A study on Metformin (1, 1-Dimethylbiguanidemonohydrochloride) reported adverse events as observed in Eudravigilance database

Transcription

1 A study on Metformin (1, 1-Dimethylbiguanidemonohydrochloride) reported adverse events as observed in Eudravigilance database Contract Research Organization / Terzetto Pharma Metrics NIVETHA CHELLAPATHY AND BANU PRIYA

2 Contents ABSTRACT... 3 INTRODUCTION... 3 MECHANISM OF ACTION... 4 Pharmacokinetics... 4 MANUFACTURER INFORMATION... 5 CURRENT PATENT HOLDERS... 5 PHARMACOECONOMICS... 6 DATA COLLECTION... 7 INTERPRETATION... 7

3 A study on Metformin (1, 1-Dimethylbiguanide monohydrochloride) reported adverse events as observed in Eudravigilance database Abstract Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Objective : To study the adverse reaction reported for metformin in different type of SOC (System Organ Classification). Method : Data was extracted and complied from the European Database of suspected adverse drug reaction reports. These data are segregated into individual cases and cases based on reaction groups such as age, sex, group and geographic origin. Introduction Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose ( Error! Reference source not found. ).

4 Therapeutic Class: Biguanides Chemical Name: 1, 1-Dimethylbiguanide monohydrochloride Molecular Formula: C 4 H 11 N 5. HCI Mechanism of action Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves nsulin sensitivity by increasing peripheral glucose uptake and utilization. Pharmacokinetics The absolute bioavailability of a Metformin hydrochloride 500 mg tablet given under fasting conditions is approximately 50% to 60%.Food decreases the extent of and slightly delays the absorption of Metformin. 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours ( Error! Reference source not found. ). In 1957, metformin was studied in several trials in Paris and has shown to lower blood glucose in patients with type 2 diabetes. Metformin was manufactured by small France Company and initially it was prescribed in France and Scotland. As number of lactic acidosis and deaths increased, Metformin was removed from USA and many other

5 countries. Metformin was approved in Canada in 1972 ( Error! Reference source not found. ), but did not receive approval by the U.S. Food and Drug Administration (FDA) for type 2 diabetes until Produced under license by Bristol-Myers Squibb, Glucophage was the first branded formulation of metformin to be marketed in the United States, beginning on March 3, Many studies were performed, and among them the most influential has been the UK Prospective Diabetes study. As a result, metformin rose as the first choice of treatment for obese patient with type 2 diabetes. The drug s anti-atherosclerotic and cardio protective effects have been confirmed. In 2012 diabetes experts in USA and Europe declared that metformin is the drug of the first choice for all patients with type 2 diabetes (Error! Referencee source not found.). Manufacturer Information Metformin hydrochloride is the generic ingredient in sixteen branded drugs marketed by Bristol Myers Squibb, Apotex, Ranbaxy Labs Ltd, Torrent Pharms, Mylan, Torrent Pharm, Aurobindo Pharma Ltd, Watson Labs Inc, Cspc Ouyi Pharm Co, Ipca Labs Ltd,Sandoz, Sun Pharm Inds, Torrent Pharms Ltd, Teva, Atlas Pharms Llc, Sun Pharm Inds (in),ivax Sub Teva Pharms, Santarus Inc, Indicus Pharma, Impax Labs, Elizabeth, Provident, Nostrum Pharms Llc, Zydus Pharms Use, Watson Labs Florida, Barr,Lupin Ltd, Granules India, Sun Pharm Inds Inc, Actavis Labs Fl Inc, Mylan Pharms Inc,Sciegen Pharms Inc, Glenmark Generics, Chartwell Life Sic, Andrx Labs Llc, Watson Labs,Amneal Pharms Ny, Alkem, Zydus Hlthcare, Dr Reddys Labs Inc, Marksans Pharma, Sun Pharm Inds Ltd, Inventia Hlthcare, Aurobindo, Macleods Pharms Ltd, Takeda Pharms Use, Teva Pharms Use, Novo Nordisk Inc, Sb Pharmco, Astrazeneca Ab, and Merck Sharp Dohme, and is included in eigthy-five NDAs.. This ingredient has 129 patent family members in 33 countries ( Error! Reference source not found. ).

6 Current patent holders Ranbaxy Laboratories Limited, New Delhi-Patent NO : ( Error! Reference source not found. ) Torrent Pharm,Ahmedabad Approval date Dec,30 /2009 Takeda pharms, USA May 12, 2009 Pharmacoeconomics Records of the Drug Controller General (India) show that between 1961 and February 2013, approved a total of 1,125 FDC formulations. The first metformin FDC was approved in November Since then, of the 42 anti-diabetes FDCs approved, 25 are metformin formulations. Data from PharmaTrac (November 2007 to October 2012) however revealed as many as 1,144 anti-diabetes products in the market. Of these, 575 were FDC and 569 were Single Dose Formulations (SDF). Metformin FDCs comprised 93 per cent (536/575) of the anti-diabetes FDCs and metformin SDFs comprised only 22 per cent (123/569) of the anti-diabetes SDFs. Data from PharmaTrac (November 2007 to October 2012) however revealed as many as 1,144 anti-diabetes products in the market. Of these, 575 were FDC and 569 were Single Dose Formulations (SDF). Metformin FDCs comprised 93 per cent (536/575) of the anti-diabetes FDCs and metformin SDFs comprised only 22 per cent (123/569) of the anti-diabetes SDFs ( Error! Reference source not found. ).

7 Indian data shows that metformin FDCs dominated over metformin SDFs by a ratio of 3:1 between the years In 2012, metformin FDCs comprised 56% of oral diabetes drugs sold in volume. In 2012, annual sales volume of metformin FDCs is 455.4(millions of unit), but SDFs sales volume is 148.0(millions of units). Countries like England and Australia SDFs (15.60) annual sale is more than the FDCs annual sale (0.30) ( Error! Reference source not found. ). Data collection The drug substance information was extracted and compiled from the European database of suspected adverse drug reaction reports (website: The information on metformin was updated within years 2013 to The information available in the above website was collected from adverse drug reactions of substances, stating the data available for metformin. The data was segregated into individual cases and casess based on reaction groups such as age, sex, reporter group and geographic origin. Interpretation Based on the data collected from the European database of suspected adverse drug reaction of Metformin, 15,375 ADR cases have been reported. Among these cases, age group between yrs (39.5%) and yrs (40.9%) maximum cases was reported. More female patients (51.1%) had experienced adverse drug reaction than male patients (43.5%). Among these cases non-european economic area (54.3%) has reported more ADR than European economic area ( Error! Reference source not found. ).

8 System Organ Classification: SOC is the highest level of the hierarchy that provides the broadest concept for data retrieval. There are 26 SOC. SOCs comprise groupings by: Etiology (e.g., SOC Infections and infestations) Manifestation site (e.g., SOC Gastrointestinal disorders) Purpose (e.g., SOC Surgical and medical procedures) The total Number of cases reported is 34,819.Among 26 System Organ Classification(SOC), Metabolism and nutrition disorders was found to have reported the maximum number of cases 6,961, in which maximum number of cases was reported in age group between years 3,494(50%) and also female patient group(54.08%)reported more cases than male patient group(41..20%).the highest reporting group is HCP( (85.50%).The highest frequency of cases was reported from European Economic area(57.60%). Second SOC with maximum number of adr reported was General disorders and administration site conditions, in which more cases reported in age group between years 1,320(42.7%) and female patients (52.76%) reported maximum number of cases than male patients (42.60%).Healthcare Professional (70.65%) is significantly high than non- HCP (26.98%).The highest frequency of cases was reported form Non European Economic area (66.87%). In Gastrointestinal Disorder, 3048 cases were reported. Among them 1,378(45.21%) cases are reported in age group between years. Female patients group (58.53%) is

9 significantly high than the male patients group (38.25%). 2,332(76.5%) cases was reported by HCP and 56% of cases are reported from Non European Economic area. 2,895 cases was reported in Investigational SOC, in which 43.10% cases are reported under years age group and 53.67% cases were reported in female patients group.67.87% cases was reported by HCP and 1,994(68.87%) cases was reported from Non European Economic area. In Renal and Urinary disorders SOC, 2835 cases were reported. Among them 1,433(50.5%) cases are reported in age group between years. Female patients groups(54%)was significantly high than the male patients group(42%) ).82.89% cases was reported by HCP and 1,554(54.81%) cases was reported from European Economic area. 2,426 cases was reported in Nervous system disorder SOC, in which 1,,051(43.32%) cases reported in age group between years % cases are reported in female patients group and 1,788( (73.70%) cases are reported by HCP. Non European Economic area (57.79%) is highly significant than European Economic area (42.20%). In Injury, poisoning and procedural complications SOC, 2,084 cases are reported. Among them 50% cases are reported in age group between years. Female patients (53.67%) are more significant than male patients (38.77%).1, 655 cases are reported by HCP and 68.52% cases are reported from Non European Economic area. In Cardiac disorder and psychiatric disorder SOC, 43.1% and 59.8% cases are reported in age group between years respectively. In both SOC, Female patients group reported (46% and 49%) significant number of cases than male patients.80% cases are reported by HCP and 68.5 % of cases are reported from Non European Economic area. In Respiratory, thoracic and mediastinal disorder, Skin and subcutaneous tissue disorder and Vascular disorder SOC, maximum number of cases are reported in age group

10 between years and 54.4% are reported in female patient group. Maximum numbers of cases are reported by HCP in Non European Economic area. In Blood and lymphatic system disorder and Infection and infestations, 51.7% and 41.3% cases are reported in years age group. In Blood and lymphatic system disorder 49.5% cases are reported in male patients whereas in Infection and infestations 57.1% cases are reported in female patients % of reports were reported by HCP.53.7 % and 73.7% cases are reported from Non European Economic area. In Eye disorder, Hepatobiliary disorder and Musculoskeletal and connective tissue disorder 47.6% cases are reported in age group between years. In Eye disorder and Musculoskeletal and connective tissue disorder 55.8% cases were reported in female patients group whereas in Hepatobiliary disorder maximum number of cases reported in male patients group (48%). Maximum numbers of cases were reported by HCP from Non European Economic area % cases in Pregnancy, puerperium and perinatal conditions and Surgical and medical procedures are reported in age group between years and 68% cases reported in female patients group. Maximum numbers of cases are reported by HCP. Non European Economic area (68%) is highly significant than European Economic area. 359 cases are reported in Neoplasm, benign, malignant and unspecified(incl cysts and polyps) SOC, in which 42.61% cases reported in years age group and equal number of cases are reported both in male and female patients group. 61% of cases are reported by HCP. 74.9% cases reported from Non European Economic area. Congenital, familial and genetic disorder, Endocrine disorder, Immune system disorder, Product issues and Reproductive system and breast disorder in these SOC 41.8% cases

11 are reported in years age group and significant number cases are reported in female patients. Maximumm numbers of cases are reported by HCP. Except Congenital, Familial and genetic disorder in all SOC maximum number of cases reported from Non European Economic area. Least number of cases reported in following SOCs, Ear and labyrinth disorder and Social circumstances SOC, 43.7% and 50.6% cases are reported in years age group. 51.8% of cases are reported in female patients. Maximum numbers of cases are reported by HCP and 76.8% cases are reported from Non European Economic area.

12 THANK YOU. FOR MORE INFORMATION CONTACT: Dr. Nivetha - info@tpmet.com