This supplement has been developed in partnership with Takeda UK Ltd. Guidance Update

Transcription

1 This supplement has been developed in partnership with Takeda UK Ltd cpd credits Guidance Update Diabetes NICE guidance on glycaemic control of adults with type 2 diabetes mellitus This supplement has been sponsored by Takeda UK Ltd. The sponsorship fee included the honorarium for the author. Takeda UK Ltd suggested the topic and the author, commented on the author brief and commissioned the production of the supplement. The content has also been checked to ensure its compliance with appropriate regulations. MGP has paid the author s honorarium on behalf of Takeda UK Ltd. The views and opinions of the author are not necessarily those of Takeda UK Ltd or of Guidelines in Practice, its publisher, advisers, or advertisers No part of this publication may be reproduced in any form without the permission of the publisher. Prescribing information can be found on the back cover. UK/VIP/1601/0011 MGP Ltd 2017 Date of preparation: September 2017

2 Current NICE guidance emphasises the importance of timely glycaemic control in patients with type 2 diabetes mellitus Dr Stephen Lawrence, GPwSI Diabetes, Principal Clinical Teaching Fellow, Warwick University Medical School, Coventry Introduction The treatment of diabetes and the management of associated complications represents a significant clinical challenge and financial concern in all parts of the world, with over 400 million adults currently estimated to have diabetes, and an unprecedented prevalence of 6.2% in the UK. 1 It is estimated that 90% of people in the UK with diabetes have type 2 diabetes mellitus. 2 An increasing number of people are at significant risk of developing type 2 diabetes mellitus, and the resulting burden on limited NHS resources mandates action by healthcare professionals to stay up to date with current evidence-based guidance. This is essential for appropriate clinical management in an area of medicine that is the subject of rapid change and development. NICE Guideline 28 NICE Guideline 28 (NG28), Type 2 diabetes in adults: management, originally published in December 2015 and updated in May 2017, 3 superceded the previous NICE Clinical Guideline 87 (CG87) published in June 2009, and provided a long awaited extension to the number of potential cost-effective, evidence-based treatment options. Clearly, any guideline publication will speak to the clinical evidence-base and pharmacological advances pertinent at the time of data analysis. The rate of pharmacological advancement in type 2 diabetes mellitus, whilst heralded as a great asset for patient care, nonetheless presents a challenge for NICE that potentially renders the guideline out of date within a relatively short period of time. However, this limitation should not nullify continued application of some of the high-value advice within the guideline. It is important to recognise that the NICE guideline is not simply glucocentric, but also provides important steers with regards to other aspects relevant to the management of complications of diabetes. This article will primarily concentrate on glycaemic control in diabetes. Glycaemic control Monitoring control Firstly, with regards to glycaemic control, NG28 places a strong emphasis on the principle of lifestyle management, stating that advice on diet, physical activity, and losing weight should be reinforced at every opportunity. 3 The requirement to check glycaemic control at least every 6 months (using International Federation of Clinical Chemistry [IFCC] standardised equipment only) is also introduced. 3 Of note, healthcare professionals are advised to consider the limitations of standard glycated haemoglobin (HbA 1c ) monitoring in patients where the longevity of erythrocytes may be affected or in those who may have an abnormal haemoglobin type, and to consider alternative tests such as fructosamine estimation, quality controlled plasma glucose profiles, or total glycated haemoglobin estimation. 3 The guideline references the Driver and Vehicle Licensing Agency (DVLA) guidance on offering self-monitoring of blood glucose (SMBG) to adults with type 2 diabetes mellitus who take insulin or oral agents that may cause hypoglycaemia. 4 The DVLA guidance states SMBG should be offered at times relevant to driving, and referencing this is a welcome acknowledgement by NICE of the prescriber s responsibility to not withhold the option of SMBG in such cases. However, this will have additional cost implications on the prescribing of sulfonylureas and glinides that otherwise have a low acquisition cost, due to the hidden costs associated with the use and disposal of sharps necessary for SMBG. Whilst there is no argument against the appropriate use of SMBG in patients receiving insulin treatment, the costs and increased resource use associated with the monitoring of patients receiving sulfonylureas may compare unfavourably with the convenience of prescribing their dipeptidyl peptidase-4 (DPP-4) inhibitor, pioglitazone, or sodium-glucose co-transporter-2 (SGLT-2) inhibitor counterparts. HbA 1c targets In contrast to the previous guideline (CG87), the patient s HbA 1c target following diagnosis is dependent on the potential 2

3 risk of hypoglycaemia associated with the method of glucose management. The recommended HbA 1c target is 48 mmol/mol, unless prescribing a drug that can cause hypoglycaemia, at which point the target rises to 53 mmol/mol. 3 Given the weight of evidence from landmark studies such as the UK Prospective Diabetes Study (UKPDS), which highlights the benefits of early, tight glycaemic control, 5,6 it is somewhat incongruous that NG28 supports waiting until the HbA 1c rises to 58 mmol/ mol before engaging in first. There is, of course, a caveat recommendation that an individualised approach is maintained when deciding on an HbA 1c target, and that the patient should be involved in the decision process. 3 However, this requirement may raise a conflict of interest if a practice is close to the threshold for exception reporting. Pharmacological management Initial therapy NICE Guideline 28 introduces the terminology first and second of pharmacological management. 3 This nomenclature assumes the pre-existence of a starting blood-glucose controlling drug, which is likely to be, but is not exclusively, metformin. First and second then denotes the second and third drugs added after diagnosis, respectively. Table 1 (see p. 4) details key clinical considerations for each of the drug classes included as options for first and second in NG28, and Figure 1 (see p. 5) displays the treatment combinations available at each stage of in line with the recommendations in NG28. In situations where metformin is either contraindicated or not tolerated, the guideline recommends initial monotherapy with a DPP-4 inhibitor,* pioglitazone, or a sulfonylurea. 3 Monotherapy with a SGLT-2 inhibitor may also be recommended under the specific directions detailed in NICE Technology Appraisal 390, published in May 2016, and supported by the May 2017 update to NG28. 3,7 NICE Guideline 28 states that the glinide, repaglinide, may be considered in patients in whom metformin is contraindicated or not tolerated. 3 Glinides have an advantage over traditional sulfonylureas in that they have a significantly reduced half-life, which reduces the chances of severe and prolonged hypoglycaemic episodes. 8 However, the guideline states that it must be made known to the patient that there are no licensed non-metformin-based combinations containing repaglinide that can be offered beyond initial therapy. 3 With all oral hypoglycaemic agents, the risk of adverse side-effects increases with the presence of co-morbidities and intercurrent acute illness. 9,10 Patients should therefore be issued with sick-day rules, including advice on alteration of medication dose in the presence of illness where appropriate, and staying well hydrated. 9,10 *Alogliptin is not licensed for monotherapy 3 First With regard to the therapeutic options available at the two levels of, NG28 is quite proscriptive (Figure 1). 3 Assuming the most likely situation of metformin being the initial drug of choice, NG28 advocates the use of first options, including DPP-4 inhibitors, pioglitazone, SGLT-2 inhibitors (subject to individual technology appraisal guidance), or sulfonylureas. 3 However, the addition of choice may hamper the decision-making process, especially in light of the underpinning advice running through the NG28 guideline to ensure that treatment is individualised. Options for treatment in those individuals in whom initial monotherapy with metformin is contraindicated or not tolerated, are shown in Figure 2 (see p. 5). Second If a patient fails to achieve the individualised glycaemic target following the first step of with metformin, the NG28 guideline recommends a second level of to triple therapy (Figure 1, p. 5) or insulin-based treatment. 3 Options beyond triple therapy For patients who fail to reach their individualised target at the second level of, combination treatment with metformin, a sulfonylurea, and a glucagon-like peptide-1 (GLP-1) mimetic is supported. 3 However, the caveats for continuing GLP-1 mimetic treatment remain in the guideline (Table 1, p. 4). While it is important to acknowledge these caveats with regards to this relatively expensive therapeutic group, both prescribers and patients may struggle to accede to this ruling, especially when a significant improvement in weight loss or glycaemic control, but not both, has been observed. Many practitioners, being observant of the need to control prescribing costs in a financially constrained NHS environment, choose to adopt a rather more pragmatic approach whereby significant progress needs to be demonstrated 6 months after initiation of treatment with a GLP-1 mimetic with either glycaemic control or weight loss. It should be noted that combination treatment with a GLP- 1 mimetic in addition to insulin is reserved for specialist multidisciplinary teams. NICE Quality Standard 6 on Diabetes in adults NICE quality standards are a concise set of prioritised statements that aim to drive improvements in healthcare quality by changing culture and behaviour. For any particular area of care, the standards focus on the principle of measurable improvements in patient safety, patient experience, and clinical effectiveness.

4 Table 1: Key clinical considerations for the drug classes covered by NICE NG28 in the management of blood glucose levels Drug class Key clinical considerations Further advice when selecting drug for first Biguanide: metformin DPP-4 inhibitors: alogliptin linagliptin saxagliptin sitagliptin vildagliptin Glinides: repaglinide nateglinide GLP-1 mimetics: albiglutide dulaglutide exenatide liraglutide lixisenatide Thiazolidinediones: pioglitazone SGLT-2 inhibitors: canagliflozin dapagliflozin empagliflozin Sulfonylureas: glibenclamide gliclazide glimepiride glipizide tolbutamide In order to avoid adverse gastrointestinal side-effects the dose of metformin should be gradually increased over several weeks and, while no optimal dose is specified in the guideline, the pragmatic dose is 1000 mg twice-daily 11 For patients failing to tolerate standard-release metformin, consider a trial of modified-release metformin 3 If egfr falls below 30 ml/min/1.73 m 2 use of metformin should be stopped 3 Guidance on the use of metformin in patients with declining renal function to below 45 ml/min/1.73 m 2 is less clear accepted advice is that the metformin dose is halved once the egfr falls below 45 ml/min/1.73 m 2 (use of metformin is contraindicated when egfr falls below 30 ml/min/1.73 m 2 ). 12 Refer to relevant summary of product characteristics for information on any dose adjustments that may be required in patients with renal impairment When a DPP-4 inhibitor is used in combination with a sulfonylurea, a lower dose of sulfonylurea may be considered to reduce the risk of hypoglycaemia A warning has been issued regarding the rare complication of pancreatitis. 18 No dose adjustment of repaglinide is required in patients with renal impairment: 19 a small fraction (<8%) of one dose of repaglinide is excreted through the kidneys and total plasma clearance of the product is decreased in patients with renal impairment insulin sensitivity is increased in patients with diabetes and renal impairment, so caution is advised when titrating these patients Nateglinide is not licensed for monotherapy. 20 Treatment with GLP-1 mimetics should only be continued if the patient has had a beneficial response (a reduction of at least 11 mmol/mol [1.0%] in HbA 1c and weight loss of at least 3% of initial body weight in 6 months) 3 A warning has been issued regarding the rare complication of pancreatitis. 18 NG28 states that pioglitazone should not be offered or continued if the patient has any of the following: 3 heart failure or a history of heart failure hepatic impairment diabetic ketoacidosis current, or a history of, bladder cancer uninvestigated macroscopic haematuria. NG28 refers to the use of SGLT-2 inhibitors by way of the corresponding technology appraisal guidance which currently differs for each member of the class 3 The SGLT-2 inhibitor class of drugs offers patients durable glycaemic control compared with sulfonylurea, combined with the possibility of some weight loss 21,22 Many patients may see potential weight loss as a reasonable trade-off for the increased risk of urinary tract infections 21,22 These drugs should not be initiated in patients with an egfr below 60 ml/min/1.73 m Suitable for patients who are overweight, as the weight neutrality associated with this class of drugs may encourage good compliance The low risk of hypoglycaemia associated with this drug class may be beneficial for patients where avoidance of hypoglycaemia is a priority. NICE NG28 does not recommend the use of glinides at first. NICE NG28 does not recommend the use of GLP-1 mimetics at first. Suitable for treatment of patients who are highly insulin resistant, for example those who are very overweight or those of South-Asian descent who may exhibit high insulin resistance at a relatively low BMI The patient should be made aware of the potential weight gain and risk of fractures, and to seek medical attention in cases of unexplained weight gain, shortness of breath, or swelling of the hands, ankles, or feet. May be preferable in patients with increased blood pressure, and in individuals where potential weight loss may be beneficial Due to potential biomedical issues associated with SGLT-2 inhibtors (e.g. diabetic ketoacidosis), it is the author s opinion that these drugs are reserved for patients who are compliant with treatment and who are likely to be aware of red flags associated with adverse events. The dose of sulfonylurea should be revised if a patient demonstrates declining renal function 23 Recommended for patients with no insulin resistance, in whom weight gain is not a primary concern; these patients are likely to present without a high BMI. egfr=estimated glomerular filtration rate; DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; HbA 1c =glycated haemoglobin; NG28=NICE Guideline 28; SGLT-2=sodium-glucose co-transporter-2; BMI=body mass index

5 Quality Standard 6 aims to support timely of blood glucose therapy. Patients who undergo early of medication in order to achieve glycaemic control attain significant and maintained reductions in HbA 1c faster than those whose is delayed. 24 Unfortunately, within the UK it is not unusual for patients to have an HbA 1c of 58 mmol/mol (7.5%) for almost 2 years before treatment and addition of a second or third agent. 25 However, the August 2016 update to NICE Quality Standard 6 on Diabetes in adults includes the statement of Adults with type 2 diabetes whose HbA 1c is 58 mmol/mol (7.5%) or above after 6 months with single-drug treatment are offered dual therapy. 26 Given the vast number of patients occupying the clinical cohort in question, implementation of this NICE quality statement would appear to be entirely appropriate. The implication of meeting this clinical need is an increased number of patients being offered dual therapy at an earlier stage when appropriate. As a result, CCGs would be required to acknowledge and plan for the likely budgetary implications. Rationale for selecting pharmacological treatment Given the increased emphasis on ensuring patients are offered timely of pharmacological therapy, it is important to consider which patients may benefit from each of the drug classes recommended as options for first. All treatment options should be discussed with the patient and, in the author s experience, some drug classes may be more or less suitable for first of therapy in some patients based on certain characteristics (Table 1, p. 4). Figure 1: First and second options in patients who can take metformin 3 Initial monotherapy Metformin First DPP-4 inhibitor Pioglitazone Sulfonylurea SGLT-2 inhibitor* Second Sulfonylurea SGLT-2 inhibitor* DPP-4 inhibitor Pioglitazone Sulfonylurea Pioglitazone Sulfonylurea SGLT-2 inhibitor* * Refer to criteria in associated technology appraisal guidance (NICE Technology Appraisals 288, 315, 336, and 418) DPP-4=dipeptidyl peptidase-4; SGLT-2=sodium-glucose co-transporter-2 Figure 2: Options for initial monotherapy and first if metformin contraindicated or not tolerated 3 Initial monotherapy DPP-4 inhibitor* Pioglitazone Sulfonylurea Repaglinide SGLT-2 inhibitor First Pioglitazone DPP-4 inhibitor DPP-4 inhibitor Sulfonylurea Sulfonylurea Pioglitazone *Alogliptin is not licensed for monotherapy Refer to criteria in associated technology appraisal guidance (NICE Technology Appraisal 390) DPP-4=dipeptidyl peptidase-4; SGLT-2=sodium-glucose co-transporter-2 5

6 When a choice is available to the healthcare professional as to the drug within a particular class that will be prescribed, NICE NG28 advises that the choice is based on: 3 effectiveness safety and tolerability the individual s clinical circumstances the individual s preferences and needs the licensed indications or combinations available cost (if two drugs in the same class are appropriate, the option with the lowest acquisition cost should be chosen). While the guideline gives advice to prescribers to consider all of the above issues when prescribing, there is no advice on the relative weighting of each factor. For some healthcare professionals, this may cause a degree of confusion in the decision-making process, while others may interpret it as freedom to individualise the treatment. Resource impact Clinical Commissioning Groups are required to plan and commission health services in line with local needs. While CCGs are not legally mandated to comply with NICE guidelines, they are required to justify why any general policy fails to comply with NICE guidance. The equal weighting in NICE NG28 given to DPP-4 inhibitors, pioglitazone, SGLT-2 inhibitors, and sulfonylurea as options for initial therapy when metformin is contraindicated and as options at first in combination with metformin, has the potential to be associated with increased prescribing costs. However, the clinician also has a responsibility to ensure that the selection of a particular drug represents the outcome of a joint decision made with a fully informed patient. The Resource impact report published by NICE alongside NG28 states that the anticipated resource impact is likely to come from a shift from sulfonylureas to more expensive DPP-4 inhibitors, a cost that will need to be addressed by CCGs. In practice, this shift is likely to be limited to newly diagnosed patients and those undergoing treatment. 27 Conclusion As NG28 advocates that patients with type 2 diabetes mellitus are involved in the decision-making process surrounding their treatment, it is incumbent on healthcare practitioners to ensure that information regarding the potential benefits and risks of any particular treatment, or treatment combination, is provided. Whilst no drug is without a side-effect profile, experience tells us that, given the choice, patients will opt for therapeutic regimens that achieve glycaemic control without increasing the likelihood of weight gain and hypoglycaemia. Key points Lifestyle interventions for patients with type 2 diabetes mellitus should be reinforced at every opportunity With regard to both the setting of glycaemic targets and initiating treatment, the guideline supports involvement of the patient in the decision-making process NICE Guideline 28 significantly extended the available options for healthcare professionals in the management of glycaemic control in patients with type 2 diabetes mellitus The options for first of treatment include the addition of a DPP-4 inhibitor, pioglitazone, an SGLT-2 inhibitor, or sulfonylurea in combination with metformin For patients in whom metformin is contraindicated or not tolerated, options are presented for monotherapy and first The use of SGLT-2 inhibitors is included within the guidance, although this is redirected through specific NICE technology appraisal guidance recommendations NICE Quality Standard 6 reinforces the importance of offering patients dual therapy if they are unresponsive to monotherapy after 6 months of treatment There is likely to be a resource impact associated with continued implementation of NICE Guideline 28, so CCGs should be aware of the potential financial implications and clinicians should continue to prescribe responsibly. DPP-4=dipeptidyl peptidase-4; SGLT-2=sodium-glucose co-transporter-2 Conflicts of interest Dr Lawrence has previously received honoraria for providing services for the following companies: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Lilly UK, Merck Sharp & Dohme Ltd, Novo Nordisk Limited, and Takeda UK Ltd. References 1. International Diabetes Federation. IDF diabetes atlas seventh edition. IDF, Available at: 2. Diabetes UK. Facts and stats. DUK, Available at: org.uk/documents/position%20statements/diabetesuk_facts_ Stats_Oct16.pdf 3. NICE. Type 2 diabetes in adults: management. NICE Guideline 28. NICE, Available at: 4. DVLA. Assessing fitness to drive a guide for medical professionals. DVLA, Available at: assessing-fitness-to-drive-a-guide-for-medical-professionals 5. UK Prospective Diabetes Study (UKPDS) Group. Intensive bloodglucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352 (9131):

7 6. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998; 352 (9131): NICE. Canagliflozin, dapagliflozin and empagliflozin as monotherapies for treating type 2 diabetes. NICE Technology Appraisal 390. NICE, Available at: 8. Guardado-Mendoza R, Prioletta A, Jimenez-Ceja L. The role of nateglinide and repaglinide, derivatives of meglitinide, in the treatment of type 2 diabetes mellitus. Arch Med Sci 2013; 9 (5): Diabetes UK. Dealing with illness. DUK, Available at: (accessed 27 September 2017) 10. NICE. Diabetes - type 2 managing intercurrent illness. NICE Clinical Knowledge Summary. NICE, Available at: cks.nice.org.uk/ diabetes-type-2#!scenariorecommendation:5 11. British National Formulawry. Metformin hydrochloride. Available at: bnf.nice.org.uk/drug/metformin-hydrochloride.html (accessed 27 September 2017) 12. Lipska K, Bailey C, Inzucchi S. Use of metformin in the setting of mildto-moderate renal insufficiency use of metformin in the setting of mildto-moderate renal insufficiency. Diabetes Care 2011; 34 (6): Takeda UK Limited. Vipidia 6.25mg, 12.5mg, 25mg film-coated tablets summary of product characteristics. January uk/emc/medicine/ Boehringer Ingelheim Limited. Trajenta 5 mg film-coated tablets summary of product characteristics. March emc/medicine/ AstraZeneca UK Limited. Onglyza 2.5mg & 5mg film-coated tablets summary of product characteristics. June emc/medicine/ Merck Sharp & Dohme Limited. Januvia 25mg, 50mg, 100mg filmcoated tablets summary of product characteristics. January www. medicines.org.uk/emc/medicines/ Novartis Pharmaceuticals UK Ltd. Galvus 50 mg tablets summary of product characteristics. April medicine/ Egan A, Blind E, Dunder K. Pancreatic safety of incretin-based drugs FDA and EMA assessment. N Engl J Med 2014; 370 (9): Novo Nordisk Limited. Prandin 0.5mg, 1mg, 2mg tablets summary of product characteristics. June medicine/ British National Formulary. Nateglinide. Available at: bnf.nice.org.uk/drug/nateglinide.html (accessed 27 September 2017) 21. Leiter L, Yoon K, Arias P. Canagliflozin provides durable glycemic improvements and body weight reduction over 104 weeks versus glimepiride in patients with type 2 diabetes on metformin: a randomized, double-blind, phase 3 study. Diabetes Care 2015; 38 (3): Matthaei S, Bowering K, Rohwedder K. Dapagliflozin improves glycemic control and reduces body weight as add-on therapy to metformin plus sulfonylurea: a 24-week randomized, double-blind clinical trial. Diabetes Care 2015; 38 (3): Ioannidis I. Diabetes treatment in patients with renal disease: Is the landscape clear enough? World J Diabetes 2014; 5 (5): Watson L, Das R, Farguhar R. Consequences of delaying treatment in type 2 diabetes: evidence from a UK database. Curr Med Res Opin 2016; 23: Khunti K, Wolden M, Thorsted B. Clinical inertia in people with type 2 diabetes. Diabetes Care 2013; 36 (11): NICE. Diabetes in adults. Quality Standard 6. NICE, Available at: NICE. Resource impact report: type 2 diabetes in adults: management (NG28). NICE, Available at: resources/resource-impact-report-pdf

8 Vipidia (alogliptin) PRESCRIBING INFMATION Refer to summary of Product Characteristics (SmPC) before prescribing. Presentation: Alogliptin 6.25 mg, 12.5 mg and 25 mg film-coated tablets. Indication: Adults aged 18 years and older with Type 2 diabetes mellitus to improve glycaemic control in combination with other glucose lowering medicinal products including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control. Dosage & Administration: In adults the usual recommended dose of Vipidia is one tablet of 25 mg once daily (o.d.) with or without food. Elderly: No dose adjustment is necessary. Renal impairment: Mild renal impairment, no dose adjustment is necessary. Moderate renal impairment 12.5 mg o.d. Severe renal impairment or end-stage renal disease requiring dialysis 6.25 mg o.d. Experience in patients on dialysis is limited. Vipidia has not been studied in patients undergoing peritoneal dialysis. Hepatic impairment: No dose adjustment is necessary for patients with mild to moderate hepatic impairment. Has not been studied in patients with severe hepatic impairment, therefore not recommended for use in these patients. Paediatric population: No data are available. Contraindications: Hypersensitivity to the active substance or to its excipients or history of a serious hypersensitivity reaction to any dipeptidyl-peptidase-4 (DPP-4) inhibitor. Warnings & Precautions: General: Do not use in patients with Type 1 diabetes mellitus or for treatment of diabetic ketoacidosis. Use with other antihyperglycaemic medicinal products and hypoglycaemia: When used in combination with a sulphonylurea, insulin or combination therapy with thiazolidinedione plus metformin, a lower dose of these medications may be considered to reduce the risk of hypoglycaemia. Combinations not studied: Has not been studied in combination with sodium glucose cotransporter 2 (SGLT-2) inhibitors or glucagon like peptide 1 (GLP-1) analogues nor formally as triple therapy with metformin and sulphonylurea. Renal impairment: Renal function assessment is recommended prior to initiation of Vipidia therapy and periodically thereafter. Cardiac failure: Caution for use in patients with congestive heart failure of New York Heart Association (NYHA) functional class III IV due to limited experience. Hypersensitivity reactions: Anaphylactic reactions, angioedema and exfoliative skin conditions including Stevens-Johnson syndrome and erythema multiforme have been observed for DPP-4 inhibitors and have been spontaneously reported for alogliptin in the post-marketing setting. Acute pancreatitis: Use of DPP-4 inhibitors has been associated with a risk of developing acute pancreatitis. Spontaneous reports of adverse reactions of acute pancreatitis in the post-marketing setting. Patients should be informed of the characteristic symptoms of acute pancreatitis. If pancreatitis is suspected, Vipidia should be discontinued; if acute pancreatitis is confirmed, Vipidia should not be restarted. Caution should be exercised in patients with a history of pancreatitis. Hepatic effects: Postmarketing reports of hepatic dysfunction, including failure, have been received. Patients should be observed for possible liver abnormalities and liver function should be obtained promptly in patients with any symptoms. Discontinue Vipidia treatment if an abnormality is found and an alternative aetiology is not established. Interactions: Primarily excreted unchanged in the urine and metabolism by the cytochrome (CYP) P450 system is negligible. Studies show no clinically relevant pharmacokinetic interactions. Fertility, Pregnancy & Lactation: No data from use in pregnant women. Avoid use during pregnancy. Unknown whether Vipidia is excreted in human milk, a risk to the suckling child cannot be excluded. Consider the risk-benefit balance of use in breast-feeding mothers. The effect of Vipidia on fertility in humans has not been studied. Undesirable Effects: Common ( 1/100 to <1/10): Upper respiratory tract infections; nasopharyngitis; headache; abdominal pain; gastro-oesophageal reflux disease; pruritis; rash. Other serious undesirable effects (frequency unknown): Acute pancreatitis; hepatic dysfunction including hepatic failure; angioedema; hypersensitivity; exfoliative skin conditions. Refer to the SmPC for details on full side effect profile and interactions. Basic NHS Price: for 28 tablets Legal Classification: POM. Marketing Authorisation: EU/1/13/844/ mg; EU/1/13/844/ mg; EU/1/13/844/ mg. Takeda UK Ltd. is responsible for the sale and supply of Vipidia in the UK. Further information is available from Takeda UK Ltd, Building 3, Glory Park, Glory Park Avenue, Wooburn Green, Bucks, HP10 0DF. Tel Fax PI Approval Code: UK/VIP/1604/0044 Date of revision: April 2016 Please refer to the summary of product characteristics for details on the full side-effect profile and drug interactions of Vipidia. Adverse events should be reported. Reporting forms and information can be found at Adverse events should also be reported to Takeda UK Ltd VIPIDIA is a registered trademark of Takeda Pharmaceutical Company Limited. ACTOS (pioglitazone HCl) PRESCRIBING INFMATION Refer to Summary of Product Characteristics before prescribing Presentations: Actos tablets: pioglitazone as hydrochloride, 15 mg, 30 mg and 45 mg. Indications: Second or third line therapy in adult patients with type 2 diabetes and insufficient glycaemic control as follows: monotherapy when inadequately controlled by diet and exercise for patients whom metformin is inappropriate because of contraindications or intolerance; dual oral therapy despite maximally tolerated dose of either metformin or a sulphonylurea (for patients whom metformin is not tolerated or contraindicated); as triple oral therapy with metformin and a sulphonylurea; in combination with existing insulin for patients whom metformin is not tolerated or contraindicated. Patients should be reviewed 3 to 6 months after initiation of therapy, and at subsequent routine reviews, to assess adequacy of response to treatment. In patients who fail to show an adequate response, pioglitazone should be discontinued. Dosage and administration: 15mg or 30mg once daily with or without food. Dose may be increased in increments up to 45mg once daily. In combination therapy with insulin, the current insulin dose can be continued. If patients report hypoglycaemia, the dose of insulin should be decreased. Elderly: No dosage adjustment required. Renal impairment: No dosage adjustment required if creatinine clearance >4 ml/min. Pioglitazone should not be used in dialysed patients. Children and adolescents (under 18 years): Not recommended. Contraindications: Hepatic impairment. Hypersensitivity. Cardiac failure or history of cardiac failure (NYHA stages I to IV). Diabetic ketoacidosis. Current or a history of bladder cancer. Uninvestigated macroscopic haematuria. Precautions: Can cause fluid retention, which may exacerbate or precipitate heart failure. Observe patients for signs and symptoms of heart failure, weight gain or oedema particularly those with reduced cardiac reserve or on insulin. Discontinue if deterioration in cardiac status occurs. For patients with at least one risk factor for congestive heart failure, start therapy with the lowest dose of pioglitazone and increase gradually. Assess risk factors for bladder cancer before initiating pioglitazone treatment (e.g. age, smoking history, exposure to some occupational or chemotherapy agents). Investigate macroscopic haematuria before starting pioglitazone therapy. Patients should be advised to promptly contact their physician if macroscopic haematuria or other symptoms such as dysuria or urinary urgency develop during treatment. Check liver enzymes prior to initiation and then periodically based on clinical judgement. Do not start treatment in patients with increased baseline liver enzyme levels (ALT >2.5x upper limit of normal [ULN]). If ALT levels increase to 3x ULN, reassess as soon as possible. If ALT levels remain > 3x ULN or jaundice is observed, discontinue therapy. If symptoms suggest hepatic dysfunction, check liver enzymes. Advise patients to adhere strictly to a calorie-controlled diet and monitor weight. In some cases, an increase in weight may be a symptom of cardiac failure. Small reductions in haemoglobin and haematocrit, consistent with haemodilution have been noted. In dual or triple therapy with a sulphonylurea or dual therapy with insulin, dose-related hypoglycaemia may occur. Treatment in patients with polycystic ovarian syndrome may result in ovulation. If a patient wishes to become pregnant or if pregnancy occurs, discontinue treatment. The risk of fractures should be considered in the long term care of patients treated with pioglitazone. Be alert to possible macular oedema if patients report visual disturbances. Actos tablets contain Lactose monohydrate. Elderly: Start treatment with the lowest available dose and increase the dose gradually, particularly when pioglitazone is used in combination with insulin. Combination use with insulin should be considered with caution in the elderly because of increased risk of serious heart failure. In light of age-related risks (especially bladder cancer, fractures and heart failure), the balance of benefits and risks should be considered carefully both before and during treatment. Interactions: Use with caution during concomitant administration of cytochrome P450 2C8 inhibitors (e.g. gemfibrozil) or inducers (e.g. rifampicin). Monitor glycaemic control. Fertility, pregnancy and lactation: Do not use. Potential risk unknown. Undesirable effects: Suspected adverse reactions reported as more than an isolated case in double-blind studies listed below. Very common: >10%, common: 1-10%, uncommon: 0.1-1%, rare: % and very rare: < 0.01%. In monotherapy: visual disturbance, upper respiratory tract infection, weight increased, bone fracture, hypoaesthesia. Uncommon: bladder cancer, insomnia. Not known: macular oedema, alanine aminotransferase increased, hypersensitivity and allergic reactions. With metformin: Common: anaemia, weight increased, headache, visual disturbance, arthralgia, haematuria, erectile dysfunction, upper respiratory tract infection, hypoaesthesia, bone fracture. Uncommon: bladder cancer. Not known: macular oedema, alanine aminotransferase increased, hypersensitivity and allergic reactions. With sulphonylurea: Common: weight increased, dizziness, flatulence, upper respiratory tract infection, hypoaesthesia, bone fracture. Uncommon: bladder cancer, visual disturbance. Not known: macular oedema, alanine aminotransferase increased, hypersensitivity and allergic reactions. With metformin and sulphonylurea: Very common: hypoglycaemia. Common: weight increased, blood creatinine phosphokinase increased, upper respiratory tract infection, hypoaesthesia, bone fracture, arthralgia. Uncommon: bladder cancer. Not known: macular oedema, alanine aminotransferase increased, hypersensitivity and allergic reactions. With insulin: Very common: oedema. Common: dyspnoea, bone fracture, hypoglycaemia, bronchitis, weight increased, back pain, arthralgia, upper respiratory tract infection, hypoaesthesia, heart failure. Uncommon: bladder cancer. Not known: macular oedema, alanine aminotransferase increased, hypersensitivity and allergic reactions. Refer to the SmPC for details and full side effect profile and interactions. Basic NHS price: blister packs of 28; 15 mg ; 30 mg ; 45 mg Legal category: POM. Marketing Authorisation Number: 15 mg -EU/1/00/150/001; 30 mg -EU/1/00/150/004; 45 mg -EU/1/00/150/015; Marketing Authorisation Holder: Takeda Pharma A/S (Denmark). Takeda UK Ltd is responsible for the sale and supply of Actos in the UK. Actos is a registered trademark owned by Takeda Pharmaceutical Company Ltd. For further information contact: Takeda UK Ltd. Building 3, Glory Park, Glory Park Avenue, Wooburn Green, BUCKS, HP10 0DF. Tel: , Fax: PI approval code: UK/ACT/1606/0003 PI Date of revision: June Please refer to the summary of product characteristics for details on the full side-effect profile and drug interactions. Adverse events should be reported. Reporting forms and information can be found at Adverse events should also be reported to Takeda UK Ltd