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Expanding treatment options for type 2 diabetes: A review of the clinical efficacy and safety profile of Jardiance® (empagliflozin) The Boehringer Ingelheim and Lilly Diabetes Alliance has provided the funding for this sponsored session, including speaker honoraria and presentation development support. The presentation has been reviewed for medical accuracy and compliance with applicable laws and regulations. Boehringer Ingelheim and Lilly Diabetes Alliance products will be discussed during this presentation. Trajenta ® (linagliptin), Jentadueto®▼ (linagliptin and metformin), Jardiance®▼ (empagliflozin), Synjardy®▼ (empagliflozin and metformin) and Abasaglar ®▼ (human insulin analogue). Prescribing information can be found at the end of this presentation. Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard Adverse events should also be reported to Boehringer Ingelheim Drug Safety on 0800 328 1627 (freephone). This presentation was developed by the Boehringer Ingelheim and Lilly Diabetes Alliance. UK/EMP/00264(1) | July 2016 Content ● Mechanism of action of SGLT2 inhibitors ● Licensed indication ● Clinical efficacy ● Impact on weight and blood pressure ● Safety and tolerability profile ● Dosing and administration UK/EMP/00264(1) | July 2016 Mechanism of action of the sodium glucose co-transporter 2 (SGLT2) inhibitors UK/EMP/00264(1) | July 2016 Drug treatments for type 2 diabetes and their sites of action Glucose absorption Acarbose Decreased glucose uptake Increased glucose production Metformin GLP-1 receptor agonists DPP-4 inhibitors Insulin Hyperglycaemia Metformin Pioglitazone Insulin Impaired insulin secretion DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; SGLT2, sodium-glucose co-transporter 2 Reference Tahrani AA, et al. Lancet. 2011;378:182–197. Increased glucose reabsorption Insulin Sulphonylureas Meglitinides GLP-1 receptor agonists DPP-4 inhibitors SGLT2 inhibitors UK/EMP/00264(1) | July 2016 Renal glucose re-absorption under healthy conditions1,2 Filtered glucose load 180 g/day Virtually all of the filtered glucose is re-absorbed in the proximal tubules In healthy through SGLT2 and individuals, SGLT1 with SGLT2 theaccounting renal glomeruli for ~180 ~ filter 90% in the gS1 of glucose per day and S2 segments and SGLT1 accounting for ~ 10% in the S3 segment SGLT2 ~ 90% SGLT1 ~ 10% SGLT, sodium glucose co-transporter. References 1. Adapted from: Gerich JE. Diabet Med. 2010;27:136–142. 2. Bakris GL, et al. Kidney Int. 2009;75;1272–1277. UK/EMP/00264(1) | July 2016 Renal glucose re-absorption in patients with diabetes1,2 Filtered glucose load > 180 g/day SGLT2 When blood glucose increases above the renal threshold (~ 11 mmol/l or 190 mg/dL), the capacity of the transporters is exceeded, resulting in urinary glucose excretion ~ 90% SGLT1 ~ 10% SGLT, sodium glucose co-transporter. References 1. Adapted from: Gerich JE. Diabet Med. 2010;27:136–142. 2. Bakris GL, et al. Kidney Int. 2009;75;1272–1277. UK/EMP/00264(1) | July 2016 Urinary glucose excretion via SGLT2 inhibition1 Filtered glucose load > 180 g/day SGLT2 inhibitors reduce glucose re-absorption in the proximal tubule, leading to urinary glucose excretion* and osmotic diuresis SGLT2 SGLT2 inhibitor SGLT1 SGLT, sodium glucose co-transporter. * Loss of ~ 78 g of glucose per day2, equating to 240-320 kcal/day. References 1. Bakris GL, et al. Kidney Int. 2009;75;1272–1277. 2. Jardiance (empagliflozin) Summary of Product Characteristics. Available at: https://www.medicines.org.uk/emc/medicine/28973 (accessed July 2016). UK/EMP/00264(1) | July 2016 SGLT2 inhibition lowers glycaemia independently of β-cell function and insulin resistance1–4 SGLT2 inhibition directly targets glucose via urinary glucose excretion Impaired β-cell function Persistent Persistent hyperglycaemia hyperglycaemia Insulin resistance SGLT2, sodium glucose co-transporter 2. References 1. Adapted from: DeFronzo RA. Diabetes. 2009;58:773–795. 2. Adapted from: Poitout V and Robertson RP. Endocrinology. 2002;143:339–342. 3. Adapted from: DeFronzo RA. Diabetes Obes Metab. 2012;14:5–14. 4. Robertson RP, et al. Diabetes. 2003;52:581–587. UK/EMP/00264(1) | July 2016 Therapeutic indication Empagliflozin is indicated for the treatment of type 2 diabetes mellitus to improve glycaemic control in adults as: Monotherapy When diet and exercise alone do not provide adequate glycaemic control in patients for whom use of metformin is considered inappropriate due to intolerance. Add-on combination therapy In combination with other glucose–lowering medicinal products including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control. Reference Jardiance (empagliflozin) Summary of Product Characteristics. Available at: https://www.medicines.org.uk/emc/medicine/28973 (accessed July 2016). UK/EMP/00264(1) | July 2016 9 NICE Technology Appraisal Guidance (TA336) In May 2015, NICE issued its Technology Appraisal Guidance (TAG) recommending empagliflozin for use within the National Health Service (NHS England) in the treatment of type 2 diabetes as follows: March 2015, TA336 ● 1.1 Empagliflozin in a dual therapy regimen in combination with metformin is recommended as an option for treating type 2 diabetes, only if: o a sulfonylurea is contraindicated or not tolerated, or o the person is at significant risk of hypoglycaemia or its consequences. ● 1.2 Empagliflozin in a triple therapy regimen is recommended as an option for treating type 2 diabetes in combination with: o metformin and a sulfonylurea or o metformin and a thiazolidinedione. ● 1.3 Empagliflozin in combination with insulin with or without other antidiabetic drugs is recommended as an option for treating type 2 diabetes. ● 1.4 People currently receiving treatment initiated within the NHS with empagliflozin that is not recommended for them by NICE in this guidance should be able to continue treatment until they and their NHS clinician consider it appropriate to stop. Reference National Institute for Health and Care Excellence (NICE), Technology Appraisal Guidance, Empagliflozin in combination therapy for treating type 2 diabetes Available at: http://www.nice.org.uk/guidance/ta336 (accessed July 2016). UK/EMP/00264(1) | July 2016 NICE Technology Appraisal Guidance (TA390) In May 2016, NICE issued another Technology Appraisal Guidance (TAG) recommending empagliflozin for use within the National Health Service (NHS England) in the treatment of type 2 diabetes as follows: May 2016, TA390 ● 1.1 Canagliflozin, dapagliflozin and empagliflozin as monotherapies are recommended as options for treating type 2 diabetes in adults for whom metformin is contraindicated or not tolerated and when diet and exercise alone do not provide adequate glycaemic control, only if: o a dipeptidyl peptidase-4 (DPP-4) inhibitor would otherwise be prescribed and o a sulfonylurea or pioglitazone is not appropriate. ● 1.2 Adults whose treatment with canagliflozin, dapagliflozin or empagliflozin as monotherapy is not recommended in this NICE guidance, but was started within the NHS before this guidance was published, should be able to continue treatment until they and their NHS clinician consider it appropriate to stop. Reference National Institute for Health and Care Excellence (NICE), Technology Appraisal Guidance, Canagliflozin, dapagliflozin and empagliflozin as monotherapies for treating type 2 diabetes. Available at: https://www.nice.org.uk/guidance/ta390 (accessed July 2016). UK/EMP/00264(1) | July 2016 Empagliflozin clinical pharmacokinetics Tablet intake: 10 mg once daily / 25 mg once daily Absorption: Peak levels at 1.5 hours after dosing No clinically relevant food effect Half-life: Estimated to be 12.4 hours, steady state reached by ~ Day 5 Metabolism: No active metabolite Target organ Selectivity: 5,000 x more selective for SGLT2 vs SGLT1 Reference Jardiance (empagliflozin) Summary of Product Characteristics. Available at: https://www.medicines.org.uk/emc/medicine/28973 (accessed July 2016). UK/EMP/00264(1) | July 2016 Empagliflozin clinical study programme across the treatment pathway Add-on to metformin ● versus placebo (EMPA-REG MET™) ● versus glimepiride (EMPA-REG H2H-SU™) Add-on to TZD Add-on to metformin + SU ● versus placebo (EMPA-REG PIO™)* ● versus placebo (EMPA-REG METSU™) Add-on to metformin + TZD ● versus placebo (EMPA-REG PIO™)* Diet and exercise Start with OAD Start dual OAD combination Start triple OAD combination Insulin-based therapies Add-on to basal insulin ● versus placebo (EMPA-REG BASAL™) Add-on to Multiple Daily Injection of insulin ● versus placebo (EMPA-REG MDI™) >4,300 empagliflozin patients *These data will not be shown in the presentation OAD, oral antidiabetic; SU, sulphonylurea; TZD, thiazolidinedione Reference Jardiance (empagliflozin) Summary of Product Characteristics. Available at: https://www.medicines.org.uk/emc/medicine/28973 (accessed July 2016). UK/EMP/00264(1) | July 2016 13 Efficacy Analysis UK/EMP/00264(1) | July 2016 In combination with other therapies, empagliflozin provides significant HbA1c reductions Mean (SE) placebo-adjusted change from baseline in HbA1c (%) Change in HbA1c was a primary endpoint in clinical trials 0.00 Add on to MET 24 weeks Empagliflozin 25 mg Empagliflozin 10 mg Add on to MET+SU 24 weeks Add on to Basal Insulin 18 weeks -0.10 -0.20 -0.30 -0.40 -0.50 -0.60 -0.70 -0.57 -0.64 -0.80 -0.90 -0.64 -0.59 -0.6 -0.7 p<0.001 vs. placebo p<0.001 vs. placebo p<0.001 vs. placebo Patients, n 217 213 225 216 132 117 BL HbA1c, % 7.94 7.86 8.07 8.10 8.3 8.3 BL, baseline; MET, metformin; SE, standard error; SU, sulphonylurea. References Adapted from: Häring H-U, et al., Diabetes Care 2014; [Epub ahead of print]:doi:10.2337/dc13-2105; Häring H-U, et al. Diabetes Care 2013;36:3396-3404; Rosenstock J, et al. Poster 1102-P, presented at American Diabetes Association (ADA) 73rd Scientific Sessions, 21-25 June 2013, Chicago, IL, USA. UK/EMP/00264(1) | July 2016 In combination with other therapies, empagliflozin provides significant FPG (mmol/L) reductions Mean (SE) placebo-adjusted change from baseline in FPG (mmol/l) Change in FPG was an exploratory endpoint in clinical trials 0.00 Add on to MET 24 weeks Empagliflozin 25 mg Empagliflozin 10 mg Add on to MET+SU 24 weeks Add on to Basal Insulin 18 weeks -0.20 -0.40 -0.60 -0.80 -1.00 -1.20 -1.40 -1.60 -1.80 -1.47 -2.00 -1.59 -1.60 p<0.001 vs. placebo -1.60 p<0.001 vs. placebo -1.57 -1.64 p<0.001 vs. placebo Patients, n 216 213 225 216 169 155 BL FPG, mmol/l 8.58 8.29 8.38 8.69 7.68 8.13 FPG, fasting plasma glucose; BL, baseline; MET, metformin; SE, standard error; SU, sulphonylurea. References Adapted from: Häring H-U, et al., Diabetes Care 2014; [Epub ahead of print]:doi:10.2337/dc13-2105; (Supplementary data); Häring H-U, et al. Diabetes Care 2013;36:3396-3404; (Supplementary data); Rosenstock J, et al. Poster 1102-P, presented at American Diabetes Association (ADA) 73rd Scientific Sessions, 21-25 June 2013, Chicago, IL, USA. UK/EMP/00264(1) | July 2016 Adding empagliflozin can provide the secondary benefit of weight loss Weight change was a secondary endpoint in clinical trials Empagliflozin is not indicated for weight loss Empagliflozin 25 mg Mean (SE) placebo-adjusted change from baseline in body weight (kg) Empagliflozin 10 mg 0.00 Add on to MET 24 weeks Add on to MET+SU 24 weeks Add on to Basal Insulin 18 weeks -0.50 -1.00 -0.9 -1.50 -2.00 -1.63 -2.01 -2.50 -1.7 -1.76 p<0.001 vs. placebo -1.99 p<0.001 vs. placebo p=0.035 p=0.293 vs. placebo vs. placebo Patients, n 217 213 225 216 169 155 BL weight, kg 81.6 82.2 77.1 77.5 91.6 94.7 BL, baseline; MET, metformin; SE, standard error; SU, sulphonylurea. References Adapted from: Häring H-U, et al., Diabetes Care 2014; [Epub ahead of print]:doi:10.2337/dc13-2105; Häring H-U, et al. Diabetes Care 2013;36:3396-3404; Rosenstock J, et al. Poster 1102-P, presented at American Diabetes Association (ADA) 73rd Scientific Sessions, 21-25 June 2013, Chicago, IL, USA. UK/EMP/00264(1) | July 2016 Adding empagliflozin can provide the secondary benefit of reduction in Systolic Blood Pressure (SBP) Mean (SE) placebo-adjusted change from baseline in SBP (mmHg) Change in SBP was an exploratory endpoint in clinical trials Empagliflozin is not indicated for blood pressure control 0.00 Add on to MET 24 weeks Empagliflozin 25 mg Empagliflozin 10 mg Add on to MET+SU 24 weeks Add on to Basal Insulin 18 weeks -1.00 -2.00 -2.10 -3.00 -2.70 -4.00 -5.00 -6.00 Patients, n BL SBP, mmHg -3.4 -4.10 -3.0 -4.80 p<0.001 vs. placebo p=0.032 p<0.005 vs. placebo vs. placebo p=0.011 p=0.027 vs. placebo vs. placebo 217 213 225 216 169 155 129.6 130.0 128.7 129.3 132.4 132.8 BL, baseline; MET, metformin; SE, standard error; SU, sulphonylurea. References Adapted from: Häring H-U, et al., Diabetes Care 2014; [Epub ahead of print]:doi:10.2337/dc13-2105; Häring H-U, et al. Diabetes Care 2013;36:3396-3404; Rosenstock J, et al. Poster 1102-P, presented at American Diabetes Association (ADA) 73rd Scientific Sessions, 21-25 June 2013, Chicago, IL, USA. UK/EMP/00264(1) | July 2016 As an add-on to metformin, empagliflozin 25 mg demonstrated superior reduction in HbA1c over glimepiride at 24 months Change from baseline in HbA1c after 104 weeks of treatment Mean baseline values for both treatment groups = 7.92% Empagliflozin 25 mg Glimepiride 1-4 mg n = 765 n = 780 Mean change from baseline in HbA1c (%) 0 -0.25 -0.5 -0.55 -0.75 -1 -1.25 -0.66 Between groups difference = -0.11% p<0.0001 for non-inferiority p=0.0153 for superiority Recommended starting dose of empagliflozin is 10mg Reference Adapted from Ridderstrale M et al., Lancet Diabetes Endocrinol 2014; [epub ahead of print]:doi: 10.1016/S2213-8587(14) UK/EMP/00264(1) | July 2016 As an add-on to metformin, empagliflozin 25 mg demonstrated superior reduction in HbA1c over glimepiride at 24 months Change from baseline in HbA1c by visit over time was an exploratory endpoint* Glimepiride 1–4 mg Mean (SE) change from baseline in HbA1c (%) over time 0.0 Empagliflozin 25 mg -0.1 -0.2 -0.3 -0.4 -0.5 -0.6 -0.7 -0.8 -0.9 0 4 12 28 40 52 65 78 91 Study week 104 Glimepiride 761 758 738 699 660 609 562 524 494 461 Empagliflozin 759 751 734 702 672 646 624 593 568 548 *Data are based on the full analysis set, observed cases analyses by Mixed Model Repeated Measures Recommended starting dose of empagliflozin is 10mg Reference Boehringer Ingelheim Ltd., Data on File EMP14-01. UK/EMP/00264(1) | July 2016 20 As an add-on to metformin, Empagliflozin 25 mg demonstrated superior weight loss over glimepiride at 24 months Weight change was a secondary endpoint in clinical trials Empagliflozin is not indicated for weight loss Glimepiride 1–4 mg (n=780) Adjusted mean (SE) change from baseline in body weight (kg) Empagliflozin 25 mg (n=765) 2.0 1.5 1.0 0.5 0.0 -0.5 -1.0 -1.5 -2.0 -2.5 -3.0 -3.5 1.34 Mean baseline: 83.03 -4.46 p<0.0001 -3.12 82.52 Recommended starting dose of empagliflozin is 10mg Reference Boehringer Ingelheim Ltd., Data on File EMP14-01. UK/EMP/00264(1) | July 2016 As an add-on to metformin, empagliflozin 25 mg demonstrated superior weight loss over glimepiride at 24 months Change in bodyweight over time was an additional exploratory endpoint* Adjusted mean (SE) change from baseline in body weight (kg) Empagliflozin is not indicated for weight loss 2 1 Glimepiride 1–4 mg Empagliflozin 25 mg 0 -1 -2 -3 -4 BL 12 28 52 Study Week 78 104 Glimepiride 745 743 703 610 526 462 Empagliflozin 739 737 706 643 595 555 *Data are based on the full analysis set, observed cases analyses by Mixed Model Repeated Measures Recommended starting dose of empagliflozin is 10mg Reference Boehringer Ingelheim Ltd., Data on File EMP14-01. UK/EMP/00264(1) | July 2016 22 In younger, overweight/obese patients with HbA1c ≥8%, empagliflozin significantly reduced HbA1c and body weight* Empagliflozin 10 mg Weight change was a secondary endpoint in clinical trials Empagliflozin is not indicated for weight loss Empagliflozin 25 mg Placebo (n=193) (n=179) (n=188) 0 -0.25 -0.17 -0.5 -0.75 -1 -1.05 -1.25 -1.15 24 weeks (Mean baseline = 79.1/79.5/79.6 kg) Adjusted mean change from baseline weight (kg) Adjusted mean change from baseline in HbA1c (%) 24 weeks (Mean baseline = 8.72/8.73/8.72%) (n=193) (n=179) (n=188) 0 -0.3 -0.5 -1 -1.5 -2 -1.9 -2.3 -2.5 p<0.001 vs placebo p<0.001 vs placebo In this pooled subgroup post-hoc analysis, adverse events were consistent with other studies Patients were treated with empagliflozin as monotherapy, add-on to metformin, add-on to metformin + sulphonylurea or add-on to metformin + pioglitazone. Empagliflozin is indicated as monotherapy when metformin is not tolerated. * post-hoc analysis of patients aged <65 years with BMI ≥25 to <35kg/m2 Reference Merker L et al. Poster 1079P presented at 74th Scientific Session of American Diabetes Association, 13-17 June 2014, San Francisco, CA, USA UK/EMP/00264(1) | July 2016 Safety Profile UK/EMP/00264(1) | July 2016 Empagliflozin safety profile Safety data reported in placebo-controlled studies by absolute frequency System organ class Very common (≥1/10) Skin and subcutaneous disorders Hypoglycaemia (when used with SU or insulin) Rare (≥1/10,000 to <1/1,000) Diabetic Ketoacidosis* Pruritis (generalised) Vascular disorders Renal and urinary disorders Uncommon (≥1/1,000 to <1/100) Vaginal moniliasis, vulvovaginitis, balanitis and other genital infection Urinary tract infection Infections and infestations Metabolism and nutrition disorders Common (≥1/100 to <1/10) Volume depletion Increased urination Dysuria In a prospective, pre-specified meta-analysis of phase II and III clinical studies involving 10,036 patients with type 2 diabetes, empagliflozin did not increase cardiovascular risk *derived from post-marketing experience Reference Jardiance (empagliflozin) Summary of Product Characteristics. Available at: https://www.medicines.org.uk/emc/medicine/28973 (accessed July 2016). UK/EMP/00264(1) | July 2016 Empagliflozin safety profile Safety data reported in placebo controlled studies Frequency of common adverse events1 Event Placebo Empagliflozin 10 mg Empagliflozin 25 mg Vaginal moniliasis, vulvovaginitis, balanitis and other genital infection 0.9% 4.1% 3.7% Increased urination (including the predefined terms pollakiurea, polyuria, and nocturia) 1.0% 3.4% 3.2% Urinary tract infection (UTI) 7.6% 9.3% 7.6% ● UTI was reported more frequently in females than in males1 ● Genital tract infections were mild or moderate in intensity and were reported more frequently in females than in males1 ● The frequency of reported nocturia for empagliflozin was <1%1 ● Discontinuations due to UTI were low (0.1 – 0.2%)2 The majority of patients who experienced a UTI or genital infection reported a single event2 References 1. Jardiance (empagliflozin) Summary of Product Characteristics. Available at: https://www.medicines.org.uk/emc/medicine/28973 (accessed July 2016). 2. Kim G, et al. Poster 74-LB, presented at 73rd Scientific Session of American Diabetes Association; June 21–25, 2013; Chicago, IL UK/EMP/00264(1) | July 2016 26 Phase III trials pooled* safety and tolerability analysis Events consistent with UTI Empagliflozin Number of episodes per patient, n (%) 0 1 2 ≥3 Placebo (n = 825) 10 mg OD (n = 830) 25 mg OD (n = 822) 757 (91.8) 62 (7.5) 6 (0.7) 0 753 (90.7) 65 (7.8) 10 (1.2) 2 (0.2) 760 (92.5) 56 (6.8) 6 (0.7) 0 OD, once daily; UTI, urinary tract infection. *Pooled analysis includes a proportion of monotherapy-treated patients Reference Kim G, et al. Poster 74-LB, presented at 73rd Scientific Session of American Diabetes Association; June 21–25, 2013; Chicago, IL UK/EMP/00264(1) | July 2016 Overall incidences of hypoglycaemic events Monotherapy1 Add-on to metformin2 Add-on to metformin + SU3 Add-on to insulin +/- metformin/SU4 Placebo (n=229) Empagliflozin 10 mg (n=224) Empagliflozin 25 mg (n=223) <1% <1% <1% Placebo (n=206) Empagliflozin 10 mg (n=217) Empagliflozin 25 mg (n=214) <1% <2% <1.5% Placebo (n=225) Empagliflozin 10 mg (n=224) Empagliflozin 25 mg (n=217) 8.4% 16.1% 11.5% Placebo (n=170) Empagliflozin 10mg (n=169) Empagliflozin 25 mg (n=155) 35% 36% 36% ● A lower dose of insulin or insulin secretagogues (eg, SUs) may be needed to reduce the risk of hypoglycaemia when empagliflozin is used in combination with these agents5 SU, sulphonylurea References 1.Roden M, et al. Lancet Diabetes Endocrinol 2013;1:208-19 2. Häring HU, et al.. Diabetes Care 2014; [Epub ahead of print]: doi:10.2337/dc13-2105 3. Häring HU, et al. Diabetes Care 2013;36:3396–3404 4. Rosenstock J, et al. Poster 1102-P, presented at American Diabetes Association (ADA) 73rd Scientific Sessions, 21-25 June 2013, Chicago, IL, USA 5. Jardiance (empagliflozin) Summary of Product Characteristics. Available at: https://www.medicines.org.uk/emc/medicine/28973 (accessed July 2016). UK/EMP/00264(1) | July 2016 28 Diabetic ketoacidosis (DKA) ● Rare cases of DKA, including life-threatening cases, have been reported in clinical trials and post-marketing in patients treated with SGLT2 inhibitors, including empagliflozin. ● Empagliflozin should not be used in patients with type 1 diabetes as safety and efficacy have not been established. Limited data from clinical trials suggest that DKA occurs with common frequency when patients with type 1 diabetes are treated with SGLT2 inhibitors ● Consider the risk of DKA in the event of non-specific symptoms such as nausea, vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual fatigue or sleepiness and assess patients for ketoacidosis immediately, regardless of blood glucose level. DKA: Diabetic Ketoacidosis Reference Jardiance (empagliflozin) Summary of Product Characteristics. Available at: https://www.medicines.org.uk/emc/medicine/28973 (accessed July 2016). UK/EMP/00264(1) | July 2016 Diabetic ketoacidosis (DKA) ● Before initiating empagliflozin, consider factors in the patient history that may predispose to ketoacidosis. Use with caution in patients who may be at higher risk of DKA. ● Treatment with empagliflozin for patients who are hospitalised for major surgical procedures or acute serious medical illnesses should be interrupted and may be restarted once the patient’s condition has stabilised ● If DKA is suspected or diagnosed, treatment with empagliflozin should be discontinued immediately DKA: Diabetic Ketoacidosis Reference Jardiance (empagliflozin) Summary of Product Characteristics. Available at: https://www.medicines.org.uk/emc/medicine/28973 (accessed July 2016). UK/EMP/00264(1) | July 2016 Empagliflozin dosing and administration ● Recommended starting dose 10 mg once daily ● For patients who tolerate 10 mg and need further glycaemic control, their dose can be increased to 25 mg once daily ● Can be taken with/without food, at any time of day ● Can be used alone or in combination with other common therapies – No clinically meaningful interactions were observed when empagliflozin was co-administered with other commonly used medications, including pioglitazone – A lower dose of insulin or insulin secretagogues (eg, sulphonylureas) may be needed to reduce the risk of hypoglycaemia when empagliflozin is used in combination with these agents ● Should not be initiated in patients with an eGFR <60 ml/min/1.73m2 ● In patients tolerating empagliflozin whose eGFR falls persistently below 60 ml/min/1.73m2 the dose of empagliflozin should be adjusted to or maintained at 10 mg once daily ● Empagliflozin should be discontinued when eGFR is persistently below 45 ml/min/1.73 m2 or CrCl persistently below 45 ml/min Reference Jardiance (empagliflozin) Summary of Product Characteristics. Available at: https://www.medicines.org.uk/emc/medicine/28973 (accessed July 2016). UK/EMP/00264(1) | July 2016 31 For the treatment of type 2 diabetes Clinical considerations when prescribing empagliflozin ● Empagliflozin should be prescribed with caution in patients aged ≥75 years and is not recommended in patients over 85 years old ● Caution should be exercised in patients for whom a empagliflozin induced drop in blood pressure could pose a risk, such as patients with known cardiovascular disease, or patients on anti-hypertensive therapy such as loop diuretics or thiazides or with a history of hypotension ● Assessment of renal function is recommended prior to empagliflozin initiation and periodically during treatment, i.e. at least yearly, and prior to the initiation of any concomitant medication that may have a negative impact on renal function ● No significant drug-drug interactions were observed when empagliflozin was co-administered with other commonly used medications ● Empagliflozin is not recommended for use in patients with severe hepatic impairment Reference Jardiance (empagliflozin) Summary of Product Characteristics. Available at: https://www.medicines.org.uk/emc/medicine/28973 (accessed July 2016). UK/EMP/00264(1) | July 2016 32 In summary ● Empagliflozin is indicated for the treatment of type 2 diabetes mellitus to improve glycaemic control in adults as: – Monotherapy • When diet and exercise alone do not provide adequate glycaemic control in patients for whom use of metformin is considered inappropriate due to intolerance. – Add-on combination therapy • In combination with other glucose–lowering medicinal products including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control. ● Empagliflozin can provide your patients with: – Significant placebo-adjusted HbA1c reductions: up to 0.64% – Secondary benefit of significant placebo-adjusted weight reduction of around 2 kg – Significant glycaemic efficacy in combination with a range of background treatment including insulin ● The most frequently reported adverse reaction was hypoglycaemia when used with a sulphonylurea or insulin ● The incidence of genital tract infections was greater in patients receiving empagliflozin than placebo ● When used in combination with empagliflozin, a lower dose of sulphonylurea or insulin should be considered to reduce the risk of hypoglycaemia ● Convenient once-daily oral dosing. Jardiance (empagliflozin) Summary of Product Characteristics. Available at: https://www.medicines.org.uk/emc/medicine/28973 (accessed July 2016). UK/EMP/00264(1) | July 2016 33 ▼Jardiance® (empagliflozin) 10mg and 25mg film-coated tablets Film-coated tablets containing 10 mg or 25 mg empagliflozin. Indication: Treatment of type 2 diabetes mellitus to improve glycaemic control in adults: As monotherapy when diet and exercise alone do not provide adequate glycaemic control in patients for whom use of metformin is considered inappropriate due to intolerance; as add-on combination therapy with other glucose–lowering medicinal products including insulin when these together with diet and exercise do not provide adequate glycaemic control. Dose and Administration: Monotherapy or add-on combination: The recommended starting dose is 10mg once daily. In patients tolerating empagliflozin 10 mg once daily who have eGFR ≥ 60 ml/min/1.73m2 and need tighter glycaemic control, the dose can be increased to 25 mg once daily. The maximum daily dose is 25 mg. When used with sulphonylurea or insulin a lower dose of these may be considered to reduce the risk of hypoglycaemia. Renal impairment: Efficacy is dependent on renal function. No dose adjustment is required for patients with an eGFR ≥60 ml/min/1.73m2 or CrCl ≥60 ml/min. Do not initiate in patients with an eGFR <60 ml/min/1.73m2 or CrCl <60 ml/min. In patients tolerating empagliflozin whose eGFR falls persistently below 60 ml/min/1.73m2 or CrCl below 60 ml/min, the dose of empagliflozin should be adjusted to or maintained at 10 mg once daily. Discontinue when eGFR is persistently below 45 ml/min/1.73m2 or CrCl persistently below 45 ml/min. Not for use in patients with end stage renal disease (ESRD) or on dialysis. Hepatic impairment: No dose adjustment is required for patients with hepatic impairment. Not recommended in severe hepatic impairment. Elderly patients: No dose adjustment is recommended based on age. In patients 75 years and older, an increased risk for volume depletion should be taken into account. Not recommended in patients 85 years or older. Paediatric population: No data are available. Method of administration: The tablets can be taken with or without food, swallowed whole with water. If a dose is missed, it should be taken as soon as the patient remembers. A double dose should not be taken on the same day. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Warnings and Precautions: Not to be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis (DKA). Rare cases of DKA, including life-threatening cases, have been reported in clinical trials and post-marketing in patients treated with SGLT2 inhibitors, including empagliflozin. Consider the risk of DKA in the event of non-specific symptoms such as nausea, vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual fatigue or sleepiness and assess patients for ketoacidosis immediately, regardless of blood glucose level. Interrupt treatment for patients hospitalised for major surgical procedures or acute serious medical illnesses. In patients where DKA is suspected or diagnosed, treatment should be discontinued immediately. Before initiating empagliflozin, consider factors in the patient history that may predispose to ketoacidosis. Use with caution in patients who may be at higher risk of DKA. Renal impairment and elderly patients: See under Dose and Administration. Monitor renal function prior to initiation and at least annually. Cases of hepatic injury have been reported with empagliflozin in clinical trials. A causal relationship between empagliflozin and hepatic injury has not been established. Osmotic diuresis accompanying therapeutic glucosuria may lead to a modest decrease in blood pressure. Therefore, caution should be exercised in patients with known cardiovascular disease, patients on anti-hypertensive therapy with a history of hypotension or patients aged 75 years and older. In case of conditions that may lead to fluid loss (e.g. gastrointestinal illness), careful monitoring of volume status and electrolytes is recommended. Temporary interruption of treatment with empagliflozin should be considered until the fluid loss is corrected. Temporary interruption of empagliflozin should be considered in patients with complicated urinary tract infections. Experience in New York Heart Association (NYHA) class I-II is limited, and there is no experience in clinical studies with empagliflozin in NYHA class III-IV. Due to its mechanism of action, patients taking Jardiance will test positive for glucose in their urine.The tablets contain lactose and should not be used in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption. Interactions: Use with diuretics may increase the risk of dehydration and hypotension. Insulin and insulin secretagogues may increase the risk of hypoglycaemia therefore, a lower dose of insulin or an insulin secretagogue may be required. The effect of UGT induction on empagliflozin has not been studied. Comedication with known inducers of UGT enzymes should be avoided due to a potential risk of decreased efficacy. Interaction UK/EMP/00264(1) | July 2016 studies conducted in healthy volunteers suggest that the pharmacokinetics of empagliflozin were not influenced by coadministration with metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, verapamil, ramipril, simvastatin, torasemide and hydrochlorothiazide. Interaction studies conducted in healthy volunteers suggest that empagliflozin had no clinically relevant effect on the pharmacokinetics of metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, simvastatin, warfarin, ramipril, digoxin, diuretics and oral contraceptives. Fertility, pregnancy and lactation: There are no data from the use of empagliflozin in pregnant women. Use should be avoided avoid during early pregnancy and is not recommended during the second and third trimester of pregnancy. No data in humans are available on excretion of empagliflozin into milk. Jardiance should not be used during breast-feeding. No studies on the effect on human fertility have been conducted for Jardiance. Undesirable effects: Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000). Very common: Hypoglycaemia (when used with sulphonylurea or insulin). Common: Vaginal moniliasis, vulvovaginitis, balanitis and other genital infections, urinary tract infection, pruritus (generalised), increased urination. Uncommon: Volume depletion,dysuria. Rare: DKA. Prescribers should consult the Summary of Product Characteristics for further information on side effects. Pack sizes and NHS price: 10 mg; 28 tablets £36.59, 25 mg: 28 tablets £36.59. Legal category: POM MA numbers:10 mg/28 tablets EU/1/14/930/013; 25 mg/28 tablets EU/1/14/930/004. Marketing Authorisation Holder: Boehringer Ingelheim International GmbH, D-55216 Ingelheim am Rhein, Germany. Prescribers should consult the Summary of Product Characteristics for full prescribing information. Prepared in May 2016. Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Boehringer Ingelheim Drug Safety on 0800 328 1627 (freephone). ▼Synjardy® (empagliflozin and metformin hydrochloride) 5 mg/850 mg, 5 mg/1000 mg, 12.5 mg/850 mg or 12.5 mg/1000 mg film coated tablets Film-coated tablets containing 5 mg empagliflozin and 850 mg metformin hydrochloride, 5 mg empagliflozin and 1000 mg metformin hydrochloride, 12.5 mg empagliflozin and 850 mg metformin hydrochloride or 12.5 mg empagliflozin and 1000 mg metformin hydrochloride. Indication: Synjardy is indicated in adults aged 18 years and older with type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycaemic control in certain patient groups. These include patients inadequately controlled on their maximally tolerated dose of metformin alone, in patients inadequately controlled with metformin in combination with other glucose-lowering medicinal products including insulin, and in patients already being treated with the combination of empagliflozin and metformin as separate tablets. Dose and Administration: Recommended dose: one tablet twice daily. The dosage should be individualised on the basis of the patient’s current regimen, effectiveness, and tolerability using the recommended daily dose of 10 mg or 25 mg of empagliflozin, while not exceeding maximum recommended daily dose of metformin. For patients inadequately controlled on metformin monotherapy or in combination with other glucose-lowering medicinal products, including insulin, the recommended starting dose of Synjardy should provide empagliflozin 5 mg twice daily (10 mg daily dose) and the dose of metformin similar to the dose already being taken. In patients tolerating a total daily dose of empagliflozin 10 mg and who need tighter glycaemic control, the dose can be increased to a total daily dose of empagliflozin 25 mg. When used in combination with insulin and/or an insulin secretagogue such as sulphonylurea, a lower dose of the insulin and/or insulin secretagogue may be required. Patients switching from separate tablets of empagliflozin (10 mg or 25 mg total daily dose) and metformin to Synjardy should receive the same daily dose of these already being taken or the nearest therapeutically appropriate dose of metformin. Hepatic impairment: Not to be used in patients with hepatic impairment. Renal impairment: No dose adjustment is recommended for patients with mild renal impairment. Synjardy must not be used in patients with moderate or severe renal impairment (creatinine clearance <60 ml/min). Elderly: Decreased renal function will result in reduced efficacy of empagliflozin. Metformin is excreted by the kidney and therefore caution should be used in elderly patients due to decreased renal function in the elderly population. Monitoring of renal function is necessary to aid in prevention of metformin-associated lactic acidosis, particularly in elderly patients. In patients 75 years and older, an increased risk for volume depletion should be taken into account. Not recommended in patients 85 years or older. Paediatric population: No data are available. Method of administration: Synjardy should be taken twice daily with meals. If a dose is missed, it should be taken as soon as the patient remembers. However, a double dose should not be taken at the same time. In that case, the missed dose should be skipped. Contraindications: Hypersensitivity to the active substances or to any of the excipients. Diabetic ketoacidosis (DKA), diabetic pre coma. Renal failure or renal dysfunction (creatinine clearance <60 ml/min). Acute conditions with the potential to alter renal function such as: dehydration, severe infection, shock. Disease which may cause tissue hypoxia (especially acute disease, or worsening of chronic disease) such as: decompensated heart failure, respiratory failure, recent myocardial infarction, shock. Hepatic impairment, acute alcohol intoxication, alcoholism. Warnings and Precautions: Not to be used in patients with type 1 diabetes or in paediatric populations. Rare cases of DKA, including life-threatening cases, have been reported in clinical trials and post-marketing in patients treated with SGLT2 inhibitors, including empagliflozin. Consider the risk of DKA in the event of non-specific symptoms such as nausea, vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual fatigue or sleepiness and assess patients for ketoacidosis immediately, regardless of blood glucose level. Interrupt treatment for patients hospitalised for major surgical procedures or acute serious medical illnesses. In patients where DKA is suspected or diagnosed, treatment should be discontinued immediately. Before initiating empagliflozin, consider factors in the patient history that may predispose to ketoacidosis. Use with caution in patients who may be at higher risk of DKA. Lactic acidosis can occur due to metformin accumulation and occurs primarily in patients with renal failure or acute worsening of renal function. In the case of lactic acidosis the patient should be hospitalised immediately. Treatment should be temporarily discontinued in situations where renal function may become impaired, e.g. in case of dehydration (severe diarrhoea or vomiting), or when initiating antihypertensive therapy or diuretic therapy and when starting therapy with a non-steroidal antiinflammatory drug (NSAID). Other risk factors should be considered such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic impairment and any condition associated with hypoxia (such as decompensated cardiac failure, acute myocardial infarction). Risk of lactic acidosis must also be considered, and treatment temporarily discontinued, in the event of non-specific signs e.g. muscle cramps and digestive disorders such as abdominal pain and severe asthenia. Physicians should alert patients on the risk and symptoms of lactic acidosis. Determine serum creatinine levels before treatment and at least annually (with normal renal function) or at least two to four times a year (with serum creatinine levels at the upper limit of normal and in elderly subjects). Renal function should be checked before initiating treatment with metformin. Patients with heart failure are more at risk of hypoxia and renal insufficiency. In patients with stable chronic heart failure, Synjardy may be used with a regular monitoring of cardiac and renal function. Synjardy must be discontinued prior to, or at the time of intravascular administration of iodinated contrast materials in radiologic studies and must not be reinstituted until at least 48 hours afterwards, and only after renal function has been re-evaluated and has not deteriorated further. Synjardy must be discontinued 48 hours before elective surgery with general, spinal or peridural anaesthesia and not be resumed earlier than 48 hours and after renal function has been re-evaluated and found to be normal. Exercise caution in patients with known cardiovascular disease, patients on anti-hypertensive therapy with a history of hypotension or patients aged 75 years and older. In case of conditions that may lead to fluid loss (e.g. gastrointestinal illness), careful monitoring of volume status and electrolytes is recommended. Temporary interruption of treatment should be considered until the fluid loss is corrected. Temporary interruption of treatment should be considered in patients with complicated urinary tract infections. Patients aged 75 years and older may be at an increased risk of volume depletion. Experience in New York Heart Association (NYHA) class I-II is limited, and there is no experience in clinical studies with empagliflozin in NYHA class III-IV. Patients taking Synjardy will test positive for glucose in their urine. Interactions: No interaction studies have been performed for Synjardy. Interactions for Empagliflozin: Use with diuretics may increase the risk of dehydration and hypotension. Insulin and insulin secretagogues may increase the risk of hypoglycaemia therefore, a lower dose of insulin or an insulin secretagogue may be required. The effect of UGT induction on empagliflozin has not been studied. Co-medication with known inducers of UGT enzymes should be avoided due to a potential risk of decreased efficacy. Interaction studies conducted in healthy volunteers suggest UK/EMP/00264(1) | July 2016 that the pharmacokinetics of empagliflozin were not influenced by coadministration with metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, verapamil, ramipril, simvastatin, torasemide and hydrochlorothiazide. Interaction studies conducted in healthy volunteers suggest that empagliflozin had no clinically relevant effect on the pharmacokinetics of metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, simvastatin, warfarin, ramipril, digoxin, diuretics and oral contraceptives. Interactions for Metformin: There is increased risk of lactic acidosis in acute alcohol intoxication (particularly in the case of fasting, malnutrition or hepatic impairment due to the metformin active substance). Consumption of alcohol and medicinal products containing alcohol should be avoided. Cationic substances that are eliminated by renal tubular secretion (e.g. cimetidine) may interact with metformin by competing for common renal tubular transport systems. The intravascular administration of iodinated contrast agents in radiological studies may lead to lactic acidosis (refer to Warnings and Precautions). Glucocorticoids (given by systemic and local routes), beta-2-agonists, and diuretics have intrinsic hyperglycaemic activity. The patient should be informed and more frequent blood glucose monitoring performed, especially at the beginning of treatment with such medicinal products. Insulin and insulin secretagogues, such as sulphonylureas, may increase the risk of hypoglycaemia. Fertility, Pregnancy and Lactation: There are no data from the use of Synjardy or empagliflozin in pregnant women. When the patient plans to become pregnant, and during pregnancy, it is recommended that diabetes is not treated with this medicinal product, but insulin be used to maintain blood glucose levels as close to normal as possible, to reduce the risk of malformations of the foetus. Synjardy should not be used during breast feeding. No studies on the effect on human fertility have been conducted for Synjardy or empagliflozin. Undesirable effects: Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), and not known (cannot be estimated from the available data). Very common: hypoglycaemia (when used with sulphonylurea or insulin), gastrointestinal symptoms. Common: vaginal moniliasis, vulvovaginitis, balanitis and other genital infections, urinary tract infection, taste disturbance, pruritus (generalised), increased urination. Uncommon: volume depletion, dysuria. Rare: DKA. Very rare: lactic acidosis, vitamin B12 deficiency, liver function tests abnormalities, hepatitis, erythema, urticaria. Prescribers should consult the Summary of Product Characteristics for further information on side effects. Pack sizes and NHS price: 56 x 1 film-coated tablets; 5 mg/850 mg: £36.59, 5 mg/1000 mg: £36.59, 12.5 mg/850 mg: £36.59 and 12.5 mg/1000 mg: £36.59. Legal category: POM. MA numbers: 5 mg/850 mg: EU/1/15/1003/004; 5 mg/1000 mg: EU/1/15/1003/013; 12.5 mg/850 mg: EU/1/15/1003/22; 12.5 mg/1000 mg: EU/1/15/1003/031. Marketing Authorisation Holder: Boehringer Ingelheim International GmbH, Binger Strasse 173, D-55216 Ingelheim am Rhein, Germany. Prescribers should consult the Summary of Product Characteristics for full prescribing information. Prepared in May 2016 Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Boehringer Ingelheim Drug Safety on 0800 328 1627 (freephone). Trajenta® (linagliptin) 5 mg film-coated tablets Film-coated tablets containing 5 mg linagliptin. Indication: Trajenta is indicated in the treatment of type 2 diabetes mellitus to improve glycaemic control in adults: as monotherapy: - in patients inadequately controlled by diet and exercise alone and for whom metformin is inappropriate due to intolerance, or contraindicated due to renal impairment; as combination therapy: - in combination with metformin when diet and exercise plus metformin alone do not provide adequate glycaemic control; - in combination with a sulphonylurea and metformin when diet and exercise plus dual therapy with these medicinal products do not provide adequate glycaemic control; - in combination with insulin with or without metformin, when this regimen alone, with diet and exercise, does not provide adequate glycaemic control. Dose and Administration: 5 mg once daily. If added to metformin, the dose of metformin should be maintained and linagliptin administered concomitantly. When used in combination with a sulphonylurea or with insulin, a lower dose of the sulphonylurea or insulin, may be considered to reduce the risk of hypoglycaemia. Renal impairment: no dose adjustment required. Hepatic impairment: pharmacokinetic studies suggest that no dose adjustment is required for patients with hepatic impairment but clinical experience in such patients is lacking. Elderly: no dose adjustment is necessary based on age however, clinical experience in patients > 80 years of age is limited and caution should be exercised when treating this population. Paediatric population: the safety and efficacy of linagliptin in children and adolescents has not yet been established. No data are available. Take the tablets with or without a meal at any time of the day. If a dose is missed, it should be taken as soon as possible but a double dose should not be taken on the same day. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Warnings and Precautions: Linagliptin should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Caution is advised when linagliptin is used in combination with a sulphonylurea and/or insulin; a dose reduction of the sulphonylurea or insulin may be considered. Acute pancreatitis: In post-marketing experience of linagliptin there have been spontaneously reported adverse reactions of acute pancreatitis. Patients should be informed of the characteristic symptoms of acute pancreatitis. If pancreatitis is suspected, Trajenta should be discontinued; if acute pancreatitis is confirmed, Trajenta should not be restarted. Caution should be exercised in patients with a history of pancreatitis. Interactions: Linagliptin is a weak competitive and a weak to moderate mechanism-based inhibitor of CYP isozyme CYP3A4, but does not inhibit other CYP isozymes. It is not an inducer of CYP isozymes. Linagliptin is a P-glycoprotein substrate and inhibits P-glycoprotein mediated transport of digoxin with low potency. Based on these results and in vivo interaction studies, linagliptin is considered unlikely to cause interactions with other P-gp substrates. The risk for clinically meaningful interactions by other medicinal products on linagliptin is low and in clinical studies linagliptin had no clinically relevant effect on the pharmacokinetics of metformin, glibenclamide, simvastatin, warfarin, digoxin or oral contraceptives (please refer to Summary of Product Characteristics for information on clinical data). Fertility, pregnancy and lactation: Avoid use during pregnancy. A risk to the breastfed child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from linagliptin therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. No studies on the effect on human fertility have been conducted for linagliptin. Undesirable effects: Adverse reactions reported in patients who received linagliptin 5 mg daily as monotherapy or as add-on therapies (frequencies identified from pooled analysis of placebo-controlled studies) in clinical trial and from post-marketing experience. The adverse reactions are listed by absolute frequency. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (<1/10,000) or not known (cannot be estimated from the available data). Very common: hypoglycaemia (combination with/add-on to metformin and sulphonylurea). Uncommon: nasopharyngitis (monotherapy; combination with/add-on to metformin; combination with/add-on to insulin); hypersensitivity e.g. UK/EMP/00264(1) | July 2016 bronchial hyperreactivity (monotherapy; combination with/add-on to metformin; combination with/add-on to metformin and sulphonylurea; combination with/add-on to insulin); cough (monotherapy; combination with/addon to metformin; combination with/add-on to insulin); pancreatitis (combination with/add-on to insulin); constipation (combination with/add-on to insulin); rash (monotherapy; combination with/add-on to metformin; combination with/add-on to metformin and sulphonylurea; combination with/add-on to insulin); amylase increased (combination with/add-on to metformin; combination with/add-on to metformin and sulphonylurea). Rare: angioedema (monotherapy; combination with/add-on to metformin; combination with/add-on to metformin and sulphonylurea; combination with/add-on to insulin); urticaria (monotherapy; combination with/add-on to metformin; combination with/add-on to metformin and sulphonylurea; combination with/add-on to insulin); amylase increased (monotherapy). Not known: nasopharyngitis (combination with/add-on to metformin and sulphonylurea); cough (combination with/add-on to metformin and sulphonylurea); pancreatitis (monotherapy; combination with/add-on to metformin; combination with/add-on to metformin and sulphonylurea); bullous pemphigoid (monotherapy; combination with/add-on to metformin; combination with/add-on to metformin and sulphonylurea; combination with/add-on to insulin); amylase increased (combination with/add-on to insulin). Prescribers should consult the Summary of Product Characteristics for further information on side effects. Pack sizes and NHS price: 28 tablets £33.26. Legal category: POM. MA number: EU/1/11/707/003. Marketing Authorisation Holder: Boehringer Ingelheim International GmbH, D-55216 Ingelheim am Rhein, Germany. Prescribers should consult the Summary of Product Characteristics for full prescribing information. Prepared in June 2016. Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Boehringer Ingelheim Drug Safety on 0800 328 1627 (freephone). ▼Jentadueto® (linagliptin and metformin hydrochloride) 2.5 mg/850 mg film-coated tablets and 2.5 mg/1,000 mg film-coated tablets Film-coated tablets containing 2.5 mg linagliptin and 850 mg metformin hydrochloride or 2.5 mg linagliptin and 1,000 mg metformin hydrochloride. Indication: Treatment of adult patients with type 2 diabetes mellitus: as an adjunct to diet and exercise to improve glycaemic control in adult patients inadequately controlled on their maximal tolerated dose of metformin alone, or those already being treated with the combination of linagliptin and metformin; in combination with a sulphonylurea (i.e. triple combination therapy) as an adjunct to diet and exercise in adult patients inadequately controlled on their maximal tolerated dose of metformin and a sulphonylurea; in combination with insulin (i.e. triple combination therapy) as an adjunct to diet and exercise to improve glycaemic control in adult patients when insulin and metformin alone do not provide adequate glycaemic control. Dose and Administration: The dose should be individualised based on the patient’s current regimen, effectiveness and tolerability, not exceeding the maximum recommended daily dose of 5 mg linagliptin plus 2,000 mg metformin hydrochloride. Patients inadequately controlled on maximal tolerated dose of metformin monotherapy: the usual starting dose should provide linagliptin 2.5 mg twice daily (5 mg total daily dose) plus the current metformin dose. Patients switching from co-administration of linagliptin and metformin: Initiate at the dose of linagliptin and metformin already being taken. Patients inadequately controlled on dual combination of the maximal tolerated dose of metformin and a sulphonylurea: The dose should provide linagliptin 2.5 mg twice daily (5 mg total daily dose) and a metformin dose similar to the dose already being taken. When linagliptin plus metformin hydrochloride is used in combination with a sulphonylurea, a lower dose of the sulphonylurea may be required to reduce the risk of hypoglycaemia. Patients inadequately controlled on dual combination with insulin and the maximal tolerated dose of metformin: The dose should provide linagliptin 2.5 mg twice daily (5 mg total daily dose) and a metformin dose similar to the dose already being taken. When linagliptin plus metformin hydrochloride is used in combination with insulin, a lower dose of insulin may be required to reduce the risk of hypoglycaemia. Elderly: As metformin is excreted by the kidney, use with caution as age increases. Monitoring of renal function is necessary. Exercise caution in patients 80 years and older as clinical experience in this age group is limited. Renal impairment: Jentadueto must not be used in patients with moderate or severe renal impairment (creatinine clearance < 60 ml/min). Hepatic impairment: Not recommended. Clinical experience in patients with hepatic impairment is lacking. Paediatric population: Safety and efficacy in children and adolescents (aged 0 to 18 years) have not been established. No data are available. Taking Jentadueto: To be taken twice daily with meals. All patients should continue their diet with an adequate distribution of carbohydrate intake during the day. Overweight patients should continue their energy-restricted diet. If a dose is missed, it should be taken as soon as the patient remembers. However, a double dose should not be taken at the same time (the missed dose should be skipped). Contraindications: Hypersensitivity to the active substances or to any of the excipients; diabetic ketoacidosis, diabetic pre-coma; renal failure or renal dysfunction (creatinine clearance < 60 ml/min); acute conditions with the potential to alter renal function such as dehydration, severe infection, shock; disease which may cause tissue hypoxia (especially acute disease, or worsening of chronic disease) such as decompensated heart failure, respiratory failure, recent myocardial infarction, shock; hepatic impairment, acute alcohol intoxication, alcoholism. Warnings and Precautions: Not to be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Caution is advised when Jentadueto is used in combination with a sulphonylurea and/or insulin due to increased incidence of hypoglycaemia. Lactic acidosis can occur due to metformin accumulation. If diagnosed the patient should be hospitalised immediately. Treatment should be temporarily discontinued in situations where renal function may become impaired e.g. dehydration (severe diarrhoea or vomiting), initiation of antihypertensive therapy, diuretic therapy or therapy with a non-steroidal anti-inflammatory drug (NSAID). Risk of lactic acidosis must also be considered, and treatment temporarily discontinued, in the event of non-specific signs e.g. muscle cramps and digestive disorders such as abdominal pain and severe asthenia. Patients should be alerted to the risk and symptoms of lactic acidosis. Serum creatinine levels should be determined before initiating treatment and regularly thereafter. Decreased renal function in older subjects is frequent and asymptomatic. Special caution should be exercised in situations where renal function may become impaired. Renal function should be checked before initiating treatment with metformin. Patients with heart failure are more at risk of hypoxia and renal impairment. In patients with stable chronic heart failure Jentadueto may be used with regular monitoring of cardiac and renal function. Treatment must be discontinued 48 hours before elective surgery with general, spinal or epidural anaesthesia, or prior to, or at the time of intravascular administration of iodinated contrast agents in radiologic studies. Therapy should usually not be resumed earlier than 48 hours following surgery or must not be reinstituted until at least 48 hours after the test and only after renal function has been re-evaluated and found to be normal (surgery) or has not deteriorated further (radiologic studies). A patient with previously well controlled type 2 diabetes on Jentadueto who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. If acidosis of either form occurs, stop treatment immediately and initiate other appropriate corrective measures. There have been spontaneously reported adverse reactions of acute pancreatitis with linagliptin. If pancreatitis is suspected, Jentadueto should be discontinued; if confirmed, treatment should not be restarted. Patients should be informed of the characteristic symptoms of acute pancreatitis. Exercise caution in patients with a history of pancreatitis. Interactions: Combination requiring precautions for use: glucocorticoids (given by systemic and local routes), beta-2-agonists, and diuretics. More frequent blood glucose monitoring should be performed, especially at the beginning of treatment with such medicinal products. If necessary, adjust the dose of Jentadueto during therapy with the other medicinal product and on its discontinuation. Combinations not recommended: Avoid consumption of alcohol and medicinal products containing alcohol due to increased risk of lactic acidosis in acute alcohol intoxication. Cationic substances that are eliminated by renal tubular secretion e.g. cimetidine. The intravascular administration of iodinated contrast agents in radiological studies may lead to renal failure, resulting in metformin accumulation and a risk of lactic acidosis (see above). Fertility, UK/EMP/00264(1) | July 2016 pregnancy and lactation: Jentadueto should not be used during pregnancy. If the patient plans to become pregnant, or if pregnancy occurs, discontinue treatment and switch to insulin treatment as soon as possible in order to lower the risk of foetal malformations associated with abnormal blood glucose levels. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Jentadueto therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. No studies on the effect on human fertility have been conducted for Jentadueto. Undesirable effects: Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) and not known (cannot be estimated from the available data). Adverse reactions reported with the fixed dose combination: Common: diarrhoea; Uncommon: nasopharyngitis; hypersensitivity e.g. bronchial hyperreactivity; cough; decreased appetite; nausea; vomiting; rash; pruritus; blood amylase increased. Rare: angioedema; urticaria. Not known: pancreatitis, bullous pemphigoid. Adverse reactions known to occur with each active substance given singly but which have not been seen in clinical trials with Jentadueto, may occur during treatment with this medicinal product. Additional adverse reactions reported when linagliptin and metformin were combined with sulphonylurea: very common: hypoglycaemia. Additional reactions reported when linagliptin and metformin were combined with insulin: Uncommon: constipation; liver function disorders. Additional information on individual components: Adverse reactions previously reported with one of the individual active substances may be potential adverse reactions with Jentadueto, even if not observed in clinical trials. Linagliptin: All identified adverse reactions of linagliptin monotherapy are also described for Jentadueto. Metformin: Known adverse reactions that were not reported in patients who received Jentadueto. Very common: abdominal pain. Common: taste disturbance. Very rare: lactic acidosis; vitamin B12 deficiency; hepatitis; skin reactions. Prescribers should consult the Summary of Product Characteristics for further information on side effects. Pack sizes and NHS price: 2.5 mg/850 mg 56 tablets £33.26; 2.5 mg/1,000 mg 56 tablets £33.26. Legal category: POM. MA numbers: 2.5 mg/850 mg (56 tablets) EU/1/12/780/005; 2.5 mg/1,000 mg (56 tablets) EU/1/12/780/019. Marketing Authorisation Holder: Boehringer Ingelheim International GmbH, D-55216 Ingelheim am Rhein, Germany. Prescribers should consult the Summary of Product Characteristics for full prescribing information. Prepared in June 2016. Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard Adverse events should also be reported to Boehringer Ingelheim Drug Safety on 0800 328 1627 (freephone). ▼ ABASAGLAR® CARTRIDGE AND KWIKPEN™ ABBREVIATED PRESCRIBING INFORMATION ABASAGLAR IS INSULIN GLARGINE (human insulin analogue) Presentation Abasaglar is a clear, colourless, sterile solution of 100 units/ml (equivalent to 3.64mg) insulin glargine (rDNA origin), available as either 3ml cartridge or 3ml KwikPen. Each cartridge/pen contains 300 units of insulin glargine in 3ml solution. Uses Treatment of diabetes mellitus in adults, adolescents, and children aged 2 years and above. Dosage and Administration The dose regimen (dose and timing) should be individually adjusted. In patients with Type 2 diabetes mellitus, Abasaglar can also been given together with orally active antidiabetic medication. Abasaglar has a prolonged duration of action, and should be administered once daily at any time, but at the same time each day. It should only be given by subcutaneous injection and should not be administered intravenously. Injection sites must be rotated within a given injection area from one injection to the next. Abasaglar must not be mixed with any other insulin or diluted. When changing from another intermediate or long-acting insulin treatment regimen to Abasaglar, a change of the dose of the basal insulin may be required and the concomitant antidiabetic treatment may need to be adjusted (dose and timing of additional regular insulins or fast-acting insulin analogues, or the dose of oral antidiabetic medicinal products). Contraindications Hypersensitivity to insulin glargine or any of the excipients. Warnings and Special Precautions Abasaglar is not the insulin of choice for the treatment of diabetic ketoacidosis. In case of insufficient glucose control, or tendency to hyper- or hypoglycaemic episodes, other relevant factors must be reviewed before dose adjustment is considered. Transferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand, type, origin, and/or method of manufacture may result in the need for a change in dose. In rare cases, insulin antibodies may necessitate dose adjustment. The time of occurrence of hypoglycaemia may change when the insulin regimen is changed, depending on the action profile of the insulins used. Caution and intensified glucose monitoring are advised in patients for whom hypoglycaemia might be of particular clinical relevance. Patients should be aware that warning symptoms of hypoglycaemia may be changed, less pronounced, or absent in certain circumstances, including: markedly improved glycaemic control; when hypoglycaemia develops gradually; in the elderly; after transfer from animal to human insulin; autonomic neuropathy; long history of diabetes; psychiatric illness; use of certain medications such as beta-blockers. This may result in severe hypoglycaemia. The prolonged effect of insulin glargine may delay recovery from hypoglycaemia. If HbA1c is low, consider possibility of recurrent, unrecognised hypoglycaemia. Adherence of the patient to the dose and dietary regimen, correct insulin administration, and awareness of hypoglycaemia symptoms are essential to reduce risk of hypoglycaemia. Factors increasing risk of hypoglycaemia require particularly close monitoring and may necessitate dose adjustment. Intercurrent illness requires intensified monitoring. Testing for ketones and dose adjustment may be necessary. Patients with Type 1 diabetes must continue to consume at least small amounts of carbohydrate and must never omit insulin entirely. The cartridges should only be used in a pen recommended for the use with Lilly insulin cartridges. The insulin label must always be checked before each injection to avoid medication errors. Cases of cardiac failure have been reported when pioglitazone was used in combination with insulin. If the combination is used, patients should be observed for signs and symptoms of heart failure and pioglitazone discontinued if any deterioration occurs. Pregnancy and Lactation No clinical data from controlled studies are available. Data from >1,000 pregnancy outcomes indicate no specific adverse effects of insulin glargine on pregnancy and no specific malformative nor feto/neonatal toxicity. The use of Abasaglar may be considered during pregnancy, if necessary. Insulin requirements may decrease during the first trimester and generally increase during the second and third trimesters. Immediately after delivery, insulin requirements decline rapidly. Careful monitoring of UK/EMP/00264(1) | July 2016 glucose control is essential. Driving, etc The patient’s ability to concentrate and react may be impaired as a result of hypo- or hyperglycaemia, or visual impairment. This may constitute a risk in situations where these abilities are of special importance (eg, driving a car or operating machines). Undesirable Effects Hypoglycaemia is very common. Injection site reactions and lipohypertrophy are common. Immediatetype allergic reactions are rare, but may be life-threatening. For full details of these and other side-effects, please see the Summary of Product Characteristics, which is available at http://www.medicines.org.uk/emc/. Legal Category POM Marketing Authorisation Numbers EU/1/14/944/003, EU/1/14/944/007 Basic NHS Cost £35.28 - 5 X 3ml cartridges, £35.28 - 5 X 3ml KwikPens Date of Preparation or Last Review May 2015 Full Prescribing Information is Available From Eli Lilly and Company Limited, Lilly House, Priestley Road, Basingstoke, Hampshire, RG24 9NL Telephone: Basingstoke (01256) 315 000 E-mail: [email protected] Website: www.lillypro.co.uk ABASAGLAR® (insulin glargine) is a registered trademark of Eli Lilly and Company. KWIKPEN™ is a trademark of Eli Lilly and Company. Adverse events should be reported. Reporting forms and information can be found at: www.mhra.gov.uk/yellowcard Adverse events and product complaints should also be reported to Lilly: please call Lilly UK on 01256 315000