Should Fda Change Metformin's Black Box Warning?
Diabetes experts are building a case to lift restrictions on using metformin in patients with moderate chronic kidney disease. Two groups of researchers who have separately filed citizens petitions with the FDA have published studies in JAMA journals in the past few weeks showing a lack of evidence for metformin-associated lactic acidosis -- a severe complication that prompted the FDA to warn against the drug's use in CKD patients when it came on the market 20 years ago. Silvio Inzucchi, MD, and Kasia Lipska, MD, MHS, of Yale, published a review in the Dec. 24/31 issue of JAMA concluding that most observational data -- there are no randomized controlled trials -- confirm the "overall safety profile" of metformin in mild-to-moderate CKD patients. And James Flory, MD, of Weill Cornell, and Sean Hennessy, PharmD, PhD, of the University of Pennsylvania, reported in a research letter in the Jan. 5 issue of the Archives of Internal Medicine, that nearly 1 million patients who have diabetes and CKD could be taking metformin but aren't. Both groups have asked the FDA to lift its black box warning that limits prescribing in CKD patients based on serum creatinine levels (1.5 mg/dL or above for men, 1.4 mg/dL for women), and asks the agency to use eGFR cutoffs instead -- typically, at 30 mL/min, where several professional societies and other international regulators draw the line. How the Black Box Came to Be When the FDA approved metformin in 1994, it slapped on the black box warning about lactic acidosis because of a similar problem with another biguanide, phenformin. This cousin to metformin was withdrawn from the market in 1977 because of an increased risk of lactic acidosis. Since metformin is also renally cleared, the agency was concerned that metabolism of the drug could co Continue reading >>
Glucophage
GLUCOPHAGE® (metformin hydrochloride) Tablets GLUCOPHAGE® XR (metformin hydrochloride) Extended-Release Tablets DESCRIPTION GLUCOPHAGE® (metformin hydrochloride) Tablets and GLUCOPHAGE® XR (metformin hydrochloride) Extended-Release Tablets are oral antihyperglycemic drugs used in the management of type 2 diabetes. Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. The structural formula is as shown: Metformin hydrochloride is a white to off-white crystalline compound with a molecular formula of C4H11N5 HCl and a molecular weight of 165.63. Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pK of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. GLUCOPHAGE tablets contain 500 mg, 850 mg, or 1000 mg of metformin hydrochloride. Each tablet contains the inactive ingredients povidone and magnesium stearate. In addition, the coating for the 500 mg and 850 mg tablets contains hypromellose and the coating for the 1000 mg tablet contains hypromellose and polyethylene glycol. GLUCOPHAGE XR contains 500 mg or 750 mg of metformin hydrochloride as the active ingredient. GLUCOPHAGE XR 500 mg tablets contain the inactive ingredients sodium carboxymethyl cellulose, hypromellose, microcrystalline cellulose, and magnesium stearate. GLUCOPHAGE XR 750 mg tablets contain the inactive ingredients sodium carboxymethyl cellulose, hypromellose, and magnesium stearate. System Components And Performance GLUCOPHAGE XR comprises a dual hydrophilic polymer matrix system. Metformin hydrochloride is combined with a drug release controlling polymer to form an “inne Continue reading >>
Metformin In The Diabetic Elderly Patient: An Old, Safe And Effective Treatment
Over-65 diabetics represent about half of the patients visiting general practitioners. Although diabetes pathogenesis in geriatric and young age are similar, treatment gold standards and clinical conditions are extremely variable, requiring a more individualised approach.1 In this context, a recent review points out that there is no clear evidence for the optimal glycaemic target in the elderly patient and that patient’s preferences and pharmacologic burden must be taken into consideration, within the therapeutic choices, together with the possible risks and benefits associated to single treatments.2 This study also suggests a HbA1c value between 7.5% and 9.0% as optimal glycaemic target in the elderly patient. Steps for the individualised treatment of diabetes in the elderly patient:2 Estimate desired benefits upon the life expectancy Estimate the risks potentially associated with intensive glycaemic control (age, polypharmacy, disease duration, social support) Identify the desired glycaemic target Minimise the risk of polypharmacy Consider patient preferences Adapted by bibliographic reference 2 Particularly in the elderly patient, the onset of hypoglycaemia is often associated with severe consequences and is facilitated by several factors, such as polypharmacy and the risk of subsequent interactions, the mistakes caused by the reduced ability of handling medicines, the inability of evaluating the relation between ingested carbohydrates and the therapy, the scarce symptomatology of neuropathies and the reduced adrenergic reaction.3 Hypoglycaemia absolute risk increases with age, therefore in elderly diabetics it is often preferable to avoid intensive hypoglycaemic treatments that increase the risk of hypoglycaemia4 whilst low hypoglycaemia risk treatments should be Continue reading >>
Contraindications To The Use Of Metformin
Contraindications to the use of metformin Evidence suggests that it is time to amend the list Department of Diabetes, Gartnavel General Hospital, Glasgow G12 0YN Copyright 2003, BMJ Publishing Group Ltd This article has been cited by other articles in PMC. According to the United Kingdom prospective diabetes study, patients with type 2 diabetes randomised to intensive treatment with metformin, sulphonylurea, or insulin had similar degrees of glycaemic control and significantly reduced microvascular end points. 1 The study showed that the use of metformin in obese patients reduced cardiovascular events. The group treated with metformin had no hypoglycaemia and less weight gain. Treatment with metformin rather than diet alone produced a significant reduction in relative risk in all cause mortality (36%, P=0.011), diabetes related deaths (42%, P=0.017), any diabetes related end point (32%, P=0.0023), and myocardial infarction (39%, P=0.01). Metformin is the only oral hypoglycaemic agent proved to reduce cardiovascular risk and is now recognised as the treatment of choice in overweight patients with type 2 diabetes. Lactic acidosis associated with metformin is a rare condition with an estimated prevalence of one to five cases per 100 000. 2 Although classically lactic acidosis associated with metformin has been thought of as lactic acidosis secondary to accumulation of metformin, the evidence for this is poor. Metformin does not affect lactate concentrations in patients with type 2 diabetes, 3 is excreted solely through the kidney, and has a short half lifeaccumulation of metformin therefore rarely occurs in the absence of advanced renal failure. 4 Accumulation of metformin alone is rarely reported as a cause of lactic acidosis, and tissue hypoxia acting as a trigger is fo Continue reading >>
Metformin Use In Renal Impairment Extended
For patients with a creatinine clearance of 45–59ml/min or an eGFR of 45–59ml/min/1.73m2, the initial dose of metformin is 500mg or 850mg once daily in the morning with food. The maximum daily dose is 1g in two divided doses with monitoring of renal function every 3–6 months. This change to the prescribing information reflects the advice given in the NICE clinical guideline on the management of type II diabetes, namely that metformin can be used with caution in patients with renal impairment but the dose should be reviewed if the patient's eGFR drops below 45ml/min/1.73m2 and treatment discontinued if the eGFR drops below 30ml/min/1.73m2. The metformin drug entry in MIMS has been updated to reflect the current Glucophage SPCs. The MIMS drug listings for products containing metformin in combination with other drugs (eg, dipeptidyl peptidase 4 inhibitors, SGLT2 inhibitors, pioglitazone) will be updated when the updated SPCs become available. Prescribers should refer to the product SPCs to check if a combination product is suitable for an individual patient with renal impairment. Follow MIMS on Twitter Continue reading >>
Metformin, Heart Failure, And Lactic Acidosis: Is Metformin Absolutely Contraindicated?
Many patients with type 2 diabetes are denied treatment with metformin because of “contraindications” such as cardiac failure, which may not be absolute contraindications Summary points Treatment with metformin is not associated with an increased risk of lactic acidosis among patients with type 2 diabetes mellitus who have no cardiac, renal, or liver failure Despite increasing disregard of contraindications to metformin by physicians, the incidence of lactic acidosis has not increased, so metformin may be safe even in patients with “contraindications” The vast majority of case reports relating metformin to lactic acidosis report at least one other disease/illness that could result in lactic acidosis Use of metformin in patients with heart failure might be associated with lower mortality and morbidity, with no increase in hospital admissions and no documented increased risk of lactic acidosis Further studies are needed to assess the risk of lactic acidosis in patients with type 2 diabetes and traditional contraindications to metformin Metformin first became available in the United Kingdom in 1957 but was first prescribed in the United States only in 1995.w1 The mechanism of action has been extensively reviewed.w2 w3 The UK prospective diabetes study showed that metformin was associated with a lower mortality from cardiovascular disease than sulphonylureas or insulin in obese patients with type 2 diabetes mellitus.1 It was also associated with reduced all cause mortality, which was not seen in patients with equally well controlled blood glucose treated with sulphonylureas or insulin.1 Despite the evidence base for the benefits of metformin, concerns remain about its side effects and especially the perceived risk of lactic acidosis in the presence of renal, hepatic Continue reading >>
Metformin May Be Effective In Previous Contraindications
Metformin May Be Effective in Previous Contraindications A recent review of current outcome data regarding metformin, a first-line drug for type 2 diabetes mellitus in the United States since the mid-1990s, has prompted new assessment of the drugs association with reduced mortality rates in patients with chronic kidney disease (CKD), congestive heart failure (CHF), and chronic liver disease (CLD). Concerns about lactic acidosis have limited the use of metformin in patients with CKD, CHF, and CLD. But, a safety announcement from the US Food and Drug Administration (FDA) in April 2016 allowed it to be used to treat certain patients with reduced kidney function. The review, published in the February 2017 issue of Annals of Internal Medicine , supported the FDAs decision and encouraged additional clinical trials to examine the effectiveness of the drug in the setting of previously contraindicated conditions. The review was supported by the US Veterans Affairs Administration in conjunction with the Durham Center for Health Services Research and Development in Primary Care. The systematic review examined existing studies, all-cause mortality, and major cardiovascular events in patients with CKD (estimated glomerular filtration rate < 60 mL/minute/1.73 m2), CHF, or CLD with hepatic impairment. Lead author Matthew J. Crowley, MD, a Duke endocrinologist and researcher, says the findings indicate metformin use may be associated with lower rates of mortality in patients with mild to moderate CKD, CHF, and CLD. This is an important topic for clinical practice because metformin has traditionally been withheld from patients with these conditions, and recent FDA changes may not be widely recognized, Crowley says. Theres justification now for using metformin more broadly. Crowley and Continue reading >>
Contraindications To Metformin Therapy Among Patients With Type 2 Diabetes Mellitus
, Volume 29, Issue6 , pp 587592 | Cite as Contraindications to metformin therapy among patients with type 2 diabetes mellitus The biguanide, metformin, is a commonly prescribed oral antihyperglycemic agent. However, there are several clinical conditions that are considered as contraindications to the use of metformin among patients with type 2 diabetes mellitus. The aim of this study was to investigate the presence and nature of contraindications to metformin therapy among patients with type 2 diabetes mellitus. A retrospective study of the medical files of diabetic patients available at Alwosta clinic, north Palestine was carried out. Information about disease and medication profile of the patients was retrieved and analyzed using SPSS during the study period in 2004/2005. Focus was on metformin users who have contraindications to metfromin therapy. Presence and number of contraindications to metformin therapy. Two hundred and seventy-two type 2 diabetic patients were identified. One hundred and twenty four of those diabetic patients were metformin users. Approximately, 60% of patients in the metformin group had a least one contraindication. Congestive heart failure and renal impairment were the most quantitatively present contraindications. Contraindications to metformin therapy are common among type 2 diabetic patients and mostly disregarded. Patients have to be critically assessed before starting therapy and in case of metformin prescribing; dose should be adjusted based on the presence of risk factors for metformin adverse effects. ContraindicationsDrug-related problemsMedication-related problemsMedication safetyMetforminPalestineType 2 diabetes mellitus This is a preview of subscription content, log in to check access The author is very grateful for the Palestini Continue reading >>
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Metformin Contraindications Creatinine Clearance 2016 Top Choice.
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Ema Approval For Metformin In Patients With Renal Impairment
The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has issued a positive opinion recommending extension of the label for all metformin-containing products to included patients with stable moderate renal failure (chronic kidney disease stage 3). The maximum daily metformin dose will be 2000 mg/day in CKD stage 3a (GFR = 45-59 ml/min) and 1000 mg/day in CKD stage 3b (GFR = 30-44 ml/min), allowing a large additional group of type 2 diabetes patients with reduced kidney function to benefit from the treatment. The product information for these medicines will be updated to revise the current contraindication and give information about doses, monitoring and precautions in patients with reduced kidney function. Following a routine evaluation of the safety of metformin medicines, it was found that based on scientific evidence and clinical guidelines, patients with moderate renal failure may stand to benefit from treatment with metformin, and that the contraindication may therefore no longer be justified. Based on this evidence, the EMA issued an Article 31 referral requesting a cumulative review of the benefit and risk in this patient group across all companies selling metformin companies in the European Union. The EMA reviewed the data submitted by all companies, and as a result, the CHMP has issued a positive opinion on lifting the contraindication for treatment of type 2 diabetes patients with renal impairment CKD stage 3. More information EMA summary on metformin in moderate renal failure Continue reading >>
Metformin Contraindications
The biguanide metformin (dimethylbiguanide) was initially introduced for use in the treatment of type 2 diabetes mellitus in the late 1950s. Today this drug is considered to be the first-choice agent and the “gold standard” for most people with type 2 diabetes. It has been estimated that the annual number of people receiving prescriptions for metformin worldwide is more than 120 million. The efficacy and benefits of metformin treatment in type 2 diabetes have been confirmed by large-scale studies and recognized by many consensus statements. Still, a large list of contraindications may increase the incidence of serious adverse effects, which precludes many patients from taking metformin. Intolerance and contraindications to metformin Three particular contraindications to the use of metformin have been suggested. They include renal impairment with elevated serum creatine levels (i.e. more than 136 mmol/l in men and 124 mmol/l in women) or abnormal creatinine clearance, congestive heart failure requiring pharmacologic treatment and advanced age (more than 80 years of age). Renal impairment represents a contraindication to metformin usage due to the increased risk of lactic acidosis (a form of metabolic acidosis due to the inadequate clearance of lactic acid from the blood). Although lactic acidosis linked to metformin is a rare condition, with an estimated prevalence of one to five cases per 100 000 population, it has a reported mortality of 30-50%. However, recent studies have suggested that metformin can be used safely, unless the estimated glomerulal filtration rate (the volume of fluid that is filtered from the capillaries of the glomeruli into the kidney tubules per unit time) falls below 30 ml/min, with a dose reduction advised at 45 ml/min. Congestive heart fail Continue reading >>
European Medicines Agency - Human Medicines - Metformin And Metformin-containing Medicines
Metformin and metformin-containing medicines Use of metformin to treat diabetes now expanded to patients with moderately reduced kidney function Recommendations for patients with kidney impairment updated in product information On 13 October 2016, the European Medicines Agency (EMA) concluded that metformin-containing medicines can now be used in patients with moderately reduced kidney function (GFR [glomerular filtration rate] = 3059 ml/min) for the treatment of type 2 diabetes. The product information for these medicines will be updated to revise the current contraindication and give information about doses, monitoring and precautions in patients with reduced kidney function. The recommendations were the result of a review by EMA of metformin-containing medicines following concerns that current scientific evidence does not justify a contraindication in patients with moderate reduction of kidney function. The current product information also varies between countries and products in the EU and is no longer consistent with clinical guidelines. Metformin may increase the risk of a rare but serious complication called lactic acidosis, which occurs when naturally produced lactic acid builds up in the blood faster than it can be removed. Currently, the product information states that metformin must not be used in patients with reduced kidney function because these patients are considered to be at a higher risk of developing lactic acidosis as their kidneys do not remove metformin efficiently enough. However, after considering the scientific literature, clinical data, epidemiological studies and clinical guidelines from medical bodies, EMA concluded that the large patient population with moderately reduced kidney function can benefit from use of metformin. Clear dosing recom Continue reading >>
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Fortamet
FORTAMET® (metformin hydrochloride) Extended-Release Tablets DESCRIPTION FORTAMET® (metformin hydrochloride) Extended-Release Tablets contain an oral antihyperglycemic drug used in the management of type 2 diabetes. Metformin hydrochloride (N, Ndimethylimidodicarbonimidic diamide hydrochloride) is a member of the biguanide class of oral antihyperglycemics and is not chemically or pharmacologically related to any other class of oral antihyperglycemic agents. The empirical formula of metformin hydrochloride is C4H11N5•HCl and its molecular weight is 165.63. Its structural formula is: Metformin hydrochloride is a white to off-white crystalline powder that is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. FORTAMET® Extended-Release Tablets are designed for once-a-day oral administration and deliver 500 mg or 1000 mg of metformin hydrochloride. In addition to the active ingredient metformin hydrochloride, each tablet contains the following inactive ingredients: candellila wax, cellulose acetate, hypromellose, magnesium stearate, polyethylene glycols (PEG 400, PEG 8000), polysorbate 80, povidone, sodium lauryl sulfate, synthetic black iron oxides, titanium dioxide, and triacetin. FORTAMET® meets USP Dissolution Test 5. System Components And Performance FORTAMET® was developed as an extended-release formulation of metformin hydrochloride and designed for once-a-day oral administration using the patented single-composition osmotic technology (SCOT™). The tablet is similar in appearance to other film-coated oral administered tablets but it consists of an osmotically active core formulation that is surrounded by a semipermeable membra Continue reading >>
Fda Issues Guidance For Metformin Use In Renal Impairment
Chris Tanski received his PharmD from the University at Buffalo School of Pharmacy and Pharmaceutical Sciences and is now working as a clinical staff pharmacist for Pinnacle Health in Harrisburg, Pennsylvania. He entered the field of hospital pharmacy directly from school, and he was one of the first to pilot a decentralized pharmacist role in the hospital. His other notable work contributions include working on palliative projects and transition of care for COPD patients. Chris was an editor and contributor to a film theory blog, a sketch comedy writer throughout pharmacy school, and he has a significant amount of experience writing drug information papers on neurology and infectious disease topics for both school and work. The FDA has issued new guidance for the use of the first-line diabetes drug metformin in patients with renal impairment. Metformin was approved by the FDA in 1994 for the management of type 2 diabetes. Since its approval, its labeling has warned of a contraindication in elevated serum creatinine (>1.5 mg/dL for males, >1.4 mg/dL for females) due to a risk of lactic acidosis secondary to metformin accumulation.1 Other risk factors for lactic acidosis include contrast dye exposure within 48 hours, chronic or excessive alcohol intake, dehydration, sepsis, acute congestive heart failure, and age. This absolute contraindication was based on clinical trials of an older biguanide called phenformin, which showed a greater risk of lactic acidosis associated with significant mortality and was subsequently pulled off the market in 1977.2 Although phenformin is no longer available in the United States, it’s still available in European and South American markets. Notably, the incidence of lactic acidosis associated with metformin is as low as 0.03 cases per 10 Continue reading >>
Metformin May Reduce All-cause Mortality In Patients With Congestive Heart Failure
A systematic review of 17 observational studies found that metformin was associated with a reduction in all-cause mortality in patients with type 2 diabetes and chronic kidney disease, congestive heart failure or chronic liver disease with hepatic impairment. Metformin was also associated with fewer heart failure readmissions in patients with chronic kidney disease or congestive heart failure. Lead researcher Matthew J. Crowley, MD, MHS, of Duke University and the Durham Veterans Affairs Medical Center in North Carolina, and colleagues published their results online Jan. 2 in the Annals of Internal Medicine. The U.S. Department of Veterans Affairs funded the study. When the FDA approved metformin in 1994, the drug became the initial treatment option for many people with type 2 diabetes in the U.S., according to the researchers. However, the FDA required a label warning against using metformin in patients with chronic kidney disease and recommended caution for patients with congestive heart failure and chronic liver disease. The researchers noted that the FDA in 2006 removed congestive heart failure as a contraindication to metformin use, although the agency still cautions against the drug’s use in patients with acute or unstable congestive heart failure. They also noted that the FDA in April 2016 revised its warning regarding metformin use in patients with chronic kidney disease. By switching to a more inclusive criteria based on estimated glomerular filtration rate, an estimated one million additional patients with moderate chronic kidney disease are eligible to receive metformin, although the drug remains contraindicated in patients with severe chronic kidney disease. For this analysis, the researchers searched databases, the ClinicalTrials.gov website and other pub Continue reading >>
