A study on metfromin

Terzetto Pharma Metrics Private Limited

A study on Me

(1, 1-Dimethylbiguanide

reported adverse events as observed in

Eudravigilance database

Contract Research Organization NIVETHA CHELLAPATHY 07.07.2016

Terzetto Pharma Metrics Private Limited | 142/2,2nd Main, Horamavu, Bangalore 560043| www.tpmet.com

A study on Metformin

Dimethylbiguanidemonohydrochloride)



Contract Research Organization / Terzetto Pharma Metrics

CHELLAPATHY AND BANU PRIYA

Main, Horamavu, Bangalore 560043

monohydrochloride)



Contents

ABSTRACT ................................

INTRODUCTION ................................

MECHANISM OF ACTION ................................

Pharmacokinetics ................................

MANUFACTURER INFORMA

CURRENT PATENT HOLDE

PHARMACOECONOMICS ................................

DATA COLLECTION ................................

INTERPRETATION ................................


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MANUFACTURER INFORMATION ................................................................

CURRENT PATENT HOLDERS ................................................................

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A study on Metformin (1, 1

monohydrochloride) reported adverse events as observed in


Abstract

Metformin is an antihyperglycemic agent which improves glucose tolerance in patients

with type 2 diabetes, lowering both basal and postprandial plasma glucose

To study the adverse reaction reported for metformin in different type of SOC (System

Organ Classification). Method :

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


with type 2 diabetes, lowering both basal and postprandial plasma gluc

Reference source not found.


A study on Metformin (1, 1-Dimethylbiguanide



antihyperglycemic agent which improves glucose tolerance in patients

with type 2 diabetes, lowering both basal and postprandial plasma glucose

o study the adverse reaction reported for metformin in different type of SOC (System

Method : Data was extracted and complied from the European




with type 2 diabetes, lowering both basal and postprandial plasma gluc

Reference source not found.).


Dimethylbiguanide


antihyperglycemic agent which improves glucose tolerance in patients

with type 2 diabetes, lowering both basal and postprandial plasma glucose. Objective :

o study the adverse reaction reported for metformin in different type of SOC (System

ata was extracted and complied from the European




with type 2 diabetes, lowering both basal and postprandial plasma glucose(Error!


Therapeutic Class: Biguanides

Chemical Name: 1, 1-Dimethylbiguanide monohydrochloride

Molecular Formula: C4H

Mechanism of action Metformin decreases hepatic glucose production, decreases intestinal absorption of

glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and

utilization.

Pharmacokinetics

The absolute bioavailability of a Metformin

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

hours. In blood, the elimination half

source not found.).

In 1957, metformin was studied in several trials in

glucose in patients with type 2 diabetes.

Company and initially it was prescribed in

acidosis and deaths increased, Metformin was removed from USA and many other


Biguanides

Dimethylbiguanide monohydrochloride

H11N5. HCI

Metformin decreases hepatic glucose production, decreases intestinal absorption of


The absolute bioavailability of a Metformin hydrochloride 500 mg tablet given under



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

studied in several trials in Paris and has shown to lower blood

glucose in patients with type 2 diabetes. Metformin was manufactured by small

and initially it was prescribed in France and Scotland. As number of lactic

increased, Metformin was removed from USA and many other


Metformin decreases hepatic glucose production, decreases intestinal absorption of


hydrochloride 500 mg tablet given under



life of approximately 6.2

Error! Reference

and has shown to lower blood

Metformin was manufactured by small France

As number of lactic

increased, Metformin was removed from USA and many other


countries. Metformin was approved in Canada in 1972

found.), but did not receive approval by the

for type 2 diabetes until 1994.

Glucophage was the first branded formulation of metformin to be marketed in the United

States, beginning on March 3, 1995.

most influential has been the UK Pro

As a result, metformin rose

diabetes. The drug’s anti

confirmed. In 2012 diabetes

drug of the first choice for all

Manufacturer Information

Metformin hydrochloride

by Bristol Myers Squibb,

Pharm, Aurobindo Pharma Ltd

Ltd,Sandoz, Sun Pharm Inds

Inds (in),Ivax Sub Teva Pharms

Provident, Nostrum Pharms Llc

Ltd, Granules India, Sun Pharm Inds Inc

Pharms Inc, Glenmark Generics

Labs,Amneal Pharms Ny

Pharma, Sun Pharm Inds Ltd

Ltd, Takeda Pharms Use, Teva Pharms

Ab, and Merck Sharp Dohme

129 patent family members in 33 countries


Metformin was approved in Canada in 1972(Error! Reference source not

but did not receive approval by the U.S. Food and Drug Administration

for type 2 diabetes until 1994. Produced under license by Bristol


States, beginning on March 3, 1995. Many studies were performed, and among them the

most influential has been the UK Prospective Diabetes study.

rose as the first choice of treatment for obese patient with type 2

The drug’s anti-atherosclerotic and cardio protective effects have b

diabetes experts in USA and Europe declared that metformin is the

drug of the first choice for all patients with type 2 diabetes(Error! Reference source not found.

Information

Metformin hydrochloride is the generic ingredient in sixteen branded drugs marketed

, Apotex, Ranbaxy Labs Ltd, Torrent Pharms

Aurobindo Pharma Ltd, Watson Labs Inc, Cspc Ouyi Pharm Co

Sun Pharm Inds, Torrent Pharms Ltd, Teva, Atlas Pharms Llc

Ivax Sub Teva Pharms, Santarus Inc, Indicus Pharma, Impax Labs

Nostrum Pharms Llc, Zydus Pharms Use, Watson Labs Florida

Sun Pharm Inds Inc, Actavis Labs Fl Inc, Mylan Pharms

Glenmark Generics, Chartwell Life Sic, Andrx Labs Llc

Amneal Pharms Ny, Alkem, Zydus Hlthcare, Dr Reddys Labs Inc

Sun Pharm Inds Ltd, Inventia Hlthcare, Aurobindo, Macleods Pharms

Teva Pharms Use, Novo Nordisk Inc, Sb Pharmco

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.


Error! Reference source not

Food and Drug Administration (FDA)

Bristol-Myers Squibb,


ormed, and among them the

as the first choice of treatment for obese patient with type 2

effects have been

experts in USA and Europe declared that metformin is the

Error! Reference source not found.).

is the generic ingredient in sixteen branded drugs marketed

Torrent Pharms, Mylan , Torrent

Cspc Ouyi Pharm Co, Ipca Labs

Atlas Pharms Llc, Sun Pharm

Impax Labs, Elizabeth,

Watson Labs Florida, Barr,Lupin

Mylan Pharms Inc,Sciegen

Andrx Labs Llc, Watson

Dr Reddys Labs Inc, Marksans

Macleods Pharms

Sb Pharmco, Astrazeneca

. This ingredient has



Current patent holdersRanbaxy Laboratories Limited, New Delhi

source not found.)

Torrent Pharm,Ahmedabad

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 1996. Since then, of the 42 anti

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 (536/57

anti-diabetes FDCs and metformin SDFs comprised only 22 per cent (123/569) of the

anti-diabetes SDFs.


1,144 anti-diabetes products in the market. Of these, 575 we

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.


Current patent holders

Ranbaxy Laboratories Limited, New Delhi-Patent NO : 6559187(Error! Refere

Ahmedabad – Approval date Dec,30 /2009

May 12, 2009

Records of the Drug Controller General (India) show that between 1961 and February


approved in November 1996. Since then, of the 42 anti-diabetes FDCs approved, 25 are


diabetes products in the market. Of these, 575 were FDC and 569 were ‘Single

Dose Formulations’ (SDF). Metformin FDCs comprised 93 per cent (536/57

diabetes FDCs and metformin SDFs comprised only 22 per cent (123/569) of the







Error! Reference

Records of the Drug Controller General (India) show that between 1961 and February


diabetes FDCs approved, 25 are






re FDC and 569 were ‘Single




Indian data shows that metformin FDCs dominated over metformin SDFs by a ratio of

3:1 between the years 2007

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

(15.60) annual sale is more than the FDCs annual sale (0.30)

not found.).

Data collection

The drug substance information was extracted and compiled from the European database

of suspected adverse drug reaction report

information on metformin was updated within years 2013 to 2016.

The information available in the above website was collected from adverse drug reactions

of substances, stating the data available for

individual cases and cases 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

group between 18-64 yrs (

More female patients (51.1%) had experienced adverse drug

(43.5%). Among these cases

ADR than European economic area



3:1 between the years 2007-’12. In 2012, metformin FDCs comprised 56% of oral

diabetes drugs sold in volume.


sales volume is 148.0(millions of units). Countries like England and Australia

15.60) annual sale is more than the FDCs annual sale (0.30)(Error! Reference source


of suspected adverse drug reaction reports (website: www.adrreports.eu). The

information on metformin was updated within years 2013 to 2016.


of substances, stating the data available for metformin. The data w



15,375 ADR cases have been reported. Among these cases, age

yrs (39.5%) and 65-85 yrs (40.9%) maximum cases was reported.

51.1%) had experienced adverse drug reaction than

43.5%). Among these cases non-European economic area (54.3%)

ADR than European economic area(Error! Reference source not found.



’12. In 2012, metformin FDCs comprised 56% of oral


sales volume is 148.0(millions of units). Countries like England and Australia SDFs

Error! Reference source


s (website: www.adrreports.eu). The


The data was segregated into



been reported. Among these cases, age

maximum cases was reported.

reaction than male patients

has reported more



System Organ Classification:

SOC is the highest level of

retrieval. There are 26 SOC.

Etiology (e.g., SOC

Manifestation site (e.g., SOC

Purpose (e.g., SOC

The total Number of cases reported is 34,819.

Classification(SOC), Metabolism and nutrition disorders was found to have reported the

maximum number of cases

age group between

group(54.08%)reported more cases than male patient group(41.20%).

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 18

64 years 1,320(42.7%) and female

than male patients (42.60%)

non- HCP (26.98%).The highest frequency of cases was reported form Non European

Economic area (66.87%).

In Gastrointestinal Disorder

cases are reported in age group between 18


System Organ Classification:

is the highest level of the hierarchy that provides the broadest concept for data

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

Metabolism and nutrition disorders was found to have reported the

maximum number of cases 6,961, in which maximum number of cases

age group between 18-64 years 3,494(50%) and also female patient

group(54.08%)reported more cases than male patient group(41.20%).


a(57.60%).


administration site conditions, in which more cases reported in age group between 18

64 years 1,320(42.7%) and female patients (52.76%) reported maximum number of cases

42.60%).Healthcare Professional (70.65%) is significantly high than

26.98%).The highest frequency of cases was reported form Non European

In Gastrointestinal Disorder, 3048 cases were reported. Among the

cases are reported in age group between 18-64 years. Female patients


the hierarchy that provides the broadest concept for data

Among 26 System Organ

Metabolism and nutrition disorders was found to have reported the

maximum number of cases was reported in

and also female patient

group(54.08%)reported more cases than male patient group(41.20%).The highest



administration site conditions, in which more cases reported in age group between 18 –

52.76%) reported maximum number of cases

significantly high than

26.98%).The highest frequency of cases was reported form Non European

reported. Among them 1,378(45.21%)

64 years. Female patients group (58.53%) is


significantly high than the male patients

reported by HCP and 56% of cases are reported

2,895 cases was reported in Investigational

under 18-64 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

1,433(50.5%) cases are reported in age group between 64

groups(54%)was significantly high than the male patients group(42%).82.89% case

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 64

patients group and 1,788(73.70%) cases are reported by HCP. Non European Economic

area (57.79%) is highly significant than European Economic

In Injury, poisoning and procedural complications SOC, 2,084 c

them 50% cases are reported in age group between 18

(53.67%) are more significant than male

HCP and 68.52% cases are reported from Non European Economic area.

In Cardiac disorder and psychiatric disorder SOC

age group between 18 –

reported (46% and 49%) significant number of cases than male patient

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


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

2,895 cases was reported in Investigational SOC, in which 43.10% cases are reported

64 years age group and 53.67% cases were reported in female patients

67.87% cases was reported by HCP and 1,994(68.87%) cases was reported from

ropean 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 64-84 years. Female patients

groups(54%)was significantly high than the male patients group(42%).82.89% case



reported in age group between 64 – 84 years. 55.31% cases are reported in female


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 18-64 years.

53.67%) are more significant than male patients (38.77%).1, 655 cases are reported by


In Cardiac disorder and psychiatric disorder SOC, 43.1% and 59.8% cases are reported in

64 years respectively. In both SOC, Female patients group

46% and 49%) significant number of cases than male patient

ported by HCP and 68.5 % of cases are reported from Non European Economic area.




38.25%). 2,332(76.5%) cases was

European Economic area.

SOC, in which 43.10% cases are reported

64 years age group and 53.67% cases were reported in female patients

67.87% cases was reported by HCP and 1,994(68.87%) cases was reported from

reported. Among them

84 years. Female patients

groups(54%)was significantly high than the male patients group(42%).82.89% cases was



. 55.31% cases are reported in female


42.20%).

ases are reported. Among

64 years. Female patients

cases are reported by


59.8% cases are reported in

64 years respectively. In both SOC, Female patients group

46% and 49%) significant number of cases than male patients.80% cases are

ported by HCP and 68.5 % of cases are reported from Non European Economic area.




between 18 – 64 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

cases are reported in 65-84 years

49.5% cases are reported in male patients whereas in Infection and infestations 57.1

cases are reported in female patients. 65

and 73.7% cases are reported fro

In Eye disorder, Hepatobiliary disorder and Musculoskeletal and connective tissue

disorder 47.6% cases are reported in age group between 18

Musculoskeletal and connective tissue

patients group whereas in Hepatobiliary disorder maximum number of cases reported in

male patients group (48%). Maximum


40-50% cases in Pregnancy, puerpe

medical procedures are reported in age group between 18

reported in female patients group.

European Economic area (

359 cases are reported in

polyps) SOC, in which 42.61% cases reported in 65

number of cases are reported both in male and female pa

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 thes


64 years and 54.4% are reported in female patient group. Maximum

reported by HCP in Non European Economic area.

In Blood and lymphatic system disorder and Infection and infestations, 51.7

84 years age group. In Blood and lymphatic system disorder

49.5% cases are reported in male patients whereas in Infection and infestations 57.1

are reported in female patients. 65 – 86% of reports were reported by HCP.53.7 %

are reported from Non European Economic area.


disorder 47.6% cases are reported in age group between 18-64 years. In Eye disorder and

Musculoskeletal and connective tissue disorder 55.8% cases were reported in female


48%). Maximum numbers of cases were reported by HCP from Non

50% cases in Pregnancy, puerperium and perinatal conditions and Surgical and

medical procedures are reported in age group between 18- 64 years and 68% cases

reported in female patients group. Maximum numbers of cases are reported by HCP. Non

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 65-85 years age group and equal

number of cases are reported both in male and female patients group. 61% of cases are

74.9% cases reported from Non European Economic area.

, familial and genetic disorder, Endocrine disorder, Immune system disorder,

Product issues and Reproductive system and breast disorder in these SOC 41.8% cases


64 years and 54.4% are reported in female patient group. Maximum

reported by HCP in Non European Economic area.

, 51.7% and 41.3%

age group. In Blood and lymphatic system disorder

49.5% cases are reported in male patients whereas in Infection and infestations 57.1%

86% of reports were reported by HCP.53.7 %


64 years. In Eye disorder and

% cases were reported in female


reported by HCP from Non

rium and perinatal conditions and Surgical and

64 years and 68% cases

reported by HCP. Non

ficant than European Economic area.

, benign, malignant and unspecified(incl cysts and

85 years age group and equal

tients group. 61% of cases are

74.9% cases reported from Non European Economic area.

, familial and genetic disorder, Endocrine disorder, Immune system disorder,

e SOC 41.8% cases


are reported in 18 – 64 years age group and significant number cases are reported in

female patients. Maximum

Familial and genetic disorder in


Least number of cases reported in following SOCs ,

circumstances SOC, 43.7% and 50.6% cases are reported in 18

51.8% of cases are reported in female patients. Maximum

by HCP and 76.8% cases are reported from Non European Economic area.


64 years age group and significant number cases are reported in

female patients. Maximum numbers of cases are reported by HCP. Except Congen

disorder in all SOC maximum number of cases reported from Non


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 18-64 years age group.

ses are reported in female patients. Maximum numbers of cases are



64 years age group and significant number cases are reported in

reported by HCP. Except Congenital,

all SOC maximum number of cases reported from Non

Ear and labyrinth disorder and Social

64 years age group.

numbers of cases are reported



THANK YOU. FOR MORE INFORMATION CONTACT:


THANK YOU. FOR MORE INFORMATION CONTACT: Dr. Nivetha - [email protected]


[email protected]

Documents

A study on metfromin