Summary of the risk management plan (RMP) for Vokanamet (canagliflozin / metformin)

Transcription

1 EMA/137565/2014 Summary of the risk management plan (RMP) for Vokanamet (canagliflozin / metformin) This is a summary of the risk management plan (RMP) for Vokanamet, which details the measures to be taken in order to ensure that Vokanamet 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 Vokanamet, which can be found on Vokanamet s EPAR page. Overview of disease epidemiology 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 known to be 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 Vokanamet has been developed as a fixed-dose combination product containing canagliflozin and metformin. Canagliflozin was authorised in the EU under the brand name Invokana in November Canagliflozin works in the kidneys, where it increases the amount of sugar in the urine, thereby lowering and helping to control blood sugar levels. The authorisation of canagliflozin was based on the results of 9 major clinical trials involving approximately 10,000 patients, including around 5,000 who took canagliflozin with metformin. Metformin works mainly by inhibiting glucose production in the liver and reducing its absorption in the gut; metformin has been available in the EU since the 1950s. When used alone or in combination with metformin, canagliflozin has been shown to improve control of blood sugar but also to decrease body weight and reduce blood pressure. In addition, the combination of canagliflozin and metformin was shown to improve control of blood sugar when used with other medicines such as insulin. Unknowns relating to treatment benefits There is limited or no information about the use of Vokanamet in children and adolescents less than 18 years old or in pregnant or breast-feeding women. Page 1/7

2 Summary of safety concerns Important identified risks Risk What is known Preventability Excessive lactic acid in the blood (Lactic acidosis) Vaginal yeast infections (Vulvovaginal candidiasis) Yeast infection of the head of the penis (Balanitis or balanoposthitis) Bladder infections (Urinary tract infections) The use of metformin has been associated with excessive lactic acid in the blood. This is a very rare complication (occurring in less than 1 in 10,000 patients) but it is serious, particularly if the kidneys are not working properly. Approximately 1 in 10 women treated with canagliflozin may experience some form of vaginal yeast infection and approximately 2 in 100 may experience more than one yeast infection while being treated with canagliflozin. These infections often respond to topical or oral antifungal treatment while the patient is continued on canagliflozin therapy. Approximately 1 in 20 men treated with canagliflozin may experience inflammation of the head of the penis associated with a yeast infection. The majority of men who experienced this are uncircumcised. Approximately 1 in 200 men stopped treatment with canagliflozin due to the infection. The majority of infections were treated with and responded to topical antifungal treatments. In rare instances, uncircumcised men reported a narrowing of the opening in the foreskin which sometimes led to circumcision being performed. Approximately 1 in 20 patients treated with canagliflozin may experience urinary tract infections, with a higher occurrence in women than men. The risk of excessive lactic acid in the blood may be significantly decreased by regular monitoring of kidney function in patients taking metformin, and by avoiding the consumption of alcohol. Elderly patients in particular should have their kidney function monitored. By providing advice regarding preventative measures (e.g. avoidance of tight-fitting undergarments). For women with recurrent infections, preventative antifungal therapy can be used. By providing patients at risk (especially uncircumcised men) advice regarding proper cleaning of the penis after urination to avoid urinary contamination of the foreskin. By providing advice regarding preventative measures (avoiding use of scented douches and hygiene sprays) and drinking 6 to 8 glasses of water every day. Page 2/7

3 Risk What is known Preventability Low blood sugar (Hypoglycaemia in combination with insulin or medicines that increase insulin secretion independent of glucose levels) Dehydration (Volume depletion) Bone fractures (Bone fractures) A few patients may experience low blood sugar due to treatment with canagliflozin. Low blood sugar may be experienced more often when a patient is already taking other medicines known to cause low blood sugar (for example, insulin or sulphonylureas) in addition to canagliflozin. Approximately 1 in 100 patients treated with canagliflozin may experience symptoms related to dehydration low blood pressure and dizziness). The symptoms of dizziness may be more common in individuals with a history of kidney disease (occurring in approximately 1 in 20 patients with history of kidney disease) or in individuals on certain water pills known as loop diuretics. In patients with a known or high risk of heart disease, approximately 2 in 100 patients treated with canagliflozin for 1 year may experience a bone fracture. In a study of older patients, canagliflozin did not reduce bone density after 2 years of treatment. Physicians should assess the patient s risk prior to starting treatment with Vokanamet, adjust other diabetes treatments as necessary and educate the patient to recognise symptoms of low blood sugar. Where possible, symptoms of dehydration observed in patients should be corrected prior to starting treatment with Vokanamet. Patients with a history of kidney disease should not take Vokanamet. Patients should be educated on the signs of dehydration and encouraged to report these should they occur. If dehydration does occur, Vokanamet may be stopped temporarily until it has resolved. Vokanamet should not be taken by patients on certain water pills known as loop diuretics. Patients in the heart disease trial may be more susceptible to dehydration if they take a medicinal product like canagliflozin that increases urination and they may be at increased risk of falls. Therefore, if symptoms of dehydration are observed in patients, such symptoms should be corrected prior to starting treatment with canagliflozin (see above section on dehydration). Important potential risks Risk What is known Reduced kidney function or kidney failure Side effects that affecting the kidney occurred slightly more often in patients who took canagliflozin than in patients who did not take Page 3/7

4 Risk (Renal impairment/renal failure) Potential consequences of increased amount of red blood cells in the blood (clinical consequences of increased haematocrit) Sensitivity to sunlight (Photosensitivity) Low blood sugar (Hypoglycaemia in the absence of insulin or medicines that increase insulin secretion independent of glucose levels) Off-label use for weight loss What is known canagliflozin. These side effects changes that showed up in blood tests) occurred more often in patients who were elderly or had a history of kidney damage and especially with the higher daily dose of 300 mg canagliflozin (compared with the lower dose of 100 mg canagliflozin). These side effects are typically mild and usually resolve or improve upon stopping Vokanamet. About 5 times more people treated with canagliflozin experienced an increase in the amount of red blood cells in their blood compared with patients not treated with canagliflozin; however, very rarely did this increase exceed the level considered normal. Increases in the amount of red blood cells in the blood may lead to the formation of blood clots in the heart, lungs, or vessels in the leg or thigh (deep vein thrombosis). If left untreated, these blood clots have the potential to cause severe heart attacks and death. In clinical trials with canagliflozin, these blood clots occurred very rarely and at the same rate in patients treated with canagliflozin and patients not treated with canagliflozin (about 2 in 1000 patients) and they did not lead to an increased rate of heart attacks or hospitalisation. In healthy volunteers treated with canagliflozin and exposed to a light intensity 30 times stronger than natural sunlight, swelling of the area of skin exposed to the light was seen. This swelling was markedly reduced when the light intensity was reduced to 3 times stronger than natural sunlight. In large clinical trials, very few patients developed a reaction to sun exposure. This reaction occurred in about 3 in 1,000 patients treated with canagliflozin and in about 2 in 1,000 patients not treated with canagliflozin. Some patients treated with canagliflozin experienced episodes of low blood sugar. In clinical trials with canagliflozin alone or in combination with other medicines not known to increase insulin secretion independent of glucose levels (e.g.metformin, sitagliptin, or pioglitazone), a small number approximately 41 in 1,000 of patients treated with canagliflozin experienced low blood sugar compared with approximately 22 in 1,000 patients not treated with canagliflozin. However, these episodes of low blood sugar were rarely severe and patients rarely required help to treat their low blood sugar. Canagliflozin reduces reabsorption of sugar into the bloodstream and increases the loss of sugar in the urine leading to weight loss. However, in non-diabetic individuals, with blood sugar levels in the normal or near normal range, canagliflozin leads to smaller increases in loss of sugar in the urine, which leads to smaller reductions in body weight than observed in clinical trials of patients with type 2 diabetes. It is acknowledged that although it seems unlikely that healthcare professionals would prescribe Vokanamet for weight reduction in nondiabetic patients, there is the potential for Vokanamet to be misused in an attempt to achieve weight loss. Page 4/7

5 Missing information Risk Long-term cardiovascular safety in patients Long-term safety data for bladder cancer Use in patients with severe heart failure Use in paediatric patients between 10 and 18 years of age Use in pregnancy What is known There is no evidence of an increased cardiovascular risk with canagliflozin relative to other treatments. Additional data are being collected to continue to evaluate long-term cardiovascular safety in patients. There is no evidence of an increased risk of bladder cancer with canagliflozin. Additional data are being collected to evaluate long-term safety data for bladder cancer. Vokanamet is contraindicated in patients with diseases which may reduce the levels of oxygen in the body such as heart failure. There is no experience with Vokanamet in paediatric patients under 18 years of age. There are no data from the use of canagliflozin alone or of Vokanamet in pregnant women. A study in young rats showed effects of canagliflozin on the developing kidney. Animal studies with metformin do not indicate harmful effects with respect to pregnancy, fetal development, delivery, or development after birth. Vokanamet should not be used during pregnancy. When pregnancy is detected, treatment with Vokanamet should be discontinued. Use during breastfeeding It is unknown whether canagliflozin is released in human milk. Available animal data have shown release of canagliflozin in milk, as well as effects in breastfeeding offspring and juvenile rats exposed to canagliflozin. Metformin is released into human breast milk in small amounts. No studies in animals that are breastfeeding have been conducted with Vokanamet. A risk to newborns/infants cannot be excluded; therefore Vokanamet should not be used during breastfeeding. Use in very elderly patients ( 85 years) Use in patients with severe liver impairment Use in patients with severe kidney impairment Data regarding the risks associated with use of canagliflozin in very elderly patients ( 85 years) are limited. Vokanamet is contraindicated in patients with reduced liver function. Vokanamet is contraindicated in patients with moderate and severe reduction in kidney function. 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, the risks and Page 5/7

6 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. The Summary of Product Characteristics and the Package leaflet for Vokanamet can be found in the Vokanamet 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 study number) Objectives Safety concerns /efficacy issue addressed Status Planned date for submission of (interim and) final results DIA3008 effects of canagliflozin on major cardiovascular events Cardiovascular safety Renal impairment/renal failure Ongoing Independent Data Monitoring Committee (IDMC) Status (MACE) in adult subjects with type 2 diabetes Clinical consequences of increased haematocrit Reports: Twice annually until study Bone fractures completion. Photosensitivity Final report: Bladder cancer 2Q 2018 DIA4003 To assess the effects of canagliflozin on renal endpoints in adult subjects with Cardiovascular safety Bladder cancer Ongoing Final report: second Q 2018 type 2 diabetes and an elevated risk of cardiovascular events Cardiovascular meta-analysis DIA3008 and DIA4003) Primary bladder cancer metaanalysis Establish the upper bound of the 2-sided 95% CI of the MACE events hazard ratio for the combined canagliflozin group compared with the placebo group excludes 1.3 post approval incidence of bladder cancer in the Cardiovascular safety Planned Final report expected fourth quarter 2017 Bladder cancer Planned Final report expected fourth quarter 2017 Page 6/7

7 Study/activity study number) Objectives Safety concerns /efficacy issue addressed Status Planned date for submission of (interim and) final results canagliflozin group DIA3008 and compared with the DIA4003) placebo group. DNE3001 effects of canagliflozin on renal and cardiovascular outcomes in subjects with type 2 diabetes and diabetic nephropathy Bladder cancer Ongoing IDMC Status Reports to be submitted twice annually until study completion. Final report expected third quarter 2019 Secondary bladder cancer meta-analysis DIA3008, DIA4003, and DNE3001),, if indicated following results of primary metaanalysis incidence of bladder cancer in the canagliflozin group compared with the placebo group. Bladder cancer Planned Final report expected third quarter 2019 Studies which are a condition of the marketing authorisation None of the above trials are conditions of the marketing authorisation. Summary of changes to the risk management plan over time Not applicable. This summary was last updated in Page 7/7