The Complications and Implications of Type 2 Diabetes

All GP s and Practice Nurses Welcome... All GP s and Practice Nurses Welcome... All GP s and Practice Nurses Meeting Developed by Eli Lilly and Co. FREE Study Morning for GP s & Practice Nurses... The Complications and Implications of Type 2 Diabetes Saturday 14th September 2013 Manchester Conference Centre Weston Building, Sackville Street, Manchester M1 3BB AT THIS EVENT Listen to Key Local Speakers Update your knowledge on Diabetes Receive a Certificate for your Appraisal Portfolio 42 St Annes Road East St Annes-on-Sea Lancashire FY8 1UR T. 01253 712894 F. 01253 714545 W. mediconf.co.uk E. janet@mediconf.co.uk

Lilly products will be discussed at this meeting

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Prescribing Information (UK) t 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. Patients with renal impairment: no dose adjustment required. Patients with 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. Trajenta can be taken 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: Trajenta 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. Pancreatitis: In post-marketing experience of linagliptin there have been spontaneously reported adverse reactions of acute pancreatitis. Patients should be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. Resolution of pancreatitis has been observed after discontinuation of linagliptin. If pancreatitis is suspected, Trajenta should be discontinued. 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 breast-fed child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Trajenta 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 Trajenta. 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 placebocontrolled 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), or very rare (<1/10,000), 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); cough (monotherapy; combination with/add-on 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 (monotherapy; combination with/add-on to metformin). Rare: hypersensitivity e.g. bronchial hyperreactivity (combination with/add-on to metformin); 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); Not known: nasopharyngitis (combination with/add-on to metformin and sulphonylurea); hypersensitivity e.g. bronchial hyperreactivity (monotherapy; combination with/add-on to metformin and sulphonylurea; combination with/add-on to insulin); 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); amylase increased (combination with/add-on to metformin and sulphonylurea; 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 May 2013. UK Prescribing Information t 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. Dose and Administration: The dose of Jentadueto 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 of metformin hydrochloride. For patients inadequately controlled on maximal tolerated dose of metformin monotherapy: the usual starting dose of Jentadueto should provide linagliptin 2.5 mg twice daily (5 mg total daily dose) plus the current dose of metformin. For patients switching from coadministration of linagliptin and metformin: Initiate Jentadueto at the dose of linagliptin and metformin already being taken. For patients inadequately controlled on dual combination of the maximal tolerated dose of metformin and a sulphonylurea: The dose of Jentadueto should provide linagliptin 2.5 mg twice daily (5 mg total daily dose) and a dose of metformin 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. Elderly: As metformin is excreted by the kidney, Jentadueto should be used with caution as age increases. Monitoring of renal function is necessary. Clinical experience with patients > 80 years of age is limited and caution should be exercised. Renal impairment: Jentadueto must not be used in patients with moderate or severe renal impairment (creatinine clearance < 60 ml/min) due to metformin. Hepatic impairment: Jentadueto is not recommended in patients with hepatic impairment due to metformin. Clinical experience with Jentadueto in patients with hepatic impairment is lacking. Paediatric population: The safety and efficacy of Jentadueto in children and adolescents (aged 0 to 18 years) have not been established. No data are available. Jentadueto should 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; acute or chronic disease which may cause tissue hypoxia such as cardiac or respiratory failure, recent myocardial infarction, shock; hepatic impairment, acute alcohol intoxication, alcoholism. Warnings and Precautions: Jentadueto should not 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 due to increased incidence of hypoglycaemia. Lactic acidosis is a very rare, but serious (high mortality in the absence of prompt treatment), metabolic complication that can occur due to metformin hydrochloride accumulation. Reported cases have occurred primarily in diabetic patients with significant renal failure. The incidence of lactic acidosis can and should be reduced by also assessing other associated risk factors. As metformin hydrochloride is excreted by the kidney, serum creatinine levels should be determined before initiating treatment and regularly thereafter. Decreased renal function in elderly subjects is frequent and asymptomatic. Special caution should be exercised in situations where renal function may become impaired. As Jentadueto contains metformin hydrochloride the 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 and therapy with Jentadueto should usually not be resumed earlier than 48 hours following surgery or test and only after renal function has been reevaluated and found to be normal. The use of Jentadueto in combination with insulin has not been adequately studied. Caution should be exercised when treating patients 80 years and older. As Jentadueto contains metformin, 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, Jentadueto must be stopped immediately and other appropriate corrective measures initiated. In postmarketing experience of linagliptin there have been spontaneously reported adverse reactions of acute pancreatitis. If pancreatitis is suspected, Jentadueto should be discontinued. 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, the dose of Jentadueto should be adjusted during therapy with the other medicinal product and on its discontinuation. Combinations not recommended: There is increased risk of lactic acidosis in acute alcohol intoxication. Consumption of alcohol and medicinal products containing alcohol. 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, pregnancy and lactation: Jentadueto should not be used during pregnancy. If the patient plans to become pregnant, or if pregnancy occurs, treatment with Jentadueto should be discontinued and switched 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: Adverse reactions reported with the fixed dose combination: Adverse reactions reported in patients who received Jentadueto (frequencies identified from pooled analysis of placebo-controlled studies) in clinical trial and from post-marketing experience. Uncommon ( 1/1,000 to < 1/100): nasopharyngitis; cough; decreased appetite; diarrhoea; nausea; vomiting; rash; pruritus; blood amylase increased. Rare ( 1/10,000 to < 1/1,000): hypersensitivity e.g. bronchial hyperreactivity; angioedema; urticaria. Not known (cannot be estimated from the available data): pancreatitis. 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. Adverse reactions reported when linagliptin and metformin were combined with sulphonylurea: additional adverse reaction very common ( 1/10): hypoglycaemia. 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 with this medicinal product. 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 ( 1/10): abdominal pain. Common ( 1/100 to < 1/10): taste disturbance. Very rare (< 1/10,000): lactic acidosis; vitamin B12 deficiency; liver function disorders, 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 May 2013. Adverse events should be reported. Reporting forms and information can be found at www.mhra.yellowcard.gov.uk. Adverse events should also be reported to Boehringer Ingelheim Drug Safety on 0800 328 1627 (freephone).

HUMULIN* VIAL, CARTRIDGE, AND KWIKPEN* HUMULIN IS HUMAN INSULIN (PRB) Presentation Humulin S is a sterile solution of 100IU/ml human insulin available as either 10ml vial or 3ml cartridge. Humulin I is a sterile suspension of 100IU/ml isophane human insulin available as either 10ml vial, 3ml cartridge, or 3ml KwikPen. Humulin M3 is a sterile suspension of 100IU/ml human insulin in the proportion of 30% soluble insulin and 70% isophane insulin available as either 10ml vial, 3ml cartridge, or 3ml KwikPen. Uses Treatment of patients with diabetes mellitus who require insulin for the maintenance of glucose homeostasis. Dosage and Administration All Humulin preparations should be given by subcutaneous injection. Only Humulin S may be given intravenously. Resuspension Humulin S does not require resuspension. Humulin I and Humulin M3 require resuspension immediately before use. Please see Summaries of Product Characteristics or Patient Information Leaflets for details on how to do this. Mixing of insulins (vials only): Humulin S may be administered in combination with Humulin I. The shorter-acting insulin (Humulin S) should be drawn into the syringe first, to prevent contamination of the vial by the longeracting preparation (Humulin I). It is advisable to inject immediately after mixing. Warnings and Special Precautions Some patients taking human insulin may require a change in dosage from that used with animal-source insulins. If an adjustment is needed, it may occur with the first dose or during the first several weeks or months. Treatment with human insulin may cause formation of antibodies, but titres of antibodies are lower than those to purified animal insulin. Prices (Humulin) 15.68-1 X 10ml vials Humulin S 19.08-5 X 3ml cartridges Humulin S 15.68-1 X 10ml vials Humulin I 19.08-5 X 3ml cartridges Humulin I 21.70-5 X 3ml Humulin I KwikPens 15.68-1 X 10ml vials Humulin M3 19.08-5 X 3ml cartridges Humulin M3 21.70-5 X 3ml Humulin M3 KwikPens Product Licence Numbers Humulin S: 00006/0216 and 0242 Humulin I: 00006/0228 and 0257 Humulin M3: 00006/0233 and 0260 Humulin I KwikPen: 00006/0338 Humulin M3 KwikPen: 00006/0341 *HUMULIN (human insulin [prb]) and KWIKPEN are trademarks of Eli Lilly and Company. HUMALOG* VIAL, CARTRIDGE, AND KWIKPEN* HUMALOG IS INSULIN LISPRO (HUMAN INSULIN ANALOGUE) Presentation Humalog is a sterile solution of 100U/ml insulin lispro available as either 10ml vial, 3ml cartridge, or 3ml KwikPen. Uses Treatment of adults and children with diabetes mellitus who require insulin for the maintenance of normal glucose homeostasis. Humalog is also indicated for the initial stabilisation of diabetes mellitus. Dosage and Administration Humalog may be given shortly before meals and, when necessary, soon after meals. Humalog should be given by subcutaneous injection or by continuous subcutaneous infusion pump. If necessary, Humalog may also be administered intravenously, for example, for the control of blood glucose levels during ketoacidosis, acute illness, or perioperatively. Humalog takes effect rapidly (approximately 15 minutes) and has a shorter duration of activity (2 to 5 hours) as compared with soluble insulin. Warnings and Special Precautions Usage in pregnancy: Data on a large number of exposed pregnancies do not indicate any adverse effect of insulin lispro on pregnancy or on the health of the foetus/newborn. Insulin lispro should be used in children only when an advantage is expected compared to soluble insulin, for example, in the timing of the injection in relation to meals. Prices (Humalog) 16.61-1 X 10ml vials 28.31-5 X 3ml cartridges 29.46-5 X 3ml Humalog KwikPens Marketing Authorisation Numbers Humalog vial: EU/1/96/007/002 Humalog cartridge: EU/1/96/007/004 Humalog KwikPen: EU/1/96/007/031 *HUMALOG (insulin lispro) and KWIKPEN are trademarks of Eli Lilly and Company. HUMALOG MIX25* VIAL, CARTRIDGE, AND KWIKPEN* HUMALOG MIX50* CARTRIDGE, AND KWIKPEN HUMALOG IS INSULIN LISPRO (HUMAN INSULIN ANALOGUE) Presentation Humalog Mix25 is a white, sterile suspension of 100U/ml 25% insulin lispro solution and 75% insulin lispro protamine suspension available as either 10ml vial, 3ml cartridge, or 3ml KwikPen. Humalog Mix50 is a white, sterile suspension of 100U/ml 50% insulin lispro solution and 50% insulin lispro protamine suspension available as either 3ml cartridge or 3ml KwikPen. Uses Treatment of patients with diabetes mellitus who require insulin for the maintenance of normal glucose homeostasis. Dosage and Administration Humalog Mix25 or Humalog Mix50 may be given shortly before meals and, when necessary, can be given soon after meals. Humalog Mix25 or Humalog Mix50 should only be given by subcutaneous injection. The rapid onset and early peak of activity of Humalog itself is observed following the subcutaneous administration of Humalog Mix25 or Humalog Mix50. The duration of action of the insulin lispro protamine suspension component is similar to that of a basal insulin. Warnings and Special Precautions Usage in pregnancy: Data on a large number of exposed pregnancies do not indicate any adverse effect of insulin lispro on pregnancy or on the health of the foetus/newborn. Administration of insulin lispro in children should be considered only in case of an expected benefit when compared to soluble insulin. Prices (Mix25/Mix50) 16.61-1 X 10ml Mix25 vial 29.46-5 X 3ml Mix25 cartridges 30.98-5 X 3ml Mix25 KwikPens 29.46-5 X 3ml Mix50 cartridges 30.98-5 X 3ml Mix50 KwikPens Marketing Authorisation Numbers Humalog Mix25 vial: EU/1/96/007/005 Humalog Mix25 cartridge: EU/1/96/007/008 Humalog Mix50 cartridge: EU/1/96/007/006 Humalog Mix25 KwikPen: EU/1/96/007/033 Humalog Mix50 KwikPen: EU/1/96/007/035 *HUMALOG MIX25, HUMALOG MIX50 (insulin lispro), and KWIKPEN are trademarks of Eli Lilly and Company. LILLY INSULINS GENERAL INFORMATION See Summaries of Product Characteristics for additional information, including time-action profiles of all formulations. Dosage and Administration (general) The dosage or type of insulin should be determined according to the requirements of the patient. The time course of action of any insulin may vary considerably in different individuals or at different times in the same individual. Vials are packed with instructions regarding dose preparation and administration, and these should be carefully followed. Lilly insulin cartridges are to be used with a CE marked pen according to the instructions provided by the device manufacturer. Patients should be advised to always keep a spare syringe and vial, or a spare pen and cartridge. Prefilled pens are packed with instructions on how to use them. These directions should be followed carefully. Do not use if, after resuspension, the insulin remains at the bottom, if there are clumps in the insulin, or if solid white particles stick to the bottom or wall giving the container a frosted appearance. Contra-indications Hypersensitivity to the active ingredient or to any of the excipients. Hypoglycaemia. Warnings and Special Precautions (general) Transferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand, type, species, and/or method of manufacture may result in the need for a change in dosage. For fast acting insulins, any patient also on basal insulin must optimise dosage of both insulins to obtain glucose control across the whole day, particularly nocturnal/fasting glucose control. Changes in early warning symptoms of hypoglycaemia may occur on transfer between different types of insulin products. Insulin requirements may be reduced in the presence of renal impairment or hepatic impairment. However, in patients with chronic hepatic impairment, an increase in insulin resistance may lead to increased insulin requirements. Insulin requirements may be increased during illness or emotional disturbances. 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 Insulin requirements usually fall during the first trimester and increase during the second and third trimesters. Patients should be advised to inform their doctors if they are pregnant or contemplating pregnancy. Driving, etc The patient s ability to concentrate and react may be impaired as a result of hypoglycaemia. This may constitute a risk in situations where these abilities are of special importance (eg, driving a car or operating machinery). Undesirable Effects Hypoglycaemia is the most frequent undesirable effect of insulin therapy. Local allergy is common and usually resolves. Systemic allergy is rare but potentially more serious since severe cases may be life-threatening. Lipodystrophy is uncommon. For full details of these and other side-effects, please see the Summary of Product Characteristics, which is available at http://emc.medicines.org.uk/. Legal Category POM Date of Preparation or Last Review March 2011 (internal review June 2013) 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: ukmedinfo@lilly.com Website: www.lillypro.co.uk Adverse events should be reported. Reporting forms and further 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 315 000.

CYMBALTA (DULOXETINE) ABBREVIATED PRESCRIBING INFORMATION Presentation Hard gastro-resistant capsules, 30mg or 60mg of duloxetine. Also contains sucrose. Uses Treatment of major depressive disorder. Treatment of generalised anxiety disorder. Treatment of diabetic peripheral neuropathic pain (DPNP) in adults. Dosage and Administration Major Depressive Disorder Starting and maintenance dose is 60mg once daily, with or without food. Dosages up to a maximum dose of 120mg per day have been evaluated from a safety perspective in clinical trials. However, there is no clinical evidence suggesting that patients not responding to the initial recommended dose may benefit from dose up-titrations. Therapeutic response is usually seen after 2-4 weeks. After establishing response, it is recommended to continue treatment for several months, in order to avoid relapse. In patients responding to duloxetine, and with a history of repeated episodes of major depression, further long-term treatment at 60 to 120mg/day could be considered. Generalised Anxiety Disorder The recommended starting dose in patients with generalised anxiety disorder is 30mg once daily, with or without food. In patients with insufficient response the dose should be increased to 60mg, which is the usual maintenance dose in most patients. In patients with co-morbid major depressive disorder, the starting and maintenance dose is 60mg once daily. Doses up to 120mg per day have been shown to be efficacious and have been evaluated from a safety perspective in clinical trials. In patients with insufficient response to 60mg, escalation up to 90mg or 120mg may therefore be considered. After consolidation of the response, it is recommended to continue treatment for several months, in order to avoid relapse. Diabetic Peripheral Neuropathic Pain Starting and maintenance dose is 60mg daily, with or without food. Doses above 60mg/day, up to a maximum dose of 120mg/day in evenly divided doses, have been evaluated from a safety perspective. Some patients that respond insufficiently to 60mg may benefit from a higher dose. The medicinal response should be evaluated after 2 months treatment. Additional response after this time is unlikely. The therapeutic benefit should regularly be reassessed. Abrupt discontinuation should be avoided. When stopping treatment with Cymbalta the dose should be gradually reduced over at least one to two weeks to reduce the risk of withdrawal reactions. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, continue decreasing the dose, but at a more gradual rate. Contraindications Hypersensitivity to any of the components. Combination with MAOIs. Liver disease resulting in hepatic impairment. Use with potent inhibitors of CYP1A2, eg, fluvoxamine, ciprofloxacin, enoxacin. Severe renal impairment (creatinine clearance <30ml/min). Should be used in pregnancy only if the potential benefit justifies the potential risk to the foetus. Breast-feeding is not recommended. Initiation in patients with uncontrolled hypertension that could expose patients to a potential risk of hypertensive crisis. Precautions Do not use in children and adolescents under the age of 18. No dosage adjustment is recommended for elderly patients solely on the basis of age. However, as with any medicine, caution should be exercised. Data on the use of Cymbalta in elderly patients with generalised anxiety disorder are limited. Use with caution in patients with a history of mania, bipolar disorder, or seizures. As with other serotonergic agents, serotonin syndrome, a potentially life-threatening condition, may occur with duloxetine treatment, particularly with concomitant use of other serotonergic agents, as described under Interactions (below). Caution in patients with increased intra-ocular pressure or those at risk of acute narrow-angle glaucoma. Duloxetine has been associated with an increase in blood pressure and clinically significant hypertension in some patients. In patients with known hypertension and/or other cardiac disease, blood pressure monitoring is recommended as appropriate, especially during the first month of treatment. Use with caution in patients whose conditions could be compromised by an increased heart rate or by an increase in blood pressure. For patients who experience a sustained increase in blood pressure while receiving duloxetine, consider either dose reduction or gradual discontinuation. Caution in patients taking anticoagulants or products known to affect platelet function, and those with bleeding tendencies. Hyponatraemia has been reported rarely, predominantly in the elderly. Caution is required in patients at increased risk for hyponatraemia, such as elderly, cirrhotic, or dehydrated patients, or patients treated with diuretics. Hyponatraemia may be due to a syndrome of inappropriate anti-diuretic hormone secretion (SIADH). Adverse reactions may be more common during concomitant use of Cymbalta and herbal preparations containing St John s Wort. Monitor for suicidal thoughts, especially during first weeks of therapy, dose changes, and in patients under 25 years old. Since treatment may be associated with sedation and dizziness, patients should be cautioned about their ability to drive a car or operate hazardous machinery. Cases of akathisia/psychomotor restlessness have been reported for duloxetine. Duloxetine is used under different trademarks in several indications (major depressive disorder, generalised anxiety disorder, stress urinary incontinence, and diabetic neuropathic pain). The use of more than one of these products concomitantly should be avoided. Cases of liver injury, including severe elevations of liver enzymes (>10-times upper limit of normal), hepatitis, and jaundice have been reported with duloxetine. Most of them occurred during the first months of treatment. Duloxetine should be used with caution in patients with substantial alcohol use or with other drugs associated with hepatic injury. Capsules contain sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption, or sucrose-isomaltase insufficiency should not take this medicine. Interactions Caution is advised when taken in combination with other centrally acting medicinal products or substances, including alcohol and sedative medicinal products; exercise caution when using in combination with antidepressants. In rare cases, serotonin syndrome has been reported in patients using SSRIs/SNRIs concomitantly with serotonergic agents. Caution is advisable if duloxetine is used concomitantly with serotonergic agents like SSRIs/SNRIs, tricyclics, MAOIs like moclobemide and linezolid, St John s Wort, antipsychotics, triptans, tramadol, pethidine, and tryptophan. Undesirable effects may be more common during use with herbal preparations containing St John s Wort. Effects on other drugs: Caution is advised if co-administered with products that are predominantly metabolised by CYP2D6 (risperidone, tricyclic antidepressants [TCAs], such as nortriptyline, amitriptyline, and imipramine) particularly if they have a narrow therapeutic index (such as flecainide, propafenone, and metoprolol). Undesirable Effects The majority of common adverse reactions were mild to moderate, usually starting early in therapy, and most tended to subside as therapy continued. Those observed from spontaneous reporting and in placebo-controlled clinical trials in depression, generalised anxiety disorder, and diabetic neuropathic pain at a rate of 1/100, or where the event is clinically relevant, are: Very common ( 1/10): Headache, somnolence, nausea, dry mouth. Common ( 1/100 and <1/10): Weight decrease, palpitations, dizziness, lethargy, tremor, paraesthesia, blurred vision, tinnitus, yawning, constipation, diarrhoea, abdominal pain, vomiting, dyspepsia, flatulence, sweating increased, rash, musculoskeletal pain, muscle spasm, dysuria, urinary frequency, ejaculation disorder, ejaculation delayed, decreased appetite, blood pressure increased, flushing, falls, fatigue, erectile dysfunction, insomnia, agitation, libido decreased, anxiety, orgasm abnormal, abnormal dreams. Clinical trial and spontaneous reports of anaphylactic reaction, hyperglycaemia (reported especially in diabetic patients), mania, hyponatraemia, SIADH, hallucinations, dyskinesia, serotonin syndrome, extra-pyramidal symptoms, convulsions, akathisia, psychomotor restlessness, glaucoma, mydriasis, syncope, tachycardia, supraventricular arrhythmia (mainly atrial fibrillation), hypertension, hypertensive crisis, epistaxis, gastritis, haematochezia, gastro-intestinal haemorrhage, hepatic failure, hepatitis, acute liver injury, angioneurotic oedema, Stevens-Johnson syndrome, trismus, and gynaecological haemorrhage have been made. Cases of suicidal ideation and suicidal behaviours have been reported during duloxetine therapy or early after treatment discontinuation. Cases of aggression and anger have been reported, particularly early in treatment or after treatment discontinuation. Cases of convulsion and tinnitus have been reported after treatment discontinuation. Discontinuation of duloxetine (particularly abrupt) commonly leads to withdrawal symptoms. Dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), fatigue, agitation or anxiety, nausea and/or vomiting, tremor, headache, irritability, diarrhoea, hyperhydrosis, and vertigo are the most commonly reported reactions. The heart rate-corrected QT interval in duloxetine-treated patients did not differ from that seen in placebo-treated patients. No clinically significant differences were observed for QT, PR, QRS, or QTcB measurements between duloxetine-treated and placebo-treated patients. In clinical trials in patients with DPNP, small but statistically significant increases in fasting blood glucose were observed in duloxetine-treated patients compared to placebo at 12 weeks. At 52 weeks there was a small increase in fasting blood glucose and in total cholesterol in duloxetine-treated patients compared with a slight decrease in the routine care group. There was also an increase in HbA 1c in both groups, but the mean increase was 0.3% greater in the duloxetine-treated group. 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/. Overdose Cases of overdoses, alone or in combination with other drugs, with duloxetine doses of 5400mg have been reported. Some fatalities have occurred, primarily with mixed overdoses, but also with duloxetine alone at a dose of approximately 1000mg. Signs and symptoms of overdose (duloxetine alone or in combination with other medicinal products) included somnolence, coma, serotonin syndrome, seizures, vomiting, and tachycardia. Legal Category POM Marketing Authorisation Numbers EU/1/04/296/001, EU/1/04/296/002 Basic NHS Cost 22.40 per pack of 28 X 30mg capsules. 27.72 per pack of 28 X 60mg capsules. Date of Preparation or Last Review July 2013 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: ukmedinfo@lilly.com Website: www.lillypro.co.uk CYMBALTA (duloxetine) is a registered trademark of Eli Lilly and Company. Adverse events should be reported. Reporting forms and further 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 315 000.