest or if the reviewer feels that a close personal or professional relationship with the author or a co-author would bias judgment of the manuscript. If there is any doubt about these prohibitions, the manuscript should be returned at once to the editor with an explanation. The editor should also be notified if the reviewer has previously reviewed the manuscript for another journal. The reviewer’s criticisms of a manuscript, especially if the overall judgment is unfavorable, should be detailed and supported by appropriate references. The reviewer should note whether the work of others is properly cited. Any substantial resemblance of the manuscript being reviewed to a published paper or to a manuscript submitted at the same time to another journal must be reported to the editor. Ordinarily, no part of the manuscript under review should be revealed to anyone. If a reviewer has a collaborator or consults a colleague on some special point, this fact, and the name of the collaborator or consultant, should be reported to the editor. With these exceptions, a reviewer must obtain through the editor the written permission of the authors to use or disclose any of the unpublished content of a manuscript under review.

error and, if possible, correcting it. The report may be written by the person who discovered the error or by an original author. Due Process/Administrative Procedures

Policy Regarding Advertisements

All Endocrine Society Journals contain advertisements. They are solicited and placed without knowledge of the contents or particular order of articles in any issue. Under no circumstances are prospective purchasers of advertising space in The Endocrine Society Journals given advance information about articles that are about to appear or about their particular order. The Editors are not permitted to engage in discussions about Journal content for forthcoming issues with the business office, agencies involved in soliciting advertisements, or companies purchasing advertising space. Moreover, the appearance of any advertisements does not imply warranty, endorsement, or approval of the products or services or of their effectiveness, quality, or safety by The Endocrine Society. The Society has the prerogative to reject any advertisement it deems inappropriate. It accepts advertisements only if the advertiser warrants that the advertisement does not contravene legal requirements on trade descriptions, medicines, race relations, or sex discrimination. Bibliography

In assembling these guidelines, the Publications Committee has relied on the following published reports: 1. Code of Ethics. The Endocrine Society (Bethesda, MD). The Journal of Clinical Endocrinology & Metabolism, Endocrinology, Endocrine Reviews, and Molecular Endocrinology, 2001. http://www.endo-society.org 2. ORI Handbook for Institutional Research Integrity Officers. February 1997. Office of Research Integrity, Public Health Service, Department of Health and Human Services (Washington, DC) 3. Burman KD 1982 Hanging from the masthead: reflections on authorship. Ann Intern Med 97:602– 605 4. Responsible Conduct Regarding Scientific Communication. Society for Neuroscience, 1996, 1997, 1998. http://www.sfn.org 5. Managing Allegations of Scientific Misconduct: A Guidance Document for Editors. January 2000. Office of Research Integrity, Office of Public Health and Science, U.S. Department of Health and Human Services (Washington, DC) 6. American College of Physicians Ethics Manual. American College of Physicians. Ann Intern Med 1984; 101:129 –187, 263–274 In addition, the Committee recommends reading the following: Association of American Medical Colleges 1982 The maintenance of high ethical standards in the conduct of research. Hugh EJ 1986 Guidelines on authorship of medical papers. Ann Intern Med 104:269

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The Editor-in-Chief of each journal shall investigate all allegations of scientific misconduct with a prompt and discreet initial inquiry to assess the veracity, severity, and scope of the perceived impropriety or violation. The Editor-in-Chief shall also provide written notification to the author against whom the violation is alleged and obtain information to assist him or her in this initial inquiry. The Editor-in-Chief may delay publication of a challenged paper pending the outcome of an investigation. Confidentiality shall be maintained and all possible care shall be taken so as to protect the rights and reputations of all concerned. If the Editor-in-Chief, after consultation with members of the Editorial Board of the relevant journal, the Publications Committee, and the Ethics Advisory Committee, determines that there is reasonable cause to proceed with a further investigation, he or she shall contact the Institution with which the author is associated, and where the work was conducted. The Editor-in-Chief shall request to be informed of the progress and outcome of any inquiry or investigation, including any administrative or disciplinary action taken by the Institution as a result. In the rare event that the author against whom the allegation is made does not have an Institutional affiliation, the matter may be treated as a special case by the Publications Committee. All parties involved are expected to cooperate fully to ensure fairness in the investigation. Authors are expected to cooperate by providing access to original data and laboratory notebooks or in other ways. The accused is considered innocent of wrongdoing until the evidence or investigation indicates otherwise. Any individual who brings forward allegations in good faith shall not be subjected to retaliation; however, allegations not brought in good faith, or maliciously motivated, may be subject to disciplinary action by the Council. The outcome of the investigation shall be reported to the Council of The Endocrine Society, which reserves the right to respond to decisions or reprimand the author, and co-authors, as it deems appropriate. Sanctions may include, but are not limited to, rejection of the manuscript, dismissal from the Society for a number of years, expulsion, written notification to other professional societies, institutions, and funding agencies. If an investigation concerning a published article is determined to have contained a serious error, then a correction or retraction must be published prominently in the journal in which the original report appeared and contain the full bibliographic reference to the original article. It

shall be listed in the contents page and be prominently labeled, i.e., erratum, retraction, or apologia.

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Clinical Endocrinology Update 2005 Syllabus

HORMONES & YOU

Patient Information Page

www.hormone.org

Hormones and Your Heart

PLEASE TEAR HERE

What is cardiometabolic risk?

Who is at risk?

How is cardiometabolic risk recognized? Persons with cardiometabolic risk have several risk factors that come together. If they have one, they are likely to have others. It is the combination of the risk factors that determines if you have increased cardiometabolic risk.

EDITORS: Robert M. Carey, MD, MACP Robert S. Gibson, MD James R. Sowers, MD January 2006

Danger Zones:

Where You Want to Be:

Obesity: Waist measurement greater than 40 inches in men; greater than 35 inches in women.

A body mass index (BMI) of 18.5 to 24.9 for normal weight. (BMI is calculated from your height and weight.)

High LDL (“bad”) cholesterol: Greater than 100 mg/dl.

Less than 70 mg/dl.

Low HDL (“good”) cholesterol: Less than 40 mg/dl in men and 50 mg/dl in women.

Greater than 40 mg/dl in men and 50 mg/dl in women.

High triglycerides (blood fat): Greater than 150 mg/dl.

Less than 150 mg/dl.

High blood pressure: Systolic 130 mmHg or greater; diastolic 85 mmHg or greater.

Recommended: Systolic less than 120 mmHg and diastolic less than 80 mmHg.

Fasting blood sugar (glucose): Normal blood sugar after an 8-hour Greater than 110 mg/dl or fast is 70 to 100 mg/dl. previously diagnosed type 2 diabetes. *Even if you fall within the normal range, the lower end is better for your health.

How should cardiometabolic risk be treated? The goal of treatment is to reach the recommended levels for each separate risk factor. Changes in diet, exercise, and behavior are the first steps toward weight loss in obese patients. But if you have other medical problems, such as diabetes or heart disease, your doctor may recommend drug therapy to raise your good cholesterol, and/or lower bad cholesterol, triglycerides, blood pressure and blood sugar. All treatment options have risks. Your doctor will work with you to find the best treatment option for you. How much improvement can you expect from a healthy lifestyle and medication? One of the best things you can do to lower your risk of cardiovascular risk is to adopt a healthy lifestyle. For example,

avoid becoming overweight, exercise, eat a healthy diet, stop smoking, and be moderate in your use of alcohol. Weight loss can have a dramatic effect on improving your health. If you are overweight or obese and/or think you may have one or more of the risk factors described above, talk with your doctor. Medications that bring your risk factors under control can also improve your risk for heart disease and stroke. Resources Find-an-Endocrinologist: www.hormone.org or call 1-800-HORMONE (1-800-467-6663) Hormone Foundation fact sheets on Obesity, Diabetes, Hypertension, High Blood Fat: www.hormone.org American Heart Association: www.americanheart.org

For more information on how to find an endocrinologist, download free publications, translate this fact sheet into other languages, or make a contribution to The Hormone Foundation, visit www.hormone.org/bilingual or call 1-800-HORMONE. The Hormone Foundation, the public education affiliate of The Endocrine Society (www.endo-society.org), serves as a resource for the public by promoting the prevention, treatment, and cure of hormone-related conditions. The development of this fact sheet was supported by an unrestricted educational grant from sanofi-aventis, and may be reproduced non-commercially by healthcare professionals and health educators to share with patients and students. © The Hormone Foundation 2006

NES AND YOUR HEART

People who are obese have a greater risk of heart disease, stroke and type 2 diabetes, mainly because weight affects how insulin works in the body. Insulin, a hormone produced by the pancreas, helps manage the levels of sugar and fat (cholesterol and triglycerides) in the blood. With weight gain, insulin can become less effective so that your body does not respond well to it. When your body is resistant (or less sensitive) to insulin, more sugar ends up in the blood. This condition is called insulin resistance and can lead to diabetes. Also, high blood pressure is more common in persons with insulin resistance. However, insulin resistance sometimes happens in people who are not obese, and it increases their cardiometabolic risk just as it does in obese people.

Cardiometabolic Risk Factors

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The term cardiometabolic risk describes a person’s chances of damaging their heart and blood vessels when one or more risk factors cluster together. Risk factors include obesity, high LDL (“bad”) cholesterol, high blood fat (triglycerides), low HDL (“good”) cholesterol, high blood pressure, and insulin resistance. Each of these risk factors is dangerous on its own, but a combination greatly increases the risk of heart disease and stroke. Metabolic syndrome, syndrome X, and insulin resistance syndrome are other terms for this cluster of risk factors.

LAS HORMONAS Y USTED

Página de información para pacientes

www.hormone.org

Las hormonas y el corazón

¿Qué es el riesgo cardiometabólico?

Factores de riesgo cardiometabólico

LAS HORMONAS Y EL CORAZÓN

¿Quién está a riesgo?

Donde debe estar usted:

Obesidad: Una medida de cintura de Un índice de masa corporal (IMC) de más de 100 centímetros (40 pulgadas) 18.5 a 24.9 para un peso normal. (El en los hombres y de más de 90 IMC se calcula según la estatura y el peso.) centímetros (35 pulgadas) en las mujeres. Alto colesterol LDL (el “malo”): Más de 100 mg/dl.

Menos de 70 mg/dl.

Bajo colesterol HDL (el “bueno”): Menos de 40 mg/dl en los hombres y 50 mg/dl en las mujeres.

Más de 40 mg/dl en hombres y 50 mg/dlen las mujeres.

Triglicéridos (grasa en la sangre) elevados: Más de 150 mg/dl.

Menos de 150 mg/dl.

Presión sanguínea alta: Presión sistólica de 130 mmHg o más, diastólica de 85 mmHg o más.

Se recomienda una presión sistólica de menos de 120 mmHg, y una diastólica de menos de 80 mmHg.

Azúcar (glucosa) en la sangre en ayunas: Más de 110 mg/dl ó un diagnóstico previo de diabetes tipo 2.

El azúcar normal en la sangre después de ayunar 8 horas es de 70 a 100 mg/dl.

*Aunque usted esté dentro de los límites normales, el límite bajo es mejor para su salud.

Las personas obesas tienen un mayor riesgo de enfermedad cardiaca, derrame cerebral y diabetes tipo 2, principalmente porque el peso afecta la manera en que la insulina actúa en el cuerpo. La insulina, una hormona producida por el páncreas, ayuda a controlar los niveles de azúcar y grasa (el colesterol y los triglicéridos) en la sangre. El aumento de peso puede hacer que la insulina sea menos eficaz de manera que el cuerpo no responde tan bien como debe. Cuando el cuerpo es resistente (o menos susceptible) a la insulina, se acumula más azúcar en la sangre. Esta condición se llama resistencia a la insulina y puede conducir a la diabetes. También, la presión sanguínea alta es más común en personas que tienen resistencia a la insulina. Sin embargo, la resistencia a la insulina a veces ocurre en personas que no son obesas y les aumenta el riesgo cardiometabólico tanto como aumenta en las personas obesas. ¿Cómo se reconoce el riesgo cardiometabólico? Las personas con riesgo cardiometabólico tienen varios factores de riesgo que se agrupan. Si tienen uno, es probable que tengan otros. Es la combinación de los

EDITORES: Robert M. Carey, MD, MACP Robert S. Gibson, MD James R. Sowers, MD Enero 2006

Zonas peligrosas:

factores de riesgo lo que determina si usted está a mayor riesgo cardiometabólico. ¿Cómo se debe tratar el riesgo cardiometabólico? El objetivo del tratamiento es llegar a los niveles recomendados para cada factor de riesgo. Cambios en la dieta, el ejercicio y el comportamiento son los primeros pasos hacia la pérdida de peso en los pacientes obesos. Pero si usted tiene otros problemas médicos, tales como diabetes o enfermedad cardiaca, su médico puede recomendarle terapia con medicamentos para elevar su colesterol bueno y/o bajar su colesterol malo, triglicéridos, presión sanguínea, y azúcar en la sangre. Todas las opciones de tratamiento tienen riesgos. Su médico trabajará con usted para encontrar el tratamiento que más le conviene. ¿Qué tanta mejoría puedo esperar de un estilo de vida saludable y medicamentos?

hacer para reducir su riesgo cardiovascular es adoptar un estilo de vida saludable. Por ejemplo, evite el exceso de peso, haga ejercicio, mantenga una dieta saludable, pare de fumar y beba alcohol en moderación. La pérdida de peso puede tener un efecto impresionante en mejorarle la salud. Si tiene un exceso de peso o es obeso y cree que puede tener uno o más de los factores de riesgo descritos anteriormente, hable con su médico. Los medicamentos que controlan sus factores de riesgo también pueden mejorar el riesgo de enfermedad cardiaca y derrame cerebral. Recursos Encuentre un endocrinólogo: visite a www.hormone.org o llame al 1-800-467-6663 Hojas informativas de la Fundación de Hormonas sobre la Obesidad, la Diabetes, Hipertensión, Grasa sanguínea elevada: www.hormone.org Asociación Americana del Corazón: www.americanheart.org

Una de las mejores cosas que puede

Para más información sobre cómo encontrar un endocrinólogo, obtener publicaciones de la Internet, traducir esta hoja de datos a otros idiomas, o hacer una contribución monetaria a la Fundación de Hormonas, visite a www.hormone.org/bilingual o llame al 1-800-HORMONE (1-800-467-6663). La Fundación de Hormonas, la filial de enseñanza pública de la Sociedad de Endocrinología (www.endo-society.org), sirve de recurso al público para promover la prevención, tratamiento y cura de condiciones hormonales. La creación de esta hoja de datos fue apoyada por una donación educacional de sanofi-aventis; la página puede ser reproducida para fines no comerciales por los profesionales médicos y educativos que deseen compartirla con sus pacientes y estudiantes. © La Fundación de Hormonas 2006

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El término riesgo cardiometabólico describe la posibilidad de que a una persona se le perjudique el corazón o los vasos sanguíneos cuando se agrupan varios factores de riesgo. Los factores de riesgo incluyen la obesidad, el colesterol elevado de lipoproteínas de baja densidad (LDL— colesterol “malo”), exceso de grasa en la sangre (triglicéridos), el colesterol alto de lipoproteínas de alta densidad (HDL— colesterol “bueno”), presión sanguínea alta y resistencia a la insulina. Cada uno de estos factores es peligroso por sí solo pero cuando se combinan, aumenta grandemente el riesgo de enfermedad cardiaca y derrame cerebral. Síndrome metabólico, síndrome X y síndrome de resistencia a la insulina son otros términos para esta agrupación de factores de riesgo.



          

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ENDO O6 June 24 to 27

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AN OPPORTUNITY THIS GOOD ONLY COMES AROUND ONCE A YEAR. ENDO 2006 is designed to deliver the richness and depth of smaller meeting formats with the breadth and scope that only the world’s largest gathering of endocrinologists can provide. Rather than a single theme, there will be four special emphasis areas for each of the four meeting days:

The Endocrine Society’s 88 th Annual Meeting

•

The Endocrine Brain

•

Metabolic Syndrome and Growth Factor Signaling

•

Controversies in Endocrinology

•

Stem Cells and Transplantation

This new format offers an unprecedented opportunity to learn the latest advances in endocrine research and clinical care, while networking and collaborating with more than 6,000 colleagues from around the world.

To learn more visit www.endo-society.org

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