Janumet, INN-Sitagliptin/Metformin
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Metformin Plus Saxagliptin for Type 2 Diabetes
Treatment evaluation Metformin plus saxagliptin for type 2 diabetes André J. Scheen Division of Diabetes, Nutrition and Metabolic Disorders and Division of Clinical Pharmacology, Department of Medicine, CHU Sart Tilman, University of Liège, Liège, Belgium Running title : Saxagliptin plus metformin Word count : Abstract : 148 Main text : 2404 Tables : 4 Figures : 0 Address for correspondence : Pr André J. SCHEEN Department of Medicine CHU Sart Tilman (B35) B-4000 LIEGE 1 BELGIUM Phone : 32-4-3667238 FAX : 32-4-3667068 Page 1 Email : andre.scheen @ chu.ulg.ac.be SUMMARY Metformin is considered as the first-line drug therapy for the management of type 2 diabetes. Dipeptidyl peptidase-4 (DPP-4) inhibitors, by promoting insulin secretion and reducing glucagon secretion in a glucose-dependent manner, offer new opportunities for oral therapy after failure of metformin. Saxagliptin, a DPP-4 inhibitor, and metformin may be administered together, separately or in fixed-dose combination (FDC), either as saxagliptin added to metformin or as initial combination in drug-naive patients. Both compounds exert complementary pharmacodynamic actions leading to better improvement in blood glucose control (fasting plasma glucose, postprandial glucose, HbA1c) than either compound separately. Adding saxagliptin to metformin monthotherapy results in a consistent, sustained and safe reduction in HbA1c levels. Tolerance is excellent without hypoglycemia or weight gain. The combination saxaglitpin plus metformin may be used as first-line or second-line therapy in the management of type 2 diabetes, especially as a valuable alternative to the classical metformin-sulfonylurea combination. Key-words : DPP-4 inhibitor – Fixed-dose combination - Metformin – Saxagliptin - Type 2 diabetes mellitus Page 2 1. -
Treatment of Diabetes Mellitus
TREATMENT OF DIABETES MELLITUS DIABETES is a condition that affects how the body makes energy from food. Food is broken down into sugar (glucose) in the body and released into the blood. When the blood sugar level rises after a meal, insulin responds to let the sugar into the cells to be used as energy. In diabetes, the body either does not make enough insulin or it stops responding to insulin as well as it should. This results in sugar staying in the blood and leads to serious health problems over time. DIAGNOSIS OF DIABETES1 • A1C Test: Lab test measuring average blood sugar over past two to three months • Fasting Blood Sugar Test: Lab test measuring blood sugar after eight hours of no food or drink • Oral Glucose Tolerance Test (OGTT): Measures blood sugar before and two hours after drinking a specific sugary liquid • Random Blood Sugar Test: Measures blood sugar at a moment in time, without any kind of preparation (like fasting) FASTING BLOOD ORAL GLUCOSE TOLERANCE RANDOM BLOOD RESULT A1C TEST SUGAR TEST TEST SUGAR TEST Diabetes ≥ 6.5% ≥126 mg/dL ≥ 200 mg/dL ≥ 200 mg/dL Prediabetes 5.7 – 6.4% 100 – 125 mg/dL 140 – 199 mg/dL N/A Normal < 5.7% ≤99 mg/dL < 140 mg/dL N/A NON-DRUG TREATMENTS2 THERAPY COST WHAT TO EXPECT Diet (Mediterranean diet) and exercise (30 minutes a day, five days a week of moderate- Weight loss $-$$ intensity exercise); 7% weight loss decreases risk of diabetes3 Psychological intervention $$-$$$ Psychotherapy may reduce diabetic distress and improve glycemic control4,5 nationalcooperativerx.com PRESCRIPTION TREATMENTS -
CD26/DPP-4: Type 2 Diabetes Drug Target with Potential Influence On
cancers Review CD26/DPP-4: Type 2 Diabetes Drug Target with Potential Influence on Cancer Biology Emi Kawakita 1 , Daisuke Koya 2,3 and Keizo Kanasaki 1,3,* 1 Internal Medicine 1, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo 693-8501, Japan; [email protected] 2 Department of Diabetology & Endocrinology, Kanazawa Medical University, Uchinada 920-0293, Japan; [email protected] 3 Division of Anticipatory Molecular Food Science and Technology, Medical Research Institute, Kanazawa Medical University, Uchinada 920-0293, Japan * Correspondence: [email protected]; Tel.: +81-853-20-2183 Simple Summary: Dipeptidyl peptidase (DPP)-4 inhibitor is widely used for type 2 diabetes. Al- though DPP-4/CD26 has been recognized as both a suppressor and inducer in tumor biology due to its various functions, how DPP-4 inhibitor affects cancer progression in diabetic patients is still unknown. The aim of this review is to summarize one unfavorable aspect of DPP-4 inhibitor in cancer-bearing diabetic patients. Abstract: DPP-4/CD26, a membrane-bound glycoprotein, is ubiquitously expressed and has diverse biological functions. Because of its enzymatic action, such as the degradation of incretin hormones, DPP-4/CD26 is recognized as the significant therapeutic target for type 2 diabetes (T2DM); DPP- 4 inhibitors have been used as an anti-diabetic agent for a decade. The safety profile of DPP-4 inhibitors for a cardiovascular event in T2DM patients has been widely analyzed; however, a clear association between DPP-4 inhibitors and tumor biology is not yet established. Previous preclinical Citation: Kawakita, E.; Koya, D.; Kanasaki, K. -
Januvia (Sitagliptin) Tablets
CENTER FOR DRUG EVALUATION AND RESEARCH Approval Package for: APPLICATION NUMBER: NDA 021995/S-013 Trade Name: JANUVIA Generic Name: Sitagliptin Sponsor: Merck & Co., Inc. Approval Date: 12/28/2009 Indications: JANUVIA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: NDA 021995/S-013 CONTENTS Reviews / Information Included in this NDA Review. Approval Letter X Other Action Letters X Labeling X Summary Review Officer/Employee List Office Director Memo Cross Discipline Team Leader Review Medical Review(s) X Chemistry Review(s) Environmental Assessment Pharmacology Review(s) X Statistical Review(s) Microbiology Review(s) Clinical Pharmacology/Biopharmaceutics Review(s) Risk Assessment and Risk Mitigation Review(s) X Proprietary Name Review(s) Other Review(s) X Administrative/Correspondence Document(s) X CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: NDA 021995/S-013 APPROVAL LETTER DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration Silver Spring MD 20993 NDA 021995/S-013 SUPPLEMENT APPROVAL Merck & Co., Inc. Attention: Richard J. Swanson, Ph.D. Director, Regulatory Affairs P.O. Box 1000, UG2C-50 North Wales, PA 19454-1099 Dear Dr. Swanson: Please refer to your supplemental new drug application (S-013) dated and received March 5, 2009, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for Januvia (sitagliptin) tablets. We also refer to your supplemental new drug application (b) (4) dated and received November 13, 2009. Your submission of November 13, 2009, also constitutes a complete response to our October 16, 2009, action letter for supplemental application S-013. -
Komboglyze, INN-Saxagliptin, Metformin
ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 1. NAME OF THE MEDICINAL PRODUCT Komboglyze 2.5 mg/850 mg film-coated tablets Komboglyze 2.5 mg/1,000 mg film-coated tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Komboglyze 2.5 mg/850 mg film-coated tablets Each tablet contains 2.5 mg of saxagliptin (as hydrochloride) and 850 mg of metformin hydrochloride. Komboglyze 2.5 mg/1,000 mg film-coated tablets Each tablet contains 2.5 mg of saxagliptin (as hydrochloride) and 1,000 mg of metformin hydrochloride. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Film-coated tablet (tablet). Komboglyze 2.5 mg/850 mg film-coated tablets Light brown to brown, biconvex, round, film-coated tablets, with “2.5/850” printed on one side and “4246” printed on the other side, in blue ink. Komboglyze 2.5 mg/1,000 mg film-coated tablets Pale yellow to light yellow, biconvex, oval shaped, film-coated tablets, with “2.5/1000” printed on one side and “4247” printed on the other side, in blue ink. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Komboglyze is indicated in adults with type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycaemic control: in patients inadequately controlled on their maximally tolerated dose of metformin alone in combination with other medicinal products for the treatment of diabetes, including insulin, in patients inadequately controlled with metformin and these medicinal products (see sections 4.4, 4.5 and 5.1 for available data on different combinations) in patients already being treated with the combination of saxagliptin and metformin as separate tablets. -
Pharmacokinetics of Omarigliptin, a Once-Weekly Dipeptidyl Peptidase-4 Inhibitor
Available online a t www.derpharmachemica.com ISSN 0975-413X Der Pharma Chemica, 2016, 8(12):292-295 CODEN (USA): PCHHAX (http://derpharmachemica.com/archive.html) Mini-review: Pharmacokinetics of Omarigliptin, a Once-weekly Dipeptidyl Peptidase-4 Inhibitor Nermeen Ashoush a,b aClinical Pharmacy and Pharmacy Practice Department, Faculty of Pharmacy, British University in Egypt, El- Sherouk city, Cairo 11837, Egypt. bHead of Health Economics Unit, Center for Drug Research and Development (CDRD), Faculty of Pharmacy, British University in Egypt, El-Sherouk city, Cairo 11837, Egypt. _____________________________________________________________________________________________ ABSTRACT The dipeptidyl peptidase-4 (DPP-4) inhibitors are novel oral hypoglycemic drugs which have been in clinical use for the past 10 years. The drugs are safe, weight neutral and widely prescribed. There are currently many gliptins approved by FDA, namely sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin with several more in advanced stages of development. The gliptins may possess cardiovascular protective effects and their administration may promote β-cell survival; claims currently being evaluated in clinical and preclinical studies. The gliptins are an optional second-line therapy after metformin; they are generally well tolerated with low risk of hypoglycemia. The various compounds differ with respect to their pharmacokinetic properties; however, their clinical efficacy appears to be similar. The clinical differences between the various compounds -
TREATMENT of TYPE 2 DIABETES with BIPHASIC INSULIN ANALOGUES *Ali A
TREATMENT OF TYPE 2 DIABETES WITH BIPHASIC INSULIN ANALOGUES *Ali A. Rizvi Professor of Medicine, Department of Medicine and Director, Division of Endocrinology, University of South Carolina School of Medicine, Columbia, South Carolina, USA *Correspondence to [email protected] Disclosure: The author has received grant support, as principal investigator at the University of South Carolina site, from the National Institutes of Health (NIH) for the SPRINT Trial (Contract Number: HHSN268200900040C, ClinicalTrials.gov Identifier: NCT01206062). The contents of this paper do not necessarily represent the views of the NIH. Received: 29.03.16 Accepted: 09.09.16 Citation: EMJ Diabet. 2016;4[1]:74-83. ABSTRACT The majority of patients with Type 2 diabetes require insulin therapy for treating hyperglycaemia. There are several regimens available for insulin initiation and maintenance. Insulin analogues have been developed to mimic normal physiology as closely as possible. Biphasic analogues can target both fasting and postprandial hyperglycaemia, with the added advantage of being premixed and thus convenient for the patient. A practical and feasible option is to initiate insulin with one or more biphasic preparations at mealtimes, thus providing both basal and prandial coverage. Individual titration of dose and frequency of daily injections with biphasic insulin preparations has the potential for improving glycaemic control with a high degree of patient acceptance. Drawbacks include a more rigid regimen, a relative lack of flexibility, and a somewhat higher degree of glycaemic variability and hypoglycaemia when compared to multiple daily basal-bolus injections. Awareness of the advantages and limitations of biphasic insulin analogues can assist clinicians in their appropriate use for the treatment of patients with Type 2 diabetes. -
Sitagliptin: a New Class of Oral Drug for Type 2 Diabetes
JK SCIENCE DRUG REVIEW Sitagliptin: a New Class of Oral Drug for Type 2 Diabetes Dinesh K. Badyal, Jasleen Kaur Introduction Pharmacokinetics Type 2 diabetes is the most common form of the Bioavailability of sitagliptin is approximately 87%. Half- disease, accounting for about 90% to 95 % of all diagnosed life is between 8-14 hours. It is 38% bound to plasma cases of diabetes. In type 2 diabetes, the body does not proteins. It undergoes limited metabolism via CYP3A4 produce enough insulin or the cells ignore the insulin. and CYP2C8. Elimination is mainly through urine (5, 6). Over time, high blood sugar levels can increase the risk Clinical Use for serious complications, including heart disease, In October 2006, the U.S. Food and Drug blindness, nerve damage and kidney damage (1). Any Administration (FDA) approved sitagliptin as new oral hypoglycemic drug that can increase the control monotherapy and as add-on therapy to either of two other of blood glucose with fewer adverse effects in patients types of oral diabetes medications, metformin or with diabetes may be welcomed. Sitagliptin is the first thiazolidinediones to improve blood glucose control in and only prescription medication in a new class of oral patients with type 2 diabetes when diet and exercise are antihyperglycemic agents, which enhance the body's own not enough (5). In March, 2007 it was approved in ability to lower blood glucose when it is elevated (2). European Union. Sitagliptin is currently approved in 42 Mechanism of Action countries (7). The recommended dose of sitagliptin is Sitagliptin prolongs the activity of proteins that increase 100 mg once daily. -
Safety and Efficacy of Omarigliptin (MK-3102), a Novel Once-Weekly
2106 Diabetes Care Volume 38, November 2015 fi Wayne H.-H. Sheu,1 Ira Gantz,2 Safety and Ef cacy of Omarigliptin Menghui Chen,2 Shailaja Suryawanshi,2 Arpana Mirza,2 Barry J. Goldstein,2 (MK-3102), a Novel Once-Weekly Keith D. Kaufman,2 and Samuel S. Engel2 DPP-4 Inhibitor for the Treatment of Patients With Type 2 Diabetes Diabetes Care 2015;38:2106–2114 | DOI: 10.2337/dc15-0109 OBJECTIVE This study was conducted to determine the optimal dose of omarigliptin, a once- weekly (q.w.) dipeptidyl peptidase IV (DPP-4) inhibitor, for the treatment of patients with type 2 diabetes and evaluate the long-term safety of that dose. RESEARCH DESIGN AND METHODS In a multicenter, double-blind, 12-week, dose-range finding study, 685 oral antihy- perglycemic agent-na¨ıve or washed-out subjects with type 2 diabetes were random- ized to one of five once-weekly doses of omarigliptin (0.25 mg, 1 mg, 3 mg, 10 mg, or 25 mg) or placebo. The primary efficacy end point was change from baseline in HbA1c, and secondary end points were 2-h postmeal glucose (PMG) and fasting plasma glucose (FPG). Analysis included all patients who received at least one dose of the study medication. Subjects who completed the base study were eligible to enter a 66-week extension study. RESULTS Once-weekly treatment for 12 weeks with omarigliptin provided dose-related reduc- 1Division of Endocrinology and Metabolism, De- partment of Internal Medicine, Taichung Veterans EMERGING TECHNOLOGIES AND THERAPEUTICS tions in HbA , 2-h PMG, and FPG. -
AVANDIA (Rosiglitazone Maleate Tablets), for Oral Use Ischemic Cardiovascular (CV) Events Relative to Placebo, Not Confirmed in Initial U.S
HIGHLIGHTS OF PRESCRIBING INFORMATION ----------------------- WARNINGS AND PRECAUTIONS ----------------------- These highlights do not include all the information needed to use • Fluid retention, which may exacerbate or lead to heart failure, may occur. AVANDIA safely and effectively. See full prescribing information for Combination use with insulin and use in congestive heart failure NYHA AVANDIA. Class I and II may increase risk of other cardiovascular effects. (5.1) • Meta-analysis of 52 mostly short-term trials suggested a potential risk of AVANDIA (rosiglitazone maleate tablets), for oral use ischemic cardiovascular (CV) events relative to placebo, not confirmed in Initial U.S. Approval: 1999 a long-term CV outcome trial versus metformin or sulfonylurea. (5.2) • Dose-related edema (5.3) and weight gain (5.4) may occur. WARNING: CONGESTIVE HEART FAILURE • Measure liver enzymes prior to initiation and periodically thereafter. Do See full prescribing information for complete boxed warning. not initiate therapy in patients with increased baseline liver enzyme levels ● Thiazolidinediones, including rosiglitazone, cause or exacerbate (ALT >2.5X upper limit of normal). Discontinue therapy if ALT levels congestive heart failure in some patients (5.1). After initiation of remain >3X the upper limit of normal or if jaundice is observed. (5.5) AVANDIA, and after dose increases, observe patients carefully for signs • Macular edema has been reported. (5.6) and symptoms of heart failure (including excessive, rapid weight gain; • Increased incidence of bone fracture was observed in long-term trials. dyspnea; and/or edema). If these signs and symptoms develop, the heart (5.7) failure should be managed according to current standards of care. -
Type 2 Diabetes Adult Outpatient Insulin Guidelines
Diabetes Coalition of California TYPE 2 DIABETES ADULT OUTPATIENT INSULIN GUIDELINES GENERAL RECOMMENDATIONS Start insulin if A1C and glucose levels are above goal despite optimal use of other diabetes 6,7,8 medications. (Consider insulin as initial therapy if A1C very high, such as > 10.0%) 6,7,8 Start with BASAL INSULIN for most patients 1,6 Consider the following goals ADA A1C Goals: A1C < 7.0 for most patients A1C > 7.0 (consider 7.0-7.9) for higher risk patients 1. History of severe hypoglycemia 2. Multiple co-morbid conditions 3. Long standing diabetes 4. Limited life expectancy 5. Advanced complications or 6. Difficult to control despite use of insulin ADA Glucose Goals*: Fasting and premeal glucose < 130 Peak post-meal glucose (1-2 hours after meal) < 180 Difference between premeal and post-meal glucose < 50 *for higher risk patients individualize glucose goals in order to avoid hypoglycemia BASAL INSULIN Intermediate-acting: NPH Note: NPH insulin has elevated risk of hypoglycemia so use with extra caution6,8,15,17,25,32 Long-acting: Glargine (Lantus®) Detemir (Levemir®) 6,7,8 Basal insulin is best starting insulin choice for most patients (if fasting glucose above goal). 6,7 8 Start one of the intermediate-acting or long-acting insulins listed above. Start insulin at night. When starting basal insulin: Continue secretagogues. Continue metformin. 7,8,20,29 Note: if NPH causes nocturnal hypoglycemia, consider switching NPH to long-acting insulin. 17,25,32 STARTING DOSE: Start dose: 10 units6,7,8,11,12,13,14,16,19,20,21,22,25 Consider using a lower starting dose (such as 0.1 units/kg/day32) especially if 17,19 patient is thin or has a fasting glucose only minimally above goal. -
Januvia (Sitagliptin)
UnitedHealthcare Pharmacy Clinical Pharmacy Programs Program Number 2021 P 3084-7 Program Step Therapy – Diabetes Medications- DPP4 Inhibitors Medication Januvia (sitagliptin)*, Janumet (sitagliptin/metformin immediate- release)*, Janumet XR (sitagliptin/metformin extended-release)* P&T Approval Date 10/2016, 10/2017, 1/2018, 10/2019, 4/2020, 5/2020, 5/2021 Effective Date 8/1/2021; Oxford only: 8/1/2021 1. Background: Januvia (sitagliptin)* is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Janumet (sitagliptin/metformin)* and Janumet XR (sitagliptin/metformin extended-release)* are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both sitagliptin and metformin/metformin extended-release is appropriate. 2. Coverage Criteriaa: A. Januvia* will be approved based on the following criterion: 1. History of a three month trial resulting in a therapeutic failure, contraindication (e.g. risk factors for heart failure), or intolerance to both of the following (list reason for therapeutic failure, contraindication, or intolerance)b: a. Tradjenta (linagliptin) -AND- b. One of the following: (1) Nesina (alogliptin) (2) Onglyza (saxagliptin) Authorization will be issued for 12 months B. Janumet* and Janumet XR* will be approved based on the following criterion: 1. History of a three month trial resulting in a therapeutic failure, contraindication (e.g. risk factors for heart failure), or intolerance to all of the following (list reason for therapeutic failure, contraindication, or intolerance)b: a. Jentadueto (linagliptin/metformin immediate-release)/Jentadueto XR (linagliptin/metformin extended-release) -AND- b.