Optimal management of diabetic kidney disease hypertension and

Optimal management of diabetic kidney disease: hypertension and glycaemia SECTION F These slides were sponsored by Janssen and developed in conjunction with the BRS CKD Strategy Group, following an advisory board that JOB CODE PHGB/VOK/0914/0018 e was organised by Janssen. Bedrock Healthcare Communications provided editorial support to members of the advisory board in developing Date of preparation: January 2015 the slides. Janssen reviewed the content for technical accuracy. The content is intended for a UK healthcare professional audience only.

Objectives and background for this learning resource Introduction: This learning resource has been developed as part of a medical education initiative supported by Janssen. The content of this slide kit has been developed by an advisory board of renal physicians, GPs and specialist nurses. The panel of experts includes members of the British Renal Society Chronic Kidney Disease (CKD) Strategy Group. Bedrock Healthcare, a medical communications agency, has provided editorial support in developing the content; Janssen has reviewed the content for technical accuracy. Educational objectives: • To provide clear and applicable clinical guidance on chronic kidney disease (CKD) in people with type 2 diabetes to primary care healthcare professionals • To advise primary healthcare professionals on what people with diabetes need to know about their own condition with relation to CKD Usability objectives: • To provide essential, relevant and up to date information in concise presentations • To enable primary healthcare professionals to locate, select and use the content of the learning resource, as appropriate to their needs • To enable secondary care experts in CKD to refer their primary care colleagues to the resource 1

Contents overview This learning resource comprises the following 10 sections (A-E): Section A Introduction and overview of chronic kidney disease (CKD) in people with diabetes Section B Long-term impact of diabetes and the importance of optimal management of the condition Section C Pathophysiology of diabetic nephropathy & risk factors for the development of CKD Section D Appropriate monitoring for complications of diabetes in primary care – CKD as one of these complications Section E Prevention of diabetic kidney disease 2

Contents overview (cont. ) This learning resource comprises the following 10 sections (F-J): Section F Optimal management of diabetic kidney disease: hypertension and glycaemia Section G How to involve people with diabetes and CKD in their own care – what information must they have to manage their own condition effectively? Section H What does the future hold for a person with well-managed diabetes and CKD? Section I What do the guidelines say and what do they mean in terms of the day-to-day management of CKD in people with diabetes? Section J Sources of further information and reading list 3

Section F – 3 key learning objectives • Once diabetic kidney disease has developed, early optimal management can reduce disease progression • ACE inhibitors and ARBs improve outcomes • Presence of diabetic kidney disease implies generalised vascular disease which requires holistic management 4

ACE inhibitors or ARBs for blood pressure management • Angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) are both renin–angiotensin–aldosterone system (RAAS) antagonists 1 • Only one type of RAAS agonist should be offered to people with CKD – Combined therapy of ACE inhibitors and ARBs is not recommended 1 Reference: 1. NICE clinical guideline 182. Chronic kidney disease early identification and management of chronic kidney disease in adults in primary and secondary care. July 2014. 5

ACE inhibitors or ARBs may reduce the rate of GFR decline ACEI/ARB given Long-term slowing of reduction in GFR in people with proteinuria and normal renal perfusion e. GFR Slowly deteriorating CKD Continued rapid fall in GFR when there is renovascular disease or other cause of global reduction in renal perfusion Acute reduction e. GFR – expected (medication need not necessarily be stopped if reduction less than 25%1) Figure created from discussions with the advisory board Time Reference: 1. NICE clinical guideline 182. Chronic kidney disease early identification and management of chronic kidney disease in adults in primary and secondary care. July 2014. 6

Mode of action of ACE inhibitors and ARBs: overview of mechanisms ACE inhibitors or ARBs Glomerulosclerosis Inhibitory action Intraglomerular hypertension Decline in RENAL FUNCTION Reduction in number of functioning glomeruli Increased blood flow to remaining nephrons Figure created from discussions with the advisory board and El. Atat FA et al. 2004. 1 References: 1. El-Atat FA, et al. The Relationship between Hyperinsulinemia, Hypertension and Progressive Renal Disease. J Am Soc Nephrol 2004; 15: 2816– 2827. 7

Mode of action of ACE inhibitors and ARBs: Mechanisms in detail Systemic Hypertension Diabetes BLOCKS CONVERSION ANG I TO ANG II ACE inhibitors or ARBs Pgc SNGFR Mechanical Stress No. of functioning glomeruli Ang II Albuminuria Macrophages Fibroblasts 2° FSGS and TIF Pgc = glomerular capillary hydraulic pressure SNGFR = single nephron glomerular filtration rate Ang II = angiotensin II 2°FSGS = secondary focal segmental glomerulosclerosis TIF = tubulointerstitial fibrosis; TGF- = transforming growth factor CAMs = chorioallantoic membranes TGF- Cytokines CAMs Decline in RENAL FUNCTION Figure created from discussions with the advisory board 8

Hypertension: choice of agents • • Target BP for people with: CKD: systolic BP <140 mm. Hg / diastolic BP <90 mm. Hg 1 CKD and diabetes, and ACR ≥ 70 mg/mmol: systolic BP <130 mm. Hg / diastolic BP <80 mm. Hg 1 CKD (any stage) + • e. GFR≤ 59, diabetes and ACR*≥ 3 mg/mmol 1 • Hypertension and ACR ≥ 30 mg/mmol 1 • ACR ≥ 70 mg/mmol 1 • Under 55 yrs (regardless of proteinuria)* ACE inhibitor, ARB, direct renin inhibitor or aldosterone antagonist 1 *ACR=albumin: creatinine ratio • Over 55 yrs 2 • African or Caribbean family origin (regardless of age)2 Calcium channel blocker first line 2 *Advice from the advisory board References: 1. NICE clinical guideline 182. Chronic kidney disease early identification and management of chronic kidney disease in adults in primary and secondary care. July 2014. 2. NICE clinical guideline 127. Clinical management of primary hypertension in adults. August 2011. 9

Hypoglycaemia is a risk for patients with type 2 diabetes and CKD when taking oral glucose control therapies • Progressive CKD increases the risk of hypoglycaemia 1, 2 • With impaired kidney function, the half-life of insulin is prolonged 1, 3 • Risk of ‘hypos’ may be more difficult to predict in patients with CKD* • Symptoms of ‘hypos’ may be reduced in patients with CKD* Always ask about hypoglycaemia* • Assess ‘risk and treatment’ of hypoglycaemia 1, 2 • More tailored dosing is required 1 • Patients need to be monitored more frequently 1 Perform frequent therapy reviews, especially if patient commences dialysis* References: *Advice from the advisory board 1. Cavanaugh KL. Clinical Diabetes 2007; 25(3): 90 -97. 2. National Kidney Foundation KDOQI Clinical Practice Guidelines for Diabetes and CKD: 2012 Update. Available at http: //www. kidney. org/sites/default/files/docs/diabetes-ckd-update-2012. pdf. Website last accessed on 12. 11. 14. 3. Iglesias P & Diez JJ. Diabetes, Obesity and Metabolism 2008; 10: 811– 823. 10

Importance of testing for anaemia and monitoring Hb. A 1 c levels carefully • People with CKD are often anaemic, particularly if e. GFR <45 ml/min/1. 73 m 2 (GFR category G 3 b, G 4 or G 5)1 • Patients with anaemia (defined as Hb <110 g/L): 1, 2 – Have shortened red blood cell (RBC) lifespan (~ 90 days), which reduces Hb. A 1 c levels 3 – Have iron deficiency, which increases Hb. A 1 c (false high)4 – Are often receiving IV iron therapy or erythropoiesis-stimulating agents (ESA), both of which can reduce Hb. A 1 c in patients with diabetes and CKD 5 • It is important to test for anaemia in patients with CKD and monitor Hb. A 1 c levels carefully References: 1. NICE clinical guideline 182. Chronic kidney disease early identification and management of chronic kidney disease in adults in primary and secondary care. July 2014. 2. NICE clinical guideline 114. Anaemia management in people with chronic kidney disease. February 2011. 3. Joy MS et al, Am J Kidney Dis. 2002 Feb; 39(2): 297 -307. 4. Kim C et al. Diabetes Care 33: 780– 785, 2010. 5. Ng JM. Diabetes Care 33: 2310– 2313, 2010 11

Glucose control therapies in type 2 diabetes and CKD (1 of 4) Medication Recommended use in renal impairment Metformin • ADULT and CHILD >10 years initially 500 mg with breakfast for at least 1 week then 500 mg with breakfast and evening meal for at least 1 week then 500 mg with breakfast, lunch and evening meal; usual max. 2 g daily in divided doses 1 • Use with caution in renal impairment, avoid in significant renal impairment 1 • Determine renal function before treatment and at least annually (at least twice a year in patients with additional risk factors for renal impairment, or if deterioration suspected) 1 • NICE recommends dose review if e. GFR <45 m. L/minute/1. 73 m 2, avoid if e. GFR <30 m. L/minute/1. 73 m 2 • Withdraw or interrupt treatment in those at risk of tissue hypoxia or sudden deterioration in renal function, such as those with dehydration, severe infection, shock, sepsis, acute heart failure, respiratory failure or hepatic impairment, or those who have recently had a myocardial infarction 1 DPP 4 inhibitors • Alogliptin 1 – Reduce dose to 12. 5 mg OD if e. GFR 30– 50 m. L/minute/1. 73 m 2 – Reduce dose to 6. 25 mg OD if e. GFR <30 m. L/minute/1. 73 m 2 and use with caution • Linagliptin 1 – ADULT >18 years, 5 mg OD • Vildagliptin 1 – Reduced dose to 50 mg OD if e. GFR less than 50 m. L/minute/1. 73 m 2 • Sitagliptin 1 – Reduced dose to 50 mg OD if e. GFR 30– 50 m. L/minute/1. 73 m 2 – Reduced dose to 25 mg OD if e. GFR <30 m. L/minute/1. 73 m 2 • Saxagliptin 1 – Reduced dose to 2. 5 mg OD in moderate to severe impairment – Use with caution in severe impairment – Determine renal function before treatment and periodically thereafter ALL 1: Dose of concomitant sulfonylurea or insulin may need to be reduced References: 1. British National Formulary 2015. Available at: https: //www. medicinescomplete. com/about/subscribe. htm Website accessed 03. 02. 15. 12

Glucose control therapies in type 2 diabetes and CKD (2 of 4) Medication Sulphonylureas Recommended use in renal impairment • Glibenclamide 1 – Initially 5 mg daily with or immediately after breakfast, dose adjusted according to response (ELDERLY avoid); max. 15 mg daily • Gliclazide 1 – Initially, 40– 80 mg daily, adjusted according to response; up to 160 mg as a single dose, with breakfast; higher doses divided; max. 320 mg daily • Glimepiride 1 – Initially 1 mg daily, adjusted according to response in 1 mg steps at 1– 2 week intervals; usual max. 4 mg daily (exceptionally, up to 6 mg daily may be used); taken shortly before or with first main meal • Glipizide 1 – Initially 2. 5– 5 mg daily shortly before breakfast/lunch, adjusted according to response; max. 20 mg daily; up to 15 mg may be given as a single dose; higher doses divided • Tolbutamide 1 – 0. 5– 1. 5 g (max. 2 g) daily in divided doses with or immediately after meals or as a single dose with or immediately after breakfast ALL 1: Use with care in those with mild to moderate renal impairment, due to hypoglycaemia; avoid where possible in severe renal impairment. Glipizide should be avoided if the patient has both renal and hepatic impairment. Tolbutamide and gliclazide can be used in renal impairment, but careful monitoring of blood glucose concentration is essential. Use the lowest dose to adequately control blood glucose. Thiazolidinediones • Pioglitazone 1, 2 – ADULT >18 years, 15 mg or 30 mg OD, increased in increments up to 45 mg OD – ELDERLY, initiate with lowest possible dose and increase gradually); review treatment after 3– 6 months and regularly thereafter – No dose adjustment is needed in patients with impaired renal function (creatinine clearance >4 m. L/min) – Should not be used in dialysed patients Note: Dose of concomitant sulfonylurea or insulin may need to be reduced References: 1. British National Formulary 2015. Available at: https: //www. medicinescomplete. com/about/subscribe. htm Website accessed 03. 02. 15; 2. Takeda UK Ltd. Actos (Pioglitazone) EU SPC 2013. 13

Glucose control therapies in type 2 diabetes and CKD (3 of 4) Medication GLP-1 receptor agonists/ Mimetics cont. Recommended use in renal impairment • Exenatide 1 – ADULT >18 years, initially 5 μg twice daily within 1 hour before 2 main meals (at least 6 hours apart), increased if necessary after at least 1 month to max. 10 μg twice daily – Standard release injection: use with caution if e. GFR 30– 50 m. L/minute/1. 73 m 2; avoid if e. GFR <30 m. L/minute/1. 73 m 2 – Modified release injection: avoid if e. GFR <50 m. L/minute/1. 73 m 2 • Lixisenatide 1 – ADULT >18 years, initially 10 μg OD within 1 hour before the first meal of the day or the evening meal for 14 days, increased to 20 μg OD thereafter – Use with caution if e. GFR 30– 50 m. L/minute/1. 73 m 2 – Avoid if e. GFR less than 30 m. L/minute/1. 73 m 2—no information available • Liraglutide 1 – ADULT >18 years, initially 0. 6 mg OD, increased after at least 1 week to 1. 2 mg OD, further increased if necessary after an interval of at least 1 week to max. 1. 8 mg OD – Avoid if e. GFR less than 60 m. L/minute/1. 73 m 2—limited experience ALL 1: Note: Dose of concomitant sulfonylurea or insulin may need to be reduced Alpha glucosidase • Acarbose 1 antagonist – ADULT >18 years, initially 50 mg daily increased to 50 mg 3 times daily, then increased if necessary after 6– 8 weeks to 100 mg 3 times daily; max. 200 mg 3 times daily – Avoid if e. GFR less than 25 m. L/minute/1. 73 m 2 – To counteract possible hypoglycaemia, patients receiving insulin or a sulfonylurea as well as acarbose need to carry glucose (not sucrose—acarbose interferes with sucrose absorption) References: 1. British National Formulary 2015. Available at: https: //www. medicinescomplete. com/about/subscribe. htm Website accessed 03. 02. 15. 14

Glucose control therapies in type 2 diabetes and CKD (4 of 4) Medication SGLT-2 inhibitors Recommended use in renal impairment • Empagliflozin 1 – ADULT >18 years, 10 mg OD, if necessary and if tolerated, increase to max. 25 mg OD – ELDERLY >85 years, initiation not recommended – Avoid if e. GFR is persistently <45 m. L/minute/1. 73 m 2 – Avoid initiation if e. GFR <60 m. L/minute/1. 73 m 2 – Reduce dose to 10 mg OD if e. GFR falls persistently <60 m. L/minute/1. 73 m 2 • Dapagliflozin 1 – ADULT >18 years, 10 mg OD – ELDERLY over 75 years, initiation not recommended – Avoid if e. GFR <60 m. L/minute/1. 73 m 2 (ineffective) • Canagliflozin 1* – ADULT >18 years, 100 mg OD preferably before breakfast; if necessary and tolerated, increase to 300 mg OD – Avoid initiation if e. GFR <60 m. L/minute/1. 73 m 2 – Avoid in combination with metformin if e. GFR <60 m. L/minute/1. 73 m 2 – Reduce dose to 100 mg OD if e. GFR falls persistently <60 m. L/minute/1. 73 m 2 and existing canagliflozin treatment tolerated – Avoid if e. GFR <45 m. L/minute/1. 73 m 2 – Monitor renal function at least twice a year in moderate impairment ALL 1: Dose of concomitant insulin or drugs that stimulate insulin secretion may need to be reduced. Determine renal function before treatment and before initiation of concomitant drugs that may reduce renal function, then at least annually thereafter *Prescribing information is provided at the end of the this section References: 15 1. British National Formulary 2015. Available at: https: //www. medicinescomplete. com/about/subscribe. htm Website accessed 03. 02. 15.

Insulin in CKD • Insulin resistance and reduced clearance of insulin can lead to swings in glycaemic levels 1 • Insulin therapy requirements may reduce as kidney function declines due to: – The effect of reduced kidney function on insulin clearance 2, 3 – Reduction of gluconeogenesis in the kidney 3 – Uraemia-induced anorexia and weight loss 3 • There are no evidence-based guidelines or recommendations about which types of insulin to use or avoid depending on the severity of CKD 2 – Some studies suggest avoiding long-acting insulin, whereas others support its use 2 • Frequent monitoring is advised 2, 4 References: 1. Sobngwi E, et al. Diabetes Care 2010; 33(7): 1409 -12. 2. Cavanaugh KL. Clinical Diabetes 2007; 25(3): 90 -97. 3. Iglesias P & Diez JJ. Diabetes, Obesity and Metabolism 2008; 10: 811– 823. 4. National Kidney Foundation KDOQI Clinical Practice Guidelines for Diabetes and CKD: 2012 Update. Available at http: //www. kidney. org/sites/default /files/docs/diabetes-ckd-update-2012. pdf. Website last accessed on 12. 11. 14 16

Dialysis can effect glycaemic control and the risk of hypoglycaemic events • Haemodialysis can affect glycaemic control in the following ways: 1 – Improves insulin sensitivity – Improves insulin clearance • Insulin requirements may be 25% lower the day after dialysis compared with the day before. 1 Mean blood glucose is lower on dialysis days 2 • Inadequate gastrointestinal glucose absorption (due to gastroparesis) can also negatively influence glycaemic control in patients with diabetes undergoing dialysis 3 • Therefore in patients receiving dialysis there is a clear need to review: – Hb. A 1 c trends 4 – Current medication 4 – Hb. A 1 c levels, with regards to reliability of results 5 References: 1. Sobngwi E, et al. Diabetes Care 2010; 33(7): 1409 -12. 2. Kazempour-Ardebili S et al. Diabetes Care 32: 1137– 1142, 2009. 3. Iglesias P & Diez JJ. Diabetes, Obesity and Metabolism 2008; 10: 811– 823. 4. Cavanaugh KL. Clinical Diabetes 2007; 25(3): 90 -97. 5. Shrishrimal K, et al. Cleveland Clinic Journal of Medicine 2009; 76(11): 649 -655. 17

Management of people with diabetes who require dialysis should be a collaboration with the renal team Diabetes teams to remain involved with care of dialysis patients • Foot checks, retinal screening, adjustment of glycaemic control (insulin) Specialist members of the renal team involved in the care of renal patients receiving dialysis: Nephrologist Renal teams to adjust medications • Anti-hypertensives, diuretics Renal teams to manage complications of CKD • Anaemia, metabolic bone disease (initiate treatment, prescribe specialist drugs e. g. intravenous iron & ESA therapy, Cinacalcet®) A specialist renal dietician to provide dietary advice Renal Pharmacist Dietician THE RENAL TEAM Specialist Nurses* Counsellor Social Services rep *Specialist nurses to manage anaemia, bone management, dialysis 18

When albuminuria is not ‘diabetic’ • Suspect kidney disease other than diabetic nephropathy and consider further investigation or referral when the albumin: creatinine ratio (ACR) is raised and ANY of the following apply: 1 – There is no significant or progressive retinopathy 1 – Blood pressure is particularly high or resistant to treatment 1 – The person previously had a documented ACR <3 mg/mmol and develops heavy proteinuria (ACR >100 mg/mmol)1 – Significant haematuria is present 1 (exclude infection) – The e. GFR has worsened rapidly 1 (≥ 25% after starting ACEI or 15 ml/min/1. 73 m² within 12 months 2) – The person is systemically ill 1 (exclude acute kidney injury) References: 1. NICE clinical guideline 87. The management of type 2 diabetes. Issued: May 2009 last modified: July 2014 2. NICE clinical guideline 182. Chronic kidney disease early identification and management of chronic kidney disease in adults in primary and secondary care. July 2014. . 19

When to refer a patient to nephrology NICE referral criteria: • GFR <30 ml/min/1. 73 m 2 (GFR category G 4 or G 5), with or without diabetes 1 • ACR ≥ 70 mg/mmol, unless known to be caused by diabetes and already appropriately treated 1 • ACR ≥ 30 mg/mmol (ACR category A 3), together with haematuria 1 • Sustained decrease in GFR of ≥ 25%, and a change in GFR category or sustained decrease in GFR of ≥ 15 m. L/min/1. 73 m 2 within 12 months 1 (no requirement to be on a diuretic)* • Hypertension that remains poorly controlled despite the use of at least 4 antihypertensive drugs at therapeutic doses 1 • Known or suspected rare or genetic causes of CKD 1 • Suspected renal artery stenosis 1* Referral may also be indicated if: • Suspicion of non-diabetic kidney disease* • Advice to manage complications of CKD e. g. anaemia, acidosis 1 • To establish an alternative diagnosis* References: *Advice from the advisory 1. NICE clinical guideline 182. Chronic kidney disease early identification and management of chronic kidney disease in adults board in primary and secondary care. July 2014. 20

Section F – summary • ACE inhibitor or ARB therapy improves outcomes in diabetic kidney disease • ACE inhibitors and ARBs should not be prescribed together • Presence of diabetic kidney disease implies generalised vascular disease which requires holistic management • Oral hypoglycaemic therapy needs adjusting in people with diabetic kidney disease • Insulin may need adjusting if people with diabetes and kidney disease are receiving dialysis • Consider referral to a nephrologist when appropriate • Work collaboratively with your local renal team 21

Prescribing information INVOKANA® ▼ film-coated tablets PRESCRIBING INFORMATION. ACTIVE INGREDIENT(S): Canagliflozin hemihydrate, equivalent to 100 mg or 300 mg canagliflozin. Please refer to Summary of Product Characteristics (Sm. PC) before prescribing. INDICATION(S): In adults with type 2 diabetes mellitus to improve glycaemic control as: monotherapy when diet and exercise alone do not provide adequate glycaemic control and use of metformin considered inappropriate; add-on therapy with other glucose-lowering medicinal products including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control. DOSAGE & ADMINISTRATION: Adults: recommended starting dose: 100 mg once daily. In patients tolerating this dose and with e. GFR ≥ 60 m. L/min/1. 73 m 2 needing tighter glycaemic control, dose can be increased to 300 mg once daily. Caution increasing dose in patients ≥ 75 years old, with known cardiovascular disease or for whom initial canagliflozin-induced diuresis is a risk. Correct volume depletion prior to initiation. When add-on, consider lower dose of insulin or insulin secretagogue to reduce risk of hypoglycaemia. Children: no data available. Elderly: consider renal function and risk of volume depletion. Renal impairment: not to be initiated with e. GFR < 60 m. L/min/1. 73 m 2. If e. GFR falls below this value during treatment, adjust or maintain dose at 100 mg once daily. Discontinue if e. GFR persistently < 45 m. L/min/1. 73 m 2. Not for use in end stage renal disease or patients on dialysis. Hepatic impairment: mild or moderate hepatic impairment: no dose adjustment. Severe hepatic impairment: not studied, not recommended. CONTRAINDICATIONS: Hypersensitivity to active substance or any excipient. SPECIAL WARNINGS & PRECAUTIONS: Not studied in patients with type 1 diabetes. Not to be used for treatment of diabetic ketoacidosis. Renal impairment: e. GFR < 60 m. L/min/1. 73 m 2: higher incidence of ADRs associated with volume depletion particularly with 300 mg dose; more events of elevated potassium; greater increases in serum creatinine and BUN; limit dose to 100 mg once daily and discontinue when e. GFR < 45 m. L/min/1. 73 m 2. Not studied in severe renal impairment. Monitor renal function prior to initiation and at least annually. Volume depletion: caution in patients for whom a canagliflozin-induced drop in blood pressure is a risk (eg, known cardiovascular disease, e. GFR < 60 m. L/min/1. 73 m 2, anti-hypertensive therapy with history of hypotension, on diuretics or elderly people). Not recommended with loop diuretics or volume depleted patients. Monitor volume status and serum electrolytes. Elevated haematocrit: caution. Genital mycotic infections: risk in male and female patients, particularly in those with a history of GMI. Urine laboratory assessment: glucose in urine due to mechanism of action. Lactose intolerance: do not use in patients with galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption. SIDE EFFECTS: Very common: hypoglycaemia in combination with insulin or sulphonylurea, vulvovaginal candidiasis. Common: constipation, thirst, nausea, polyuria or pollakiuria, urinary tract infection, balanitis or balanoposthitis, dyslipidemia, hematocrit increased. Uncommon: dehydration, postural dizziness, syncope, hypotension, orthostatic hypotension, rash, urticaria, bone fracture, blood creatinine increased, blood urea increased, blood potassium increased, blood phosphate increased. Refer to Sm. PC for other side effects. PREGNANCY: No human data. Not recommended. LACTATION: Unknown if excreted in human milk. Should not be used during breast-feeding. INTERACTIONS: Diuretics: may increase risk of dehydration and hypotension. Insulin and insulin secretagogues: risk of hypoglycaemia; consider lower dose of insulin or insulin secretagogue. Effects of other medicines on Invokana: Enzyme inducers (eg, St. John’s wort, rifampicin, barbiturates, phenytoin, carbamazepine, ritonavir, efavirenz) may decrease exposure of canagliflozin; monitor glycaemic control. Consider dose increase to 300 mg if administered with UGT enzyme inducer. Cholestyramine may reduce canagliflozin exposure; take canagliflozin at least 1 hour before or 4 -6 hours after a bile acid sequestrant. Effects of Invokana on other medicines: Monitor patients on digoxin, other cardiac glycosides, dabigatran. Inhibition of Breast Cancer Resistance Protein cannot be excluded; possible increased exposure of drugs transported by BCRP (eg, rosuvastatin and some anticancer agents). Refer to Sm. PC for full details of interactions. LEGAL CATEGORY: POM PRESENTATIONS, PACK SIZES, MARKETING AUTHORISATION NUMBER(S) & BASIC NHS COSTS Invokana 100 mg film -coated tablets, EU/1/13/884/002, pack of 30 tablets: £ 39. 20. Invokana 300 mg film-coated tablets, EU/1/13/884/006, pack of 30 tablets: £ 49. 99. MARKETING AUTHORISATION HOLDER: Janssen-Cilag International NV, Turnhoutseweg 30, B-2340 Beerse, Belgium. FURTHER INFORMATION IS AVAILABLE FROM: Janssen-Cilag Ltd, 50 -100 Holmers Farm Way, High Wycombe, Buckinghamshire HP 12 4 EG UK. © Janssen-Cilag Ltd 2014 Prescribing information last revised: April 2014. PIVER 15112014 Adverse events should be reported. This medicinal product is subject to additional monitoring and it is therefore important to report any suspected adverse events related to this medicinal product. Reporting forms and information can be found at www. mhra. gov. uk/yellowcard. Adverse events should also be reported to Janssen-Cilag Ltd on 01494 567447.