Summary of the risk management plan (RMP) for Ebymect (dapagliflozin / metformin)

Transcription

1 EMA/672415/2015 Summary of the risk management plan (RMP) for Ebymect (dapagliflozin / metformin) This is a summary of the risk management plan (RMP) for Ebymect, which details the measures to be taken in order to ensure that Ebymect is used as safely as possible. For more information on RMP summaries, see here. This RMP summary should be read in conjunction with the EPAR summary and the product information for Ebymect, which can be found on Ebymect s EPAR page. Overview of disease epidemiology Ebymect is a medicine used to treat adults with type 2 diabetes. Type 2 diabetes is a condition in which the pancreas does not make enough insulin to control the level of glucose (sugar) in the blood or when the body is unable to use insulin effectively. In 2010, about 1 out of every 15 adults in Europe had this condition. Type 2 diabetes is more likely to develop in people who have family members with the condition, people with an ethnic background associated with a higher risk (for example Asian or African), people aged over 40 years old, or who are overweight or obese, do not exercise, have high blood pressure, or smoke. People with type 2 diabetes tend to have other diseases at the time of diagnosis and they are at greater risk of developing conditions such as cardiovascular disorders, diabetic eye disease, and kidney disease. Summary of treatment benefits Ebymect contains the active substances dapagliflozin and metformin. This medicine is the same as Xigduo, which is already authorised in the European Union (EU). The company that makes Xigduo has agreed that its scientific data can be used for Ebymect ( informed consent ). Dapagliflozin in combination with metformin was evaluated in 6 main studies involving 3,200 adults with type 2 diabetes. In one main study, when dapagliflozin was used at a dose of 5 mg twice a day in addition to metformin (the same combination as in Ebymect), it decreased HbA 1c (glycosylated haemoglobin) levels by 0.65% after 16 weeks, compared with a reduction of 0.30% with placebo (a dummy treatment) and metformin. HbA 1c is a substance in the blood which gives an indication of how well the blood glucose is controlled. Two other studies showed that dapagliflozin taken with metformin and another diabetes medicine, sitagliptin or insulin, for 24 weeks, further decreased HbA 1c : the dapagliflozin combination decreased HbA 1c levels by 0.40% more than placebo and metformin when added to sitagliptin, and by 0.61% more than placebo and metformin when added to insulin. Further studies confirmed that different doses of dapagliflozin with metformin decreased HbA 1c more than placebo plus comparable doses of metformin, and that dapagliflozin plus metformin was at least as effective in reducing HbA 1c levels as the diabetes medicine glipizide (a type of medicine known as a sulphonylurea). One study showed that after 24 weeks of treatment, patients taking dapagliflozin plus metformin had an average reduction in body weight of around 2 kg more than those taking placebo plus metformin. Page 1/7

2 Unknowns relating to treatment benefits In the studies to determine how well dapagliflozin worked, most people were white and aged 18 to 65 years. Although fewer people in the study were non-white and/or older than 65 years, there is no evidence showing dapagliflozin would not work as well in these individuals. Summary of safety concerns Important identified risks Risk Preventability Yeast infections of the vagina, vulva or penis (genital infections) Bladder and urinary system infection (urinary tract infection) Build up of lactic acid in the body (lactic acidosis) One of the active substances in Ebymect, dapagliflozin, increases the amount of sugar in the urine, which may encourage the growth of bacteria and fungi in the genital area due to exposure to this urinary sugar. Yeast infections of the genitals were reported in about 1 patient in 20 over a 6-month period in the studies. Yeast infections may be more likely in women and in patients who have previously had this type of infection. Dapagliflozin increases the amount of sugar in the urine, which may encourage the growth of bacteria. Infections of the bladder or urinary system occurred in about 4 patients in 100 during the studies. Such infections may be more likely in women and in people with a history of bladder infections. Metformin, one of the active substances in Ebymect, is removed from the body by the kidneys and in patients with kidney disease, the levels of metformin in the body may increase. Too much metformin can in turn lead to a build-up of a substance called lactic acid in the body. This is very rare but also very serious and can be life threatening. Cleanliness of the vagina and external genitals will lower the risk of yeast infections. If genital yeast infections occur they are treatable with usual antifungal medicines and patients should consult their doctor or pharmacist for treatment. If infections of the bladder and urinary system occur they can be treated with antibiotics. It is very important that patients receive prompt and appropriate antibiotic treatment as an untreated bladder infection may cause a very serious kidney infection which can lead to permanent kidney damage. Doctors should consider temporarily interrupting treatment when treating certain infections. Patients medications and overall health should be regularly reviewed by their doctor. Patients must not take more medicine than recommended by the doctor. They should avoid drinking alcohol heavily or frequently as it can increase the risk of lactic acidosis with metformin. People with serious kidney or liver disease should not take Ebymect. Patients should be instructed to call their doctor and go to the hospital immediately if they develop symptoms of lactic acidosis such as stomach pain, cramps, sleepiness, feeling very sick or fast breathing. Page 2/7

3 Important potential risks Risk Low blood sugar levels (hypoglycaemia) Loss of body fluid (volume depletion ) Kidney (renal) failure Abnormal blood test (clinical consequence of increased haematocrit) Broken bone ( Bone fracture ) Liver injury Hypersensitivity reactions (intolerance, allergy) Bladder cancer Diabetes medicines can sometimes lower blood sugar levels too much, which can be very serious and life threatening. In studies, patients taking dapagliflozin did not develop hypoglycaemia any more often than patients taking a placebo (dummy treatment). When dapagliflozin was added to other diabetic medicines, the frequency of hypoglycaemia was similar to that with the other. Hypoglycaemia occurred most frequently in individuals who were also using insulin. Because of the way dapagliflozin works, patients pass more urine. This may reduce fluid in the blood stream. Less than 1 patient in 100 may have symptoms related to this loss of fluid (dehydration), including feeling dizzy or light-headed, having low blood pressure and feeling thirsty. Because of the way dapagliflozin works there is a possibility that it could affect the kidneys and stop them working properly (renal failure). However, studies with the medicine have not shown that dapagliflozin causes kidney failure or worsens kidney failure. Dapagliflozin causes a small increase in the number of red blood cells. This is measured by blood tests called haematocrit or haemoglobin tests. These small increases are of most importance for individuals who already have high haematocrit or haemoglobin levels in whom care is needed as high haematocrit or haemoglobin levels may be associated with the blood not flowing as well or with increased blood clotting. Dapagliflozin may affect the way the body maintains and strengthens bones, so an increased likelihood of broken bones is considered a risk with Ebymect. However, in a year-long study, 10 patients on dapagliflozin had a broken bone, which was similar to the rate in the group not taking dapagliflozin. A longer, 2-year study is ongoing to evaluate effects on bones. Data so far do not indicate dapagliflozin contributes to bone weakness or causes broken bones. Liver injury is considered a potential risk of dapagliflozin. One patient in studies to approve the medicine for licensing had a very serious liver injury but this appears to have been from another medical condition. A small number of patients had less serious liver injury. In these patients, there were other potential causes of liver injury, such as alcohol use. The risk of liver injury is part of ongoing safety monitoring with the medicine. Patients have reported skin reactions and itching occurring after starting dapagliflozin. Patients given other medicines similar to dapagliflozin have also reported side effects like skin rash, hives and itching. These reports may indicate this group of medicines has the potential to cause hypersensitivity reactions. However, evidence of allergy or intolerance to dapagliflozin was not seen in studies to approve the medicine for licensing. In studies, a small number of patients taking dapagliflozin were diagnosed with bladder cancer and this was seen more often than in patients taking placebo. However, in most of these patients tests indicated the possible presence of the cancer very early on, often before taking the medicine, suggesting that it did not play a role in cancer development. Almost all Page 3/7

4 Risk patients also had risk factors for bladder cancer, such as smoking. There is no evidence from laboratory studies that raises concern about dapagliflozin causing or encouraging the growth of any type of cancer including bladder cancer, but the potential risk continues to be monitored. Individuals taking another diabetes medicine, pioglitazone, may be at higher risk of developing bladder cancer and, as a precaution, Ebymect is not recommended for use in patients also taking pioglitazone. Breast cancer In clinical studies, a small number of women treated with dapagliflozin had breast cancer (12 women out of over 5,900, or about 2 cases per 1,000 patients). Breast cancer was also seen in these studies in women who were not taking the medicine (3 women out of 1,500, also representing about 2 cases per 1,000 patients). There is no evidence from laboratory studies that raises concern about dapagliflozin causing or encouraging the growth of any type of cancer including breast cancer, but the potential risk continues to be monitored. Prostate cancer Use of the medicine outside the approved conditions (off-label use) Men who took dapagliflozin did not have prostate cancer any more often than men using the placebo. There is no evidence from laboratory studies that raises concern about dapagliflozin causing or encouraging the growth of any type of cancer including prostate cancer. There is a potential risk that Ebymect may be used in patients outside its licensed and approved conditions. It should not be taken by: individuals 75 years of age or older those with severe kidney disease those taking a loop diuretic such as furosemide those taking the diabetes medicine pioglitazone Missing information Risk Children (paediatric population) Pregnant women and women who are breastfeeding (pregnancy and lactation) Elderly patients (over 65 years) Severely reduced kidney function (severe renal Ebymect has not been studied in children, and they should not take this medicine. Ebymect has not been studied in pregnant women or in women who are breastfeeding. Use of dapagliflozin beyond the first trimester of pregnancy or during breastfeeding may increase the risk of kidney malformation in the developing fetus, and of decreased growth in the child. For this reason, these women should not take dapagliflozin. Older patients may have poorer kidney function and may be more prone to dehydration. This medicine requires adequate kidney function to be effective and it may cause dehydration. Clinical trial participation was limited in patients 75 years old or older. Adults aged 75 years or older should not start treatment with dapagliflozin. Ebymect must not be used in patients with moderately or severely reduced kidney function. Page 4/7

5 Risk impairment) Moderately and severely reduced liver function (hepatic impairment) Severe heart failure (congestive heart failure defined as New York Heart Association (NYHA) class III and IV) Ebymect must not be used in patients with reduced liver function. No clinical studies on dapagliflozin have included people with severe heart failure. For this reason, people with severe heart failure should not take dapagliflozin. Summary of risk minimisation measures by safety concern All medicines have a summary of product characteristics (SmPC) which provides physicians, pharmacists and other healthcare professionals with details on how to use the medicine, and also describes the risks and recommendations for minimising them. Information for patients is available in lay language in the package leaflet. The measures listed in these documents are known as routine risk minimisation measures. The SmPC and the package leaflet are part of the medicine s product information. The product information for Ebymect can be found on Ebymect s EPAR page. This medicine has no additional risk minimisation measures. Planned post-authorisation development plan List of studies in post-authorisation development plan Study/activity (including study number) Objectives Safety concerns /efficacy issue addressed Status Planned date for submission of (interim and) final results Study of severe complications of urinary tract infections in treated with dapagliflozin (MB102103) Study of liver injury in diabetic patients treated often patients are admitted to hospital or treated in emergency department for severe complications of urinary tract infections. often patients are admitted to Urinary system infection (urinary tract infection) Ongoing in 2019 Liver injury Ongoing in 2019 Page 5/7

6 Study/activity (including study number) Objectives Safety concerns /efficacy issue addressed Status Planned date for submission of (interim and) final results with dapagliflozin (MB102104). Study of kidney disease in diabetic patients treated with dapagliflozin (MB102110). Study of cancer in treated with dapagliflozin (MB102118). Study of cardiovascular disease in diabetic patients treated with dapagliflozin (MB102117/D169 3C00001). hospital for liver injury. often patients are admitted to hospital for kidney disease. often patients develop breast or bladder cancer. To investigate the effect of Forxiga (dapagliflozin) on cardiovascular disease in patients with type 2 diabetes Reduced kidney function (renal failure) Ongoing in 2019 Risk of cancer Ongoing in Cardiovascular Ongoing disease in 2020 Study to investigate if patients who should not be treated with dapagliflozin still are (MB102134). To investigate if Xigduo/Ebymect is used in individuals 75-years-old or older, in individuals with severe kidney disease, in individuals taking a loop diuretic medicine or in individuals taking the diabetes Use of the medicine outside the approved conditions ( offlabel use) Ongoing in 2017 Page 6/7

7 Study/activity (including study number) Objectives Safety concerns /efficacy issue addressed Status Planned date for submission of (interim and) final results medicine pioglitazone. Studies which are a condition of the marketing authorisation None of the above studies is a condition of the marketing authorisation. Summary of changes to the risk management plan over time Major changes to the Risk Management Plan over time Not applicable. This summary was last updated in Page 7/7