Summary of Risk Management Plan for VOKANAMET (Canagliflozin/Metformin Hydrochloride Fixed Dose Combination)

Transcription

1 Summary of Risk Management Plan for VOKANAMET (Canagliflozin/Metformin Hydrochloride Fixed Dose Combination) This is a summary of the risk management plan (RMP) for VOKANAMET. The RMP details important risks of VOKANAMET, how these risks can be minimised, and how more information will be obtained about VOKANAMET s risks and uncertainties (missing information). VOKANAMET s summary of product characteristics (SmPC) and its package leaflet (PL) provide essential information to healthcare professionals and patients on how VOKANAMET should be used. This summary of the RMP for VOKANAMET should be read in the context of all this information including the assessment report of the evaluation and its plainlanguage summary, all which is part of the European Public Assessment Report (EPAR). Important new concerns or changes to the current ones will be included in updates of VOKANAMET s RMP. I. The Medicine and What it is Used For VOKANAMET is authorised for treatment of adults with insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise (see SmPC for the full indication). VOKANAMET is a fixed dose combination containing canagliflozin and metformin as two different active substances. These are two medicines that work together in different ways to lower blood glucose (sugar) levels and can help prevent heart disease in adults with type 2 diabetes. It can be used by itself, or in combination with other medicinal products for the treatment of diabetes. It also can be used in patients already being treated with the combination of canagliflozin and metformin as separate tablets. VOKANAMET is given as an oral film-coated tablet (canagliflozin/metformin hydrochloride 50 mg/850 mg, 50 mg/1000 mg, 150 mg/850 mg, 150 mg/1000 mg). Further information about the evaluation of VOKANAMET s benefits can be found in VOKANAMET s EPAR, including in its plain-language summary, available on the EMA website, under the medicine s webpage:

2 II. Risks Associated with the Medicine and Activities to Minimise or Further Characterise the Risks Important risks of VOKANAMET, together with to minimise such risks and the proposed studies for learning more about VOKANAMET risks, are outlined below. Measures to minimise the risks identified for medicinal products can be: Specific information, such as warnings, precautions, and advice on correct use, in the package leaflet and SmPC addressed to patients and healthcare professionals; Important advice on the medicine s packaging; The authorised pack size the amount of medicine in a pack is chosen so to ensure that the medicine is used correctly; The medicine s legal status the way a medicine is supplied to the patient (e.g. with or without prescription) can help to minimise its risks. Together, these constitute routine risk minimisation. In the case of VOKANAMET, these are supplemented with additional risk minimisation mentioned under relevant important risks, below. In addition to these, information about adverse reactions is collected continuously and regularly analysed, including Periodic Safety Update Report (PSUR) assessment so that immediate action can be taken as necessary. These constitute routine pharmacovigilance activities. If important information that may affect the safe use of VOKANAMET is not yet available, it is listed under missing information below. II.A. List of Important Risks and Missing Information Important risks of VOKANAMET are risks that need special risk management activities to further investigate or minimise the risk, so that the medicinal product can be safely taken. Important risks can be regarded as identified or potential. Identified risks are concerns for which there is sufficient proof of a link with the use of VOKANAMET. Potential risks are concerns for which an association with the use of this medicine is possible based on available data, but this association has not been established yet and needs further evaluation. Missing information refers to information on the safety of the medicinal product that is currently missing and needs to be collected (eg, on the long-term use of the medicine). List of Important Risks and Missing Information Important identified risks Volume depletion

3 List of Important Risks and Missing Information Important potential risks Missing information II.B. Bone fractures Renal impairment/renal failure Diabetic ketoacidosis with atypical presentation Lower limb amputation Lactic acidosis Clinical consequences of increased haematocrit Photosensitivity Pancreatitis Long-term safety data for bladder cancer Use in pregnancy Use in nursing mothers Summary of Important Risks Important Identified Risk: Volume depletion Adverse events related to reduced intravascular volume (eg, events of low blood pressure, dizziness or low blood pressure with standing, dehydration, and fainting) in association with canagliflozin have been reported in previously completed randomised, double-blind, controlled clinical trials, and are also described in the current prescribing information for canagliflozin. Patients on a loop diuretic, those with moderate renal impairment (estimated glomerular filtration rate [egfr] 30 to <60 ml/min/1.73 m 2 ) or patients 75 years of age had a higher occurrence of adverse reactions related to volume depletion on treatment with canagliflozin relative to control. Decrease in intravascular volume is also reflected by increases in blood urea nitrogen (BUN) and serum creatinine (with commensurate small decreases in egfr).

4 Important Identified Risk: Volume depletion Additional pharmacovigilance activities Routine risk minimisation : SmPC Section 4.8 and PL Section 4. Recommendations regarding appropriate dosing and patient management (including advice on correction of volume depletion prior to initiating therapy, monitoring of volume status, temporary interruption) are provided in SmPC Sections 4.2 and 4.4; Recommendations to patient regarding prevention and management of dehydration (including advice to discontinue treatment and contact physician if dehydration occurs) is provided in PL Sections 2 and 4. Additional risk minimisation : None. Additional pharmacovigilance activities: Analysis of events from DNE3001 (CREDENCE).

5 Important Identified Risk: Bone fractures Additional pharmacovigilance activities At the onset of the clinical development programme, an extensive clinical assessment of bone health was undertaken based on the finding of hyperostosis in canagliflozin-treated rats. As part of the Phase 3 programme, bone mineral density (BMD) were done in the 104-week Phase 3 trial and fractures across ongoing trials were collected and adjudicated. Since the inception of the clinical programme and based on the outcome of nonclinical and clinical mechanistic studies, hyperostosis was deemed to not be of relevance to human safety. In the DIA3008 [CANVAS] trial, a cardiovascular outcome trial in T2DM subjects with known, or at high risk of, cardiovascular disease, an increased risk of bone fracture with canagliflozin treatment was reported. However, in a sister study with a nearly identical population (DIA4003 [CANVAS-R]), no increased risk was observed. In other canagliflozin trials that enrolled a population not at high risk for cardiovascular disease, no difference in fracture risk was observed relative to comparators. Fracture is described in the current prescribing information for canagliflozin. In the canagliflozin clinical trial programme, subjects treated with canagliflozin with known or at high risk for cardiovascular disease (ie, subjects from the DIA3008 trial) were identified as having a higher risk for bone fractures than subjects in the general T2DM population. Routine risk minimisation : SmPC Section 4.8 and PL Section 4. Additional risk minimisation : None. Routine pharmacovigilance activities beyond adverse reactions reporting and signal detection: Adjudication of all bone fracture events from ongoing clinical trials for type of fracture (low trauma, high trauma, pathologic, stress, other) by an independent blinded committee. Additional pharmacovigilance activities: Analysis of events from DNE3001 (CREDENCE).

6 Important Identified Risk: Renal impairment/renal failure Additional pharmacovigilance activities In previously completed randomised, double-blind, controlled clinical trials in T2DM patients, reductions in egfr in association with canagliflozin have been reported, and are described in the current prescribing information for canagliflozin. Renal failure (mainly related to volume depletion) in association with canagliflozin has been observed during postmarketing experience, and is also described in the current prescribing information for canagliflozin. Subjects treated with canagliflozin who were on loop diuretics, those with moderate renal impairment at baseline (egfr 30 to < 60 ml/min/1.73 m 2 ), or patients 75 years of age had an increased incidence of larger reductions in egfr relative to non-canagliflozin-treated subjects, with a greater increase observed with 300 mg relative to 100 mg of canagliflozin. Routine risk minimisation : SmPC Section 4.8 and PL Section 4. Recommendations regarding appropriate dosing and patient management (including advice on discontinuation) provided in SmPC Section 4.2; Advice to patients who have kidney problems is provided in PL Sections 2 and 3; Advise on the use of canagliflozin in patients at increased risk of renal impairment provided in SmPC Section 4.2; Advise on the monitoring of renal function is described in SmPC Section 4.4 and PL Section 2. Additional risk minimisation : None Additional pharmacovigilance activities: Analysis of events from DNE3001 (CREDENCE).

7 Important Identified Risk: Diabetic ketoacidosis with atypical presentation Diabetic ketoacidosis (DKA) has been reported during postmarketing experience with canagliflozin in type 2 diabetes mellitus (T2DM) patients, including cases with fatal outcomes. An atypical presentation (blood glucose values less than 13.9 mmol/l [250 mg/dl]) has been observed with diagnosis of DKA. Cases of ketoacidosis have occurred during off-label use of sodium-glucose co-transporter 2 (SGLT2) inhibitors in type 1 diabetes mellitus (T1DM) patients and in T1DM clinical trials (European Medicines Agency [EMA], 2017). In an 18-week Phase 2 trial in subjects with T1DM (DIA2004), the frequency of DKA was relatively more frequent to the rate observed in T2DM clinical trials. The available clinical trial data suggest that patients diagnosed as having T2DM or misdiagnosed as T2DM (eg, T1DM, latent autoimmune diabetes of adulthood [LADA]), and who have a low beta-cell reserve, are unable to produce sufficient insulin to suppress hepatic ketogenesis and peripheral lipolysis. In the setting of known DKA precipitating factors, such as an acute illness (and associated increase in insulin resistance), these patients can develop DKA.

8 Important Identified Risk: Diabetic ketoacidosis with atypical presentation Additional pharmacovigilance activities Routine risk minimisation : SmPC Section 4.8. Recommendations regarding appropriate dosing and patient management (including advice on discontinuation and restart) provided in SmPC Section 4.4; Advice to patients who have diabetic ketoacidosis, including a warning that canagliflozin should not be used to treat this condition, is provided in PL Sections 2 and 4; Advice on when to suspect DKA is provided in SmPC Section 4.4 and PL Sections 2 and 4; Description of factors that may predispose patients to DKA, and advice on use in patients at higher risk for DKA are provided in SmPC Section 4.4 and PL Section 2; Warning not to use canagliflozin in patients with T1DM is provided in Section 4.4 and PL Section 2. Additional risk minimisation : DHPC. Routine pharmacovigilance activities beyond adverse reactions reporting and signal detection: Specific adverse reaction follow-up questionnaire; Adjudication of diabetic ketoacidosis events from ongoing clinical trials by an independent blinded committee. Additional pharmacovigilance activities: Nonclinical Study 1; Nonclinical Study 2; Retrospective Drug Utilisation Study 1; Retrospective DKA Epidemiology Cohort Study 2. See Section II.C of this summary for an overview of the postauthorisation development plan.

9 Important Identified Risk: Lower limb amputation In long-term clinical studies of canagliflozin in type 2 diabetes patients with cardiovascular disease or at high risk for cardiovascular disease, an increase in cases of lower limb amputation (primarily of the toe and mid-foot) has been observed in patients treated with canagliflozin, and is described in the current prescribing information for canagliflozin. In the canagliflozin clinical trial programme, subjects treated with canagliflozin with known or at high risk for cardiovascular disease (ie, subjects from the DIA3008 [CANVAS] and DIA4003 [CANVAS-R] trials) were identified as having a higher risk for amputation than subjects in the general T2DM population. Among these subjects, the 3 strongest predictors for amputation risk were a prior history of amputation, a history of peripheral vascular disease and neuropathy. Routine risk minimisation : SmPC Section 4.4 and PL Section 2; SmPC Section 4.8 and PL Section 4. Recommendations regarding management of patients at higher risk for amputation events, including monitoring, preventative, and discontinuation, are provided in SmPC Section 4.4. Additional risk minimisation : DHPC.

10 Important Identified Risk: Lower limb amputation Additional pharmacovigilance activities Routine pharmacovigilance activities beyond adverse reactions reporting and signal detection: Specific adverse reaction follow-up questionnaire for postmarketing events and a dedicated case report form page (with collection of preceding events) for ongoing trials. Additional pharmacovigilance activities: Meta-analysis of amputation events from clinical trials DIA3008 (CANVAS), DIA4003 (CANVAS-R), and DNE3001 (CREDENCE). Lower Limb Amputation Retrospective Observational Epidemiology Cohort Study See section II.C of this summary for an overview of the postauthorisation development plan. Important Identified Risk: Lactic acidosis Evidence for lactic acidosis from metformin is based on the literature, including case reports, review of clinical trials and observational studies, as well as metformin drug labels. Lactic acidosis is a rare, but serious metabolic complication that can occur due to metformin accumulation. Reported cases of lactic acidosis in patients on metformin have occurred primarily in diabetic patients with significant renal failure (Metformin SmPC, 2015). Lactic acidosis has been reported in Phase 3/4 clinical trials when canagliflozin was given to subjects who were on a background of metformin, but at a lower incidence than observed in the placebo group. Risk factors include conditions that may be associated with or promote hypoxia, including heart failure, tissue hypoxia, respiratory failure, defective lactate clearance (alcohol abuse, and liver failure), renal impairment, renal or hepatic insufficiency. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient s age. Routine risk communication: SmPC Section 4.2; SmPC Section 4.4 and PL Section 2; SmPC Section 4.8 and PL Section 4.

11 Important Identified Risk: Lactic acidosis Additional pharmacovigilance activities Contraindication in patients with an increased risk of lactic acidosis is described in SmPC Section 4.3 and PL Section 2, including detailed list of conditions; Patient management of dehydration is described in SmPC Section 4.4 and PL Section 2; Recommendations regarding concomitant use with medicinal products that acutely impair renal function or cause lactic acidosis or its use in patients with risk factors for lactic acidosis are provided in SmPC Section 4.4; Patient management of lactic acidosis, including guidance on diagnosis, discontinuation, and need for medical attention, is described in SmPC Section 4.4 and PL Section 4; Recommendations for monitoring of renal function is provided in SmPC Section 4.4 and PL Section 4; Advice on concomitant use with alcohol, medicinal products containing alcohol, cationic drugs that are eliminated by renal tubular secretion, iodinated contrast agents, and medicinal products that can adversely affect renal function is provided in SmPC Section 4.5 and PL Section 2; Advice on patient management of overdose, including how to remove lactate and metformin (haemodialysis), is provided in SmPC Section 4.9. Additional risk minimisation : None. Routine pharmacovigilance activities beyond adverse reactions reporting and signal detection: Specific adverse reaction follow-up questionnaire.

12 Important Potential Risk: Clinical consequences of increased haematocrit In previously completed randomised, double-blind, controlled clinical trials, small mean percent increases from baseline for haemoglobin, and similar increases in blood erythrocytes and haematocrit, were observed with the use of canagliflozin. There was no increase in venous thromboembolic events (eg, deep vein thrombosis or pulmonary embolism) with canagliflozin treatment. No risk or risk factors were identified for venous thromboembolic events in subjects treated with canagliflozin. Routine risk minimisation : SmPC Section 4.8 and PL Section 4. Advise on the use of canagliflozin in patients with a pre-existing elevation in haematocrit is provided in Section 4.4. Additional risk minimisation : None. Important Potential Risk: Photosensitivity The potential for phototoxicity associated with canagliflozin use was suggested by an in vitro study in 3T3 fibroblasts, and a subsequent single-dose in vivo phototoxicity study in rats. Phase 1 clinical photosensitivity found no delayed photosensitivity effect (ie, exaggerated sunburn) that would be clinically reflected as increased sensitivity as with other photosensitising agents. No to minimal immediate photosensitivity response (ie, urticaria) was demonstrated with an irradiance approximately 3-fold higher than natural sunlight. In previously completed randomised, double-blind, controlled clinical trials, the incidence of photosensitivity events was low and similar in subjects receiving canagliflozin compared to non-canagliflozin comparators. No specific at higher risk for photosensitivity were identified in the canagliflozin development programme. Patients with a lighter complexion or a prior history of sensitivity to light may be at increased risk for photosensitivity reactions.

13 Important Potential Risk: Photosensitivity No risk minimisation Important Potential Risk: Pancreatitis Additional pharmacovigilance activities No plausible biologic mechanism of pancreatitis in association with canagliflozin has been identified based on nonclinical toxicology studies. There is no evidence for nonclinical toxicity in association with canagliflozin based on chronic toxicology studies or chronic carcinogenicity studies in rodents or dogs. In previously completed randomised, double-blind, controlled clinical trials, the incidence of pancreatitis in subjects receiving canagliflozin was low and similar to subjects receiving placebo. Postmarketing reports of pancreatitis have been observed for canagliflozin; however, a causal relationship between pancreatitis and canagliflozin use has not been established. Potential risk or risk factors for experiencing an acute pancreatitis event include excessive alcohol consumption, prior history of pancreatitis, high triglycerides, family history of pancreatitis, gall stones, cigarette smoking certain medications (eg, incretins). In clinical trials with canagliflozin, identifiable risk factors, including gallstones, alcohol use, or other suspect concomitant medications (eg, dipeptidyl peptidase-4 [DPP-4] inhibitors), were observed in some cases. No risk minimisation Routine pharmacovigilance activities beyond adverse reactions reporting and signal detection: Adjudication of pancreatitis and related events from ongoing clinical trials by an independent blinded committee. Additional pharmacovigilance activities: Retrospective acute pancreatitis epidemiology cohort study. See Section II.C of this summary for an overview of the postauthorisation development plan.

14 Missing Information: Long-term safety data for bladder cancer Additional pharmacovigilance activities No risk minimisation Routine pharmacovigilance activities beyond adverse reactions reporting and signal detection: None. Additional pharmacovigilance activities: Long-term follow-up in clinical trial DNE3001 (CREDENCE); Secondary meta-analysis of bladder cancer events collected from clinical trials DIA3008 (CANVAS), DIA4003 (CANVAS-R), and DNE3001 (CREDENCE). See Section II.C of this summary for an overview of the postauthorisation development plan. Missing Information: Use in pregnancy Routine risk minimisation : SmPC Section 4.6 and PL Section 2. Recommendation regarding use of canagliflozin during pregnancy is provided in SmPC Section 4.6 and PL Section 2. Additional risk minimisation : None. Missing Information: Use in nursing mothers Routine risk minimisation : SmPC Section 4.6 and PL Section 2. Recommendation regarding use of canagliflozin during breast-feeding is provided in SmPC Section 4.6 and PL Section 2. Additional risk minimisation : None.

15 II.C. Post-authorisation Development Plan II.C.1. Studies Which are Conditions of the Marketing Authorisation There are no studies which are conditions of the marketing authorisation or specific obligation of VOKANAMET. II.C.2. Other Studies in Post-authorisation Development Plan Nonclinical Study 1 to examine the effects of both acute (single dose) and sustained (7 days) treatment with canagliflozin on renal and whole-body ketone clearance under both overnight-fasted conditions and during a period of glucagon and insulin infusions to create a hyperglucagonaemic / hypoinsulinaemic state (to mimic changes in these hormones under conditions prone to diabetic ketoacidosis). Purpose of the study: Evaluation of pathophysiological mechanisms of canagliflozin on ketone clearance and production, in order to further characterise the impact of Diabetic ketoacidosis with atypical presentation (important identified risk) on the safety profile of canagliflozin. Nonclinical Study 2 to examine the rate of increase of plasma ketone bodies during a prolonged fast when comparing dogs that have been on sustained canagliflozin treatment versus those that have been treated with vehicle. Purpose of the study: Evaluation of pathophysiological mechanisms of canagliflozin on ketone clearance and production, in order to further characterise the impact of Diabetic ketoacidosis with atypical presentation (important identified risk) on the safety profile of canagliflozin. This study is not designed to assess the extent to which observed changes are due to changes in production or clearance, but is designed to provide information about the effect of canagliflozin on the rate of increase in plasma ketone bodies under fasting conditions. DNE3001 (CREDENCE: Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation Trial) - A randomised, doubleblind, event-driven, placebo-controlled, multicentre trial of the effects of canagliflozin on renal and cardiovascular outcomes in subjects with T2DM and diabetic nephropathy. Purpose of the study: Long-term follow-up to further characterise the impact of Long-term safety data for bladder cancer (missing information) on the safety profile of canagliflozin. Data from this clinical trial will also be used in a secondary metaanalysis of bladder cancer, to further characterise Long-term safety data for bladder cancer (missing information). Data from this clinical trial will be also used in metaanalyses of amputation events, to further characterise Lower limb amputation (important identified risk). Data from this clinical trial will also be used to

16 characterise the safety concerns of bone fracture, volume depletion, and renal impairment/renal failure (important identified risks). Meta-analysis of amputation events from clinical trials DIA3008 (CANVAS), DIA4003 (CANVAS-R), and DNE3001 (CREDENCE) Purpose of the study: Evaluation of incidence rate for lower limb amputation events. Further characterise the impact of this safety concern on the safety profile of canagliflozin, to improve patient management and to update product information to inform prescribers and patients as required. Secondary meta-analysis of bladder cancer events collected from clinical trials DIA3008 (CANVAS), DIA4003 (CANVAS-R), and DNE3001 (CREDENCE). Purpose of the study: The primary meta-analysis of bladder cancer adverse events data from clinical trials DIA3008 (CANVAS) and DIA4003 (CANVAS-R) was completed. The objective of this meta-analysis is to further characterise the impact of long-term safety data for bladder cancer (missing information) on the safety profile of canagliflozin. Retrospective Drug Utilisation Study 1 to evaluate drug utilisation patterns of canagliflozin including off-label usage in type 1 diabetes mellitus (T1DM). Purpose of the study: Further characterise the impact of Diabetic ketoacidosis with atypical presentation (important identified risk) on the safety profile of canagliflozin, including off-label usage in T1DM. Retrospective DKA Epidemiology Cohort Study 2: Incidence of diabetic ketoacidosis among patients with T2DM treated with SGLT2 inhibitors or other antihyperglycaemic agents- a retrospective, observational, new-user cohort study using four administrative claims databases in the US. Purpose of the study: The original DKA epidemiologic study protocol (Retrospective DKA Epidemiology Cohort Study 1) was amended per the request from the EMA. The primary objective of the current study is to compare DKA incidence between new users of SGLT2i (combined) and new users of other AHAs (a total of 7 comparator ) among patients diagnosed with T2DM and having similar baseline characteristics Acute Pancreatitis Retrospective Observational Epidemiology Cohort Study Purpose of the study: Results from this epidemiology study will further characterise the impact of Pancreatitis (important potential risk) on the safety profile of

17 canagliflozin, by evaluation of the incidence rate and comparative hazard of acute pancreatitis in T2DM patients associated with the use of SGLT2 inhibitors. Lower Limb Amputation Retrospective Observational Epidemiology Cohort Study Purpose of the study: Results from this epidemiology study will further characterise the increased risk of SGLT2 inhibitors on lower limb amputation (important identified risk), in addition to exploring potential risk factors for this adverse event.