Metformin appears to be a useful therapeutic option for physicians wishing to use drug therapy to control blood glucose levels. 3

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1 VI.2 VI.2.1 Elements for a Public Summary Overview of disease epidemiology Type 2 diabetes mellitus Rates of diabetes are increasing worldwide. The International Diabetes Federation predicts that the number of people living with diabetes will rise from 366 million in 2011 to 552 million by The prevalence of type 2 diabetes mellitus varies widely among various racial and ethnic groups. The risk of retinopathy (disease of the retina) and kidney disease appears to be greater in blacks, Native Americans, and Hispanics. Type 2 diabetes mellitus occurs most commonly in adults aged 40 years or older, and the prevalence of the disease increases with advancing age. Indeed, the aging of the population is one reason that type 2 diabetes mellitus is becoming increasingly common. Virtually all cases of diabetes mellitus in older individuals are type 2. In addition, however, the incidence of type 2 diabetes is increasing more rapidly in adolescents and young adults than in other age groups. The disease is being recognized increasingly in younger persons, particularly in highly susceptible racial and ethnic groups and the obese. In some areas, more type 2 than type 1 diabetes mellitus is being diagnosed in prepubertal children, teenagers, and young adults. 1 An important, modifiable risk factor for type 2 diabetes is an inactive lifestyle. Observational and clinical trial data suggest that as little as 30 min/day of moderate intensity physical activity can reduce the incidence of type 2 diabetes. 2 VI.2.2 Summary of treatment benefits Type 2 diabetes mellitus A study was carried out, involving 451 patients with high blood sugar levels (upon fasting), to test the effectiveness of Metformin (doses from 500 to 2500mg daily). It was shown to lower blood sugar levels, with benefits observed using the lowest dose (500mg); however, it was most effective at the higher recommended daily dosages, and it was also well accepted by the body at all doses. Adverse effects occurred in 28% of patients, taking Metformin, which were mostly digestive problems, such as diarrhoea. Metformin appears to be a useful therapeutic option for physicians wishing to use drug therapy to control blood glucose levels. 3 VI.2.3 Unknowns relating to treatment benefits Based on the currently available data, no gaps in knowledge about efficacy in the target population were identified, that would warrant post-authorisation efficacy studies. Furthermore, there is no evidence to suggest that treatment results would be different in any subgroup of the target population, for any of the indications, taking into account factors such as age, sex, race or organ impairment. VI.2.4 Summary of safety concerns Important identified risks Lactic acidosis (high levels of lactic acid in the blood) Lactic acidosis is a rare, but serious (high death rate in the absence of prompt treatment), condition that can occur due to metformin build up. Reported cases of lactic All patients under metformin treatment should discuss with their doctors if they are having muscle cramps with digestive disorders, such as abdominal pain, and severe PhV Page 1/5

2 acidosis in patients on metformin have occurred primarily in diabetic patients with significant kidney failure and in patients with other associated risk factors. Liver insufficiency Use of metformin before elective surgery Hypoglycaemia (low blood sugar) following coadministration with other antidiabetic agents It is not indicated to use metformin in patients with liver insufficiency It is recommended to discontinue metformin treatment, 48 hours before elective surgery, involving general, spinal or peridural anaesthesia. Therapy may be restarted no earlier than 48 hours following surgery or resumption of eating normally, provided normal kidney function has been established. Caution is advised when metformin is used in combination with insulin or other oral antidiabetics (e.g. sulphonylureas or meglitinides) in order to avoid hypoglycaemia asthenia (weakness / loss of strength), as these symptoms are characteristic of lactic acidosis. Patients with liver insufficiency should avoid use of metformin Patients should consult with their doctors and interrupt treatment with metformin before surgery. When using metformin in combination with insulin or other oral antidiabetics patient should always take the exact dose specified by their physicians. Monitoring of blood glucose is necessary frequently. Hypoglycaemia (low blood sugar) following coadministration with drugs with intrinsic sympathomimetic activity (affect on the sympathetic nervous system, which is involved in producing stress / emergency related responses) including glucocorticoids and sympathomimetics Medicinal products with intrinsic blood sugar increasing activity (e.g. glucocorticoids (systemic and local routes) and sympathomimetics) must be taken with caution due to their opposing action when taken with metformin. Patients should discuss with physicians if they need to take medicinal products with intrinsic blood sugar increasing activity. Use in patients with kidney impairment. Decreased kidney function in elderly subjects is frequent and symptom free. Elderly patients should adjust the metformin dosage due to the potential for decreased kidney function. It is not indicated to use metformin in patients with kidney failure or kidney dysfunction (creatinine clearance < 60 ml/min). Regular assessment of kidney function is necessary Creatinine clearance (amount of creatinine in urine in comparison to the blood) should be determined before initiating treatment and regularly thereafter. Simultaneous use of iodi- Intravascular administration of PhV Page 2/5

3 nated contrast media. iodinated contrast media may must be discontinued prior lead to kidney failure, resulting to, or at the time of the test in metformin build up and a risk and not reinstituted until 48 of lactic acid accumulation in hours afterwards, and only the blood.. after kidney function has been re-evaluated and found to be normal. Important potential risks Risk Missing information Risk What is known (Including reason why it is considered a potential risk) What is known In the absence of available data, Metformin prolonged release tablets should not be used in children. VI.2.5 Summary of risk minimisation measures by safety concern All medicines have a Summary of Product Characteristics (SmPC) which provides physicians, pharmacists and other health care professionals with details on how to use the medicine, the risks and recommendations for minimising them. An abbreviated version of this in lay language is provided in the form of the package leaflet (PL). The measures in these documents are known as routine risk minimisation measures. This medicine has no additional risk minimisation measures. VI.2.6 Planned post authorisation development plan No post-authorisation safety or efficacy studies are ongoing or are planned to be conducted for Metformin Hydrochloride VI.2.7 Summary of changes to the Risk Management Plan over time Major changes to the Risk Management Plan over time Version Date Safety Concerns Comment 002(Arrrow) Important identified risks: Lactic acidosis Concomitant use of iodinated contrast media Use in patients with renal impairment Initial version Important potential risks: Concomitant use of insulin or other oral antidiabetics leading to hypoglycaemia Liver function test abnormalities or hepatitis PhV Page 3/5

4 Version Date Safety Concerns Comment Important missing information: 2.0 Important identified risks: Lactic acidosis Hepatic insufficiency Use of metformin before elective surgery Hypoglycaemia following coadministration with other antidiabetic agents Hypoglycaemia following coadministration with drugs with intrinsic sympathomimetic activity including glucocorticoids and sympathomimetics Use in patients with renal impairment. Concomitant use of iodinated contrast media. Important potential risks: Missing information: New important safety risks were included. PhV Page 4/5

5 References: 1 Romesh Khardori, MD, et. al ( 2013, Sept 3), Type 2 Diabetes Mellitus, retrieved on , from 2 Bassuk, Shari S., and JoAnn E. Manson. "Epidemiological evidence for the role of physical activity in reducing risk of type 2 diabetes and cardiovascular disease." Journal of Applied Physiology 99.3 (2005): Garber AJ Efficacy of metformin in type II diabetes: results of a double-blind, placebocontrolled,dose-response trial, Am J Med Dec;103(6): PhV Page 5/5